Microbicides and Prevention

posted: 01/03/2011

There’s been much more progress in developing gels that help prevent HIV infection. The first trial of rectal use of a tenofovir microbicidal gel has produced useful results and boosted hopes.

Last year we heard of the first successful trial of a vaginal HIV prevention gel. Using this gel in the rectum for HIV prevention caused some side effects and may not be safe, the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, USA, has just heard. However the problems found are already being solved and new microbicides are under exploration.
 

80% preventive but few liked it
Although the gel was 80% effective in inhibiting HIV from infecting rectal cells, it caused stomach side effects as cramps and discomfort among some, and was unpopular, with only 25% of users liking it.
 

Next: 2nd attempt at anal gel
They are now working out a new version designed just for rectal use, and they are seeing if tenofovir can be given as a HIV prevention douche or enema.
 

Complex rectal microbicide study

• The study was complex and needed a lot of commitment from the 18 people who took part – all HIV-negative, 14 men and four women. First they had a single dose of oral tenofovir and then waited two weeks. During this time they had five rectal examinations and biopsies.
   
• Then they were either given one dose of either the CAPRISA tenofovir gel, or a placebo (fake) gel and again waited two weeks and had five more biopsies taken.
   
• Then, at last they were offered either the tenofovir or placebo (fake) gel once a day for seven days and had some final biopsies done.

Altogether 2000 biopsies were taken (they were very dedicated patients in this trial - on average each person had 111 biopsies!)
 

Why were there so many biopsies?
Somehow we need to test the gel against HIV in real life. The biopsies allowed the microbicide-treated cells to be kept alive in the laboratory to see how they respond to large doses of HIV. This is the closest we can get to doing the normal drug safety and safe doses tests.
 

Blood and rectal response
The researchers compared how much tenofovir was in the blood and rectal tissues after taking the pills and using the gel. Take the tablet and there was 30 times more tenofovir in the blood than after using the rectal gel, while using the gel meant there was 100 times more tenofovir in rectal tissues after just one rectal dose and after using it for 7 days it was 500 times higher. After seven days of rectal use HIV had 80% less viral infectivity.
 

Works, but side effects and unloved
So the gel shows signs of working well, but there were significant side effects and, perhaps most importantly, it was disliked by most.
 

Two volunteers reported grade three adverse events, meaning diarrhoea, cramps and discomfort. These were bad enough for the two to stop before completing the seven-day course. There were also some signs of cell damage being caused.
 

Only 25% of users said they liked the tenofovir gel, although 75% of people said they would be prepared to use it again if it proved protective against HIV.
 

Enemas and new versions, new microbicides
The tenofovir gel is now being reworked to be less toxic to cells.
The first trials of an enema delivering the anti-HIV drug involved nine gay men trying two different enema formulations and distilled water as the base for the enemas. Men preferred the enema which was designed to be in balance with the body (so it doesn’t draw out moisture from the tissues), and they found it went much further up the colon so would protect more, and found it was also the least toxic to cells.
 

Other experimental microbicides
Results for other experimental microbicides were also presented at the conference, including hi-tech ones containing broadly neutralising antibodies, which would act like a short-lived ‘mucosal vaccine’.
So there is more work to be done but microbicides are looking much more hopeful now than even 2 or 3 years ago.
 

Source with abstracts and references

Crunch Time for Microbicides

posted: 25/05/2010

Professor Robin Shattock, director of the microbicide research at at St George’s Hospital in London, warned the opening session of Microbicides 2010 Conference in Pittsburgh, USA that “we stand at a critical time point in microbicide development. There is a recognised need to prioritise and accelerate efficacy testing in clinical trials,” before funders lose interest in microbicides.
 

Since all the first attempts at non-ARV-based microbicides have failed, there are now just three possible microbicides being studied.
 

Three possible microbicides left
 

• The first is CAPRISA in South Africa, a phase 2b trial of tenofovir gel - expect results in July at the Vienna International AIDS Conference 
• VOICE, a phase 3 trial testing tenofovir gel and tenofovir and tenofovir/FTC PrEP, is recruiting now with results next year. 
• The long-awaited IPM009 trial of dapivirine in a vaginal ring and/or gel is not due to start till 2012.

Microbicides once were the best new hope for prevention, but now what is called ‘pre-exposure prophylaxis’ – giving HIV drugs to people who do not have HIV to prevent HIV infection - is pulling ahead. There are now more ‘pre-exposure prophylaxis’ trials underway or planned than the three trials we have for microbicides.
However, microbicides still look far more hopeful than attempting to make a workable HIV vaccine.
 

Microbicide possibilities
There are now 13 different compounds that might work if used in microbicides being tried out, and more than 20 studies. The compounds that might be used for microbicides range from drugs as familiar as tenofovir, to ones as exotic as nucleocaspid protein inhibitors, and broadly neutralising antibodies. These have all been shown to block HIV infection in monkeys.
 

Next steps – and some of the problems
“Biological plausibility for microbicides has never been stronger,” he said. “But how can this knowledge bridge to better human trials?”

• One problem is making sure any drug reaches the place it needs to, in the right amount, and in a state which will work. We need better ways of measuring these things in people. People are already working on solving this.

Real life practicalities

• An even bigger problem is designing microbicides that will work in the real world. Doctors and researchers usually describe this as an adherence problem – making sure people use the microbicides properly. But if the instructions are unreasonable and don’t fit with real life needs and situations, any unreasonable instructions will be ignored. We learnt that many women simply find it impossible to re-apply a microbicide, when they have sex more than once a night. We learnt this from the Carraguard trial which failed two years ago precisely because this turns out to be a real life requirement.

Professor Shattock told the conference that we need better formulations to maximise adherence. New ways of monitoring adherence would also be needed to measure how well the new microbicides work in real life. Vaginal rings, like those used for contraception, that supply a constant level of drugs, would be one way to overcome this 'adherence' problem.
 

• Microbicides which use a combination of two of three drugs also look a good prospect for investigation.

Money is the key
The challenge now, Shattock told a press conference, is not developing more possible things that might work as a microbicide – there were plenty of those – but finding the money to start trials.
 

Anti-HIV drug microbicides cheaper
You need very little of a HIV drug in a microbicide for it to work – far less than you need when treating someone with HIV. That makes using the same drugs in microbicides relatively cheap compared with the cost of treating someone after infection. A single maraviroc tablet has enough of the drug for up to 20 doses if it is used as a microbicide. “But,” he added, “Without success or even an indication of success soon it will be impossible to sustain the funding for microbicides.”
 

Nono Eland of the South African Treatment Action Campaign, speaking after Shattock, commented that “if we fail on prevention, we will lose the progress we’ve made on treatment,” because funders will be unwilling to provide ever-expanding funding for an uncontainable disease.
 

Waiting women

We seem to have reached a critical moment for the future of microbicides. Microbicides need money now if we are ever to have any that will work. Microbicides are a gender issue. Women's need for an independent form of protection must be taken seriously.
 

Women are still waiting for any type of HIV prevention that will work when men won’t use condoms or it is too risky to suggest this to men. Microbicides are one of the best hopes we have for offering HIV prevention to women.

Source
Shattock R. State of the ART for microbicides. Opening plenary, Microbicides 2010 Conference, Pittsburgh. Presentation #1. 2010.
 

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