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

HIV Microbicide Success

posted: 20/07/2010

A vaginal microbicide gel containing the anti-HIV drug tenofovir (Viread) reduces the risk to women of HIV infection by 39%, results of a study show. This is the most hopeful news in the years long search for something that women can use to protect themselves from HIV risk. There was a recent flurry of hope about another microbicide which showed some signs of working but further study showed it wasn't good enough.

Women who used this new gel more reliably, during four out of the last five times they had had sex saw their risk of HIV infection reduced by 54%. The microbicide also had another useful sexual health benefit, halving the risk of infection with genital herpes.
 

Other reports about this microbicide explain that women must apply the gel 12 hours before sex and once again as soon afterwards as possible.

There is more work to be done before this microbicide can supplied publicly, but this was a top-notch scientific study, a randomised, placebo-controlled trial – called CAPRISA 004 – in South Africa. 889 HIV-negative women were randomly divided into two groups, one was given the tenofovir-containing gel and the other group was also given gel that looked exactly like the first but without any tenofovir in it. No-one (neither women nor the clinic staff) knew who was getting what. Both groups of women got advice about safer sex and free condoms. The women were monitored for two and a half years.
 

Results from the study will be officially presented to the AIDS 2010 conference in Vienna today, but they have already generated a lot of excitement.
“This is an important day,” said Yasmin Halima, director of the Global Campaign for Microbicides. “We now have evidence that a vaginal gel can help prevent HIV. This is good news for women, good news for the field and a good day for science.”
 

Next Steps

To stimulate and prioritise rapid action, WHO and UNAIDS announced that they will convene an expert consultation in August with women’s health and HIV prevention advocates, scientists, microbicide research teams and product developers, and public health experts to discuss the next steps with the product.

A webcast of this session and interviews are available on the Kaiser Family Foundation website

More information from NAM/aidsmap.com

Image - Prof. Quarraisha Abdool Karim, Associate Scientific Director of CAPRISA, explains how to use an applicator with gel       from blogs.timeslive.co.za

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.
 

Microbicides - Women Wait

posted: 18/05/2010

Next week’s International Microbicides Conference in Pittsburgh, USA will hear about the progress made in producing microbicides, that will help protect women and gay men from HIV.
 

Numerous past attempts at microbicides have failed. Using an anti-HIV drug in a microbicide is one of the attempts now being made to find some method of HIV prevention that women can use themselves. Women face problems protecting themselves from HIV, especially when their partners refuse to use condoms, or when simply suggesting condoms may put the woman in danger.
 

Is tenofovir part of the answer?

Tests are underway to see if tenofovir, one of the commonly used anti-HIV drugs, would work in vaginal gels and contraceptive-style rings. Experiments are also underway with quick-dissolving anti-HIV films, like those used for breath-fresheners or allergy medicines, but these are made for vaginal use.
In July we should have the results from the first study to see if tenofovir works in a microbicide — South African women are testing a gel made with it.
 

Cautious Hope
"Frankly, blocking transmission of the virus appears to be a lot harder than anyone understood it would be at the beginning," says co-chair Dr. Sharon Hillier of the University of Pittsburgh and a principal investigator of the Microbicide Trials Network. "The reason we're not depressed in the microbicide world? We actually have learned a lot and moved on to think about potent drugs and really cool delivery methods."
 

Pills for Prevention?
More than half a dozen studies of ‘pre-exposure prophylaxis’ (taking pills as treatment to prevent HIV infection happening) are also under way, and these mainly use tenofovir, because the side effects are more limited than with some other anti-HIV drugs. But even if pills for prevention works, taking HIV pills daily has drawbacks. There are the side effects, the risk of drug resistance, and people may miss doses or share the tablets with others so they wouldn’t be effective. It’s more expensive protection than condoms and the risks make it controversial.
 

Microbicide action
Microbicides are needed too. Women already make up half of the more than 33 million people worldwide living with HIV, and most of the new infections in hardest-hit sub-Saharan Africa are among young women.
"I have in fact so little to offer women in terms of HIV prevention that I sort of tear my hair out," says Dr. Salim Abdool Karim of the Centre for the AIDS Program of Research in South Africa at the University of KwaZulu-Natal. He’s leading the tenofovir gel study, his ninth microbicide study since 1994. "It must take a certain level of perseverance to want to stay in this field." Much more of the tenofovir reaches the vaginal tissue from a gel than any pill, and it doesn’t seem to move elsewhere into the body, so side effects may be minimal. He’s studying 900 HIV-negative heterosexual women to test whether tenofovir gel, applied up to 12 hours before intercourse and again within 12 hours afterward, lowers the risk of infection.
 

Next step soon
While awaiting his results in July, the U.S. National Institutes of Health is funding the next step: Researchers are already looking for 5,000 healthy women in several African countries to try two other approaches - vaginal tenofovir gel used daily rather than before and after sex, or or daily tenofovir pills. Which way is best?
 

Contraception teaches us that offering more choice about method leads to more women using something. So researchers are looking at other methods, too: a quick-dissolving tenofovir vaginal film, which should be completely invisible to the partner. Vaginal rings might be used to trickle-dose the vagina over a month. And for gay men ways to protect the rectum with tenofovir are in prospect.
Health promotion workers should get themselves ready to deal with the challenges should any of these attempts work, Dr. Regina Osih of the University of Witwatersrand will advise next week's microbicide conference.
 

HIV Damages and Sneaks Through

posted: 14/04/2010

HIV damages the cell walls of the genitals’ mucous membrane, and this lets HIV slip through to infect the vulnerable cells below, we have now learnt from a study. Most experts thought that HIV got through the mucous membrane itself, where these already had surface damage. This new scientific finding steers scientists who are creating microbicides and vaccines, to design these so they block contact between a very specific HIV protein and those in genital mucous membranes.

Microbicide hopes raised
This is an example of basic laboratory research into learning exactly how HIV attacks and works that may help solve a big HIV prevention problem. Women lack a HIV prevention method that they can control. Microbicides and vaccines are the best hope, but none have succeeded. This research gives microbicide and vaccine researchers a clear target to focus on. A few years down the line, we may see more hopeful signs of workable microbicides and vaccines appearing.

All sexual transmission of HIV occurs through mucous membranes. These researchers have basically found out that HIV has a protein that makes genital mucous membranes easier to pass through and cause infection. Previously researchers into HIV transmission had thought that transmission was most likely to occur either when the mucous membrane was damaged (for example through trauma or ulcers), or when many activated immune cells were present (such as during a sexually transmitted infection like gonorrhoea).

Disease progression?
The same ‘damage the cell walls and then sneak past’ strategy used by HIV for infecting people is thought by some experts to also help explain HIV disease progression and the development of some serious conditions, such as atherosclerosis (hardening and narrowing of the arteries).

How HIV does it
This study found that HIV weakens the integrity of surface cells, even when they are undamaged.

"It makes the electrical barrier resistance of epithelial cells decrease. By doing that, the virus can cross the barrier," said lead researcher Charu Kaushic, associate professor in the Centre for Gene Therapeutics at McMaster University, Ontario, Canada.

How does HIV actually get underneath epithelial cells to infect other cells that are susceptible to HIV? "It's not the cells on top," Kaushic said. "It is the immune cells underneath that have all the receptors that HIV likes to latch on to and that allow the virus to replicate and establish infection. But it has to cross the epithelial barrier first!"

Aisha Nazli, a researcher in Kaushic's laboratory, noticed every time she put HIV on epithelial cells, their electrical resistance went down significantly. It happened every time she tried this.

Protein break through

Kaushic said the surface protein of the virus (the gp120 surface protein) causes the epithelial barrier to break. "The surface protein signals to the inside of the epithelial cells by binding to it", she said. "The epithelial cells start making inflammatory proteins which cause these cells to go on their self-destructive pathway."

The researchers say if viral load and exposure time are enough, HIV can probably disrupt any mucosal barrier in the body, although infection may not necessarily occur every time.

"This is a significant step forward in defining where prevention strategies, such as microbicides and vaccines, need to focus. Instead of trying to stop HIV from infecting the target cells underneath the epithelium, we need to think about ways to stop the virus from attaching to epithelial cells themselves," said Charu Kaushic.

Source

Nazli A et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathogens 6 (4): e1000852, 2010. (full article, free access)