Only two years ago, we had scant evidence that a product used before sex could prevent HIV. Since then, the Caprisa 004 trial has proved that a gel applied topically to the vagina can reduce the chance of HIV infection, and several trials have shown that a tablet taken orally can do the same. Next on the agenda are rectal microbicide gels and multi prevention technologies designed to prevent pregnancy as well as HIV. But where does this new technology leave those of us who already have HIV? Adrian Ogier and Jane Costello report from the International Microbicides Conference held in Sydney in April.
‘We can finally talk about the end of the epidemic,’ announced Mitchell Warren from the Global Advocacy for HIV Prevention (AVAC) at a community forum before the conference.
‘But there are gaps that must be addressed,’ he said, referring in part to the delay between when a phase IIIA large clinical trial designed to establish whether a drug is effective and safe enough for widespread use. Phase III studies include expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. trial ends and the product finally gets into the community.
‘We need to demand biomedical prevention with as much passion as we demanded treatments in the 80s and 90s.
We must push for ARVA medication or other substance which is active against retroviruses such as HIV. prevention in the arenas where treatment is not reaching all who need it.’
African countries were particularly well represented at the conference-not surprising, considering the potential boon for the continent when these interventions are finally rolled out.
‘We have to start thinking about access now, while research is going on,’ said Milly Katana, a public health specialist from Uganda. ‘Then we will be prepared to ensure women have access to safe and effective microbicides as soon as they are introduced.’
In 2010, the CAPRISA 004 trial in South Africa found that 1% tenofovir gel reduced the risk of HIV infection via vaginal sex by 39% overall. Women were counselled to use the gel within 12 hours before and after sex.
Since then, the VOICE trial, which was designed to test both oral and topical ARV-based prevention, found that the gel did not reduce risk in women counselled to use it on a daily basis. The gel armAny of the treatment groups in a randomised trial. Most randomised trials have two "arms," but some have three "arms," or even more. of the trial was halted after they found equivalent rates of HIV infection in the active and placeboA dummy medical treatment, designed to have no pharmacological effect, administered to the control group of a clinical trial. gel recipients.
Despite the complex challenges, it is clear that microbicides signal the way forward as an HIV prevention option; particularly for women who do not have the social or economic power to negotiate safe sex or the ability to extricate themselves from situations that may place them at risk.
And it seems the appeal of the vaginal microbicide gel lies in its lubricating properties as much as it does in its potential to protect.
This was illustrated most strongly in a symposium on pleasure and biomedical prevention when Jonathan Stadler, a researcher from South Africa, told us how women utilised the gel in their sex lives.
‘It makes you feel like having sex,’ said one. ‘It makes your partner want you,’ said another.
‘We have been led to believe that for African women sex is a commercial act, a forced act or one to tolerate,’ said a fellow researcher, Mitzy Gafos, in the same session.
‘This is definitely not the case for the women of KwaZulu-Natal (one of the provinces in South Africa where the trial was rolled out).
‘Love is a verb in this environment. Women here work at love and work to maintain it.
Condoms are seen as unclean and are associated with lessened pleasure and interrupting the sex act.’
So despite disappointing results and the gel not yet being available outside of trials, women liked the stuff and by all accounts wanted to keep on using it.
There is now a proposed open-labelA clinical trial in which doctors and participants know which drug or vaccine is being administered. study (where all participants are offered the product being tested and there is no placebo) of 1% tenofovir gel, called CAPRISA 008. This study would look at effective ways to deliver the gel in communities where the CAPRISA 004 trial took place.
Researchers in the US have reformulated a gel with less glycerin to make it more agreeable for rectal use. So far it has proved effective against HIV in laboratory tests of human rectal tissue and its safety has been tested by 65 HIV negative men and women who used it rectally once a day for a week.
Because the risk of acquiring HIV through unprotected anal sex is so much higher, this represents an important step towards developing a safe and effective rectal microbicide.
MTN 017 will be the first ever Phase IIA smaller clinical trial designed to establish whether a drug is effective. Phase II studies are conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. If there is evidence that the drug is effective, a Phase III study is undertaken, with a larger number of participaants, to confirm this. trial of a rectal formulation of 1% tenofovir.
Scheduled to begin this year, over 200 gay and other MSM will be enrolledThe act of signing up participants into a study. Generally this process involves evaluating a participant with respect to the eligibility criteria of the study and going through the informed consent process. at sites in Peru, South Africa, Thailand and the US.
‘For far too long the operating principle concerning the HIV epidemic in Africa has been that it is solely heterosexual, and that sexual transmission is entirely driven by unprotected vaginal intercourse between men and women,’ said Jim Pickett, chair of the International Rectal Microbicides Alliance (IRMA).
‘But an increasing body of evidence tells us quite clearly that unprotected anal intercourse is happening all across the continent — amongst heterosexuals as well as gay men, MSM and transgender individuals.
‘Unprotected anal intercourse is not uncommon in Africa,’ he continued, ‘and compared to unprotected vaginal intercourse is 10 to 20 times more likely to result in HIV infection.’
Researchers at the University of Pittsburgh have also developed a rectal microbicide gel that contains two different antiretroviral drugs: tenofovir and griffithsin.
Griffithsin is a protein isolated from red algae, called griffithsia, and in the laboratory has been shown to be a highly potent HIV entry inhibitor and a particularly good candidate for a microbicide.
Many candidate microbicides currently being tested are widely anti-microbial and may provide protection against a range of sexually transmitted infections, including HIV. By neutralising pathogens in both semen and vaginal secretions, these products may provide bi-directional protection; that is, will help protect both parties. This will give HIV positive people a way of reducing their negative partner’s risk of HIV exposure during sex — as well as a way of reducing their own risk of contracting infections.
Dual-purpose technologies, also known as multi-prevention technologies are moving to the forefront. Dr Henry Gabelnick, Executive Director of CONRAD, spoke about the need for products that prevent pregnancy as well as HIV infection.
‘Improved prevention technology should be developed more vigorously but it is severely dependent on funders recognising that not only HIV prevention but broad spectrum microbicidal activity as well as contraception are necessary.’
PrEP for men
A range of pre exposure prophylaxis (PrEP) trials in different populations have shown effectiveness(Of a drug or treatment). The maximum ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the standard procedure, Phase II clinical trials gauge efficacy, and Phase III trials confirm it. from none, to moderate (39%-42%) to high (75%) with the degree of success linked closely to adherence.
Dr Kenneth H. Mayer of the Fenway Institute in Boston and Dean Murphy of the National Centre in HIV Social Research at the UNSW led a symposium ‘What is needed to make PrEP an effective prevention technology for gay men and other MSM?’ The session looked at lessons learned from PrEP clinical trials to date and how PrEP might be rolled out for gay men and other MSM. ‘The iPrEx study provided clues that point to what we need to do to move PrEP from clinicalPertaining to or founded on observation and treatment of participants, as distinguished from theoretical or basic science. trials to real world use,’ said Dr Mayer.
‘Our challenge now is to translate what we’ve learned into effective programs that will make PrEP available to gay men who need it in the US, Australia and around the world. There is much work to be done to ensure that gay men and their healthcare providers understand both the promises and the limitations,’ he added.
PrEP for women
Evidence suggests that oral tenofovir or tenofovir/FTC (Truvada) is also an effective prevention strategy for women, although it was reported at the conference that tenofovir may be more fragile in women than men.
Adherence is the key to the success of PrEP, as is evident by the FEM-PrEP study, stopped in April 2011 because almost as many HIV infections occurred in women given Truvada as in those given placebo.
One presentation looked at the biology of HIV transmission and the implications for the design of effective PrEP. It reported that women on PrEP could experience mucosal inflammation, and that having unprotected sex changes the mucosal environment and the effectiveness of the drug regime.
As mucosal inflammation increases the risk of HIV transmission, it was suggested that there is a need for more potent drugs or drugs that don’t require intercellular metabolism.
Positive women and prevention
ARV-based microbicides are not always suitable for women living with HIV due to possible drug interactions and resistanceHIV which has mutated and is less susceptible to the effects of one or more anti-HIV drugs is said to be resistant.; however, all but one of the microbicides in current clinical trials is ARV-based. This was one of the issues raised at a controversial symposium on women’s advocacy entitled ‘HIV prevention needs of women living with HIV’.
Anna Forbes of the Positive Women’s Network in Oakland, California examined the new HIV prevention technologies and their relevance for positive women. She highlighted the possible interaction and resistance issues and called for more research into non-ARV based microbicides to benefit those living with HIV as well as those who do not know their status. She also questioned the effectiveness of PrEP, citing two trials which did not show the same levels of protection for women as they did for men.
Ms Forbes also expressed concerns about treatment as prevention, particularly regarding adherence, potential resistance, equality in access and the protection of human rights.
‘Given the way HIV mutates and changes,’ she said, ‘HIV vaccines are very difficult to develop because HIV mutates rapidly as it reproduces.’
‘However, we should be encouraged by the proof of concept around research thus far.’
Finally, Ms Forbes noted that the female condom, while not a new HIV prevention strategy, still faces major barriers due to high cost and a lack of awareness and availability.
Jane Bruning, the coordinator of Positive Women in New Zealand, noted that the female condom comprises only 1% of the total uptake of condoms worldwide.
‘This is mainly because they are so expensive compared to other forms of barrier protection,’ she said.
Ms Bruning tabled the most recent advances including models made of nitrile rubber, a synthetic product as effective as polyurethane or latex, but less costly and able to be used with both oil and water-based lubricants.
Although women have expressed their reservations, Ms Bruning stressed the benefits.
‘The female condom enables women to gain control of their own sexual health,’ she said.
‘As well as reducing the risk of transmitting HIV, they protect the positive woman from other STIs[Sexually Transmissible (or Transmitted) Infection] Infections spread by the transfer of organisms from person to person during sexual contact. Also called venereal disease (VD) (an older public health term) or sexually transmitted diseases (STDs). as well as other strains of HIV.
Importantly, they allow her to share the responsibility for safe sex, particularly when the male partner refuses to wear a condom.
And unlike the male condom, they can be inserted in advance.’
Jane believes that women living with HIV, together with governments and other major donors, can do much to advance their accessibility and affordability.
Susan Paxton, an advisor to Women of the Asia Pacific Network of People Living with HIV (APN+Asia-Pacific Network of People Living with HIV/AIDS. ), presented some peer-led research from the region.
In an impassioned presentation, Ms Paxton revealed that only 9% of women who participated in the study (and whose HIV test was not voluntary) had received post-test counselling. She professed that a significant amount of misinformation had also been provided to these women, with most being discouraged from becoming pregnant by health care workers. Twenty-two percent of women in the study had had abortions, but 29% of those who had aborted had in fact wanted the pregnancy. Furthermore, 30% of women were encouraged to consider sterilisation, usually by gynaecologists (42%) or HIV clinicians (20%), and there was a positive correlation between women who had a caesarean and women who were recommended to be sterilised with some not knowing whether they had been sterilised during the procedure.
Ms Paxton highlighted the need for contraceptive methods that women can control such as IUDs, pills, injectables and female condoms.
Cost was clearly a major barrier for accessing health care for most of the women interviewed, and cases of discrimination were rife amongst the study’s participants. Only 7% of women had initiated ART at a CD4 count of greater than 350 cells; with the majority not starting until their count was less than 200 cells.
The research provided a number of key recommendations, including the need to invest in positive women’s organisations; expand counselling services; improve the sensitivity of maternal health services; ensure the provision of social security; and uphold positive women’s rights.
Read the full report at: www.gnpplus.net/en/regions/asia-pacific
The symposium concluded with a call to mobilise positive women’s voices in advocacy so that they are able to realise their full sexual and reproductive health and rights.
This Microbicides Conference was the seventh and last of its kind to be held. At the final plenary, representatives for joint funders, the National Institutes of Health and the Bill and Melinda Gates Foundation, announced that future biennial conferences would now integrate the spectrum of prevention technologies including vaccines, microbicides and oral PrEP.