The concept of microbicides as an HIV prevention tool was first proposed 20 years ago. Microbicide is a product applied topically in the vagina or rectum with the intention of preventing sexually transmitted infections (STIs) including HIV. It can take different forms such as a gel, foam or a ring. The idea to use the ARV-based tenovofir gel was mooted in 2003 but the proof of concept came only in 2010. The microbicide tenofovir gel was found safe and effective in reducing the risk of HIV in women who used it before and after vaginal sex in a study called CAPRISA 004. The CAPRISA 004 study demonstrated an overall 39% reduction in HIV infection, with 54% HIV reduction in women who used tenofovir gel consistently, providing proof of concept that microbicides indeed can prevent sexually transmitted HIV if used consistently.
Unfortunately, another study called VOICE found tenofovir gel was not effective among the women who were asked to use the gel every day (in CAPRISA-004 study women only used the gel before and after sex). Meanwhile, tenofovir gel continues to be evaluated in another study called FACTS-001, a Phase III confirmatory study testing the same regimen of tenofovir gel used in CAPRISA 004. FACTS 001 is expected to report results in 2014. If it confirms the CAPRISA-004 trial findings it is likely to support licensure of tenofovir gel for HIV prevention.
Another study CAPRISA-008 is to begin shortly in South to study integration of tenofovir gel into family planning services through an open-label randomized controlled trial to assess the implementation, effectiveness and safety of 1% tenofovir gel provision and will include about 700 consenting sexually active, HIV-uninfected South African women aged 18 years and older who had previously participated in the CAPRISA 004 study.
WHY MICROBICIDES?
The sheer burden of HIV/AIDS in young women and girls is massive. Based on UNAIDS estimates, the prevalence of HIV is much higher in girls than boys in the age group of 15-24 years all over Africa. Worldwide women are in urgent need of some intervention which is under their control (and not their partner) to prevent and control sexually transmitted HIV. While speaking to CNS at the recently concluded AIDS Vaccine 2012 conference Professor Salim Abdool Karim, the co principal investigator of CAPRISA 004 trial, said that, “One of the strengths of female microbicides is that, unlike the female condom, one can insert/apply it unrelated to the sex act. It has to be applied anytime 12 hours before and 12 hours after sex. The gel is clear, colourless, tasteless, and odorless. Also unlike the condom, when a woman uses this gel, nobody, not even the partner, would know about its presence. In our study 68% of the women said that their partner could not identify that the gel was used, but we told them. The rest 32% did not tell their partners and the partners could not identify it. So microbicide gels are under total control of the women.”
“However having the gel and being able to use it are two different things. It all depends on how women perceive their risk. If they do not trust their partners and think that they are at risk then in such instances the woman is ready to use it. Similarly sex workers are ready to use it. The difficulty arises where women do not have that power and self confidence. In my opinion microbicides have a lot of potential in controlling the epidemic,” said Dr Karim.
CHALLENGES
The field of microbicides, however, is beset with challenges. As pointed out by Dr Karim, “There is lack of validated surrogate markers or correlative protection in the field of microbicides. Hence the only way to assess its effectiveness is through very large studies. There is also no validated measure of the product’s biological activity. Unlike a vaccine there is no equivalent to immunogenicity in many of the microbicide products. There are also challenges in measuring drug concentrations because in applications they lead to very low systemic levels. They give very high drug levels in mucosal tissues but very low systemic exposure. The intensity of the study follow-ups is just too burdensome. In CAPRISA 004 study, a trial participant had to make, on an average, 22 study visits and undergo 7 internal examinations over an 18 months period. So the intensity of undertaking these studies and the onus it puts on women is very substantial. Another problem with microbicides is that in the absence of optimal adherence it is difficult to measure efficacy. So one has to measure efficacy of this product in the context of the real world situation—its effectiveness in preventing HIV infection in the context of poor adherence.”
The field of microbicides, however, is beset with challenges. As pointed out by Dr Karim, “There is lack of validated surrogate markers or correlative protection in the field of microbicides. Hence the only way to assess its effectiveness is through very large studies. There is also no validated measure of the product’s biological activity. Unlike a vaccine there is no equivalent to immunogenicity in many of the microbicide products. There are also challenges in measuring drug concentrations because in applications they lead to very low systemic levels. They give very high drug levels in mucosal tissues but very low systemic exposure. The intensity of the study follow-ups is just too burdensome. In CAPRISA 004 study, a trial participant had to make, on an average, 22 study visits and undergo 7 internal examinations over an 18 months period. So the intensity of undertaking these studies and the onus it puts on women is very substantial. Another problem with microbicides is that in the absence of optimal adherence it is difficult to measure efficacy. So one has to measure efficacy of this product in the context of the real world situation—its effectiveness in preventing HIV infection in the context of poor adherence.”
KEY LEARNINGS FROM CAPRISA 004
The preexisting presence of genital tract inflammation plays a key role in acquisition and is associated with a much higher increased level of susceptibility to HIV infection. Even systemic innate immune activation increases the risk of HIV acquisition. The point at which infection is actually occurring in the mucosa is quite important as to what that milieu is and the level up to which inflammation is present to influence the risk of the onset of infection. So protection of the site of infection is critical. Also, the amount of tenofovir that is present in the genital tract is a very important predictor of whether the woman would become infected or not. When tenovofir is present in the genital tract there is low incidence of HIV. To quote Mitchell Warren, Executive Director AVAC, ‘it is like having a condom which will not work if it is in your pocket. You have to use it to see its benefit.’
The preexisting presence of genital tract inflammation plays a key role in acquisition and is associated with a much higher increased level of susceptibility to HIV infection. Even systemic innate immune activation increases the risk of HIV acquisition. The point at which infection is actually occurring in the mucosa is quite important as to what that milieu is and the level up to which inflammation is present to influence the risk of the onset of infection. So protection of the site of infection is critical. Also, the amount of tenofovir that is present in the genital tract is a very important predictor of whether the woman would become infected or not. When tenovofir is present in the genital tract there is low incidence of HIV. To quote Mitchell Warren, Executive Director AVAC, ‘it is like having a condom which will not work if it is in your pocket. You have to use it to see its benefit.’
The Achilles heel of the microbicide field is adherence. To make women use microbicide products, when needed, presents a whole range of challenges. To address them, a new formulation called dipavirine in the form of a ring is currently being assessed in two separate trials in some countries of Africa, but the results are not expected to be known before 2016. It involves a monthly application of the vaginal ring with diparivine as an intervention. If successful the ring may prove to be more user-friendly as it has to be inserted once a month and then for a whole month it releases the drug. At the end of the month it has to be replaced by a new ring. Dr Karim fears that, “There are some challenges with the ring. Sometimes it may fall out and another problem is when women are menstruating. But I am very hopeful that the ring would be a good prevention option as it cheaper and it is once a month application so women do not have to worry at the last moment. Studies are underway to look for any side effects, but to date these products are very safe.”
Dr Karim informed that The World Health Organization has already started working on guidelines for tenovofir gel implementation and the first draft of it has been shared and currently being worked on. The steps to follow are dependent upon achieving licensure which will largely depend upon results from the FACTS 001 study. Following that will be the regulatory approvals and subsequently the launch and then making the gel available and reach the women who would want to use this product. If all goes well, microbicides are hoped to roll out by the middle of 2014. Till then let us keep our fingers crossed and hope for the best.
Shobha Shukla - CNS
(The author is the Managing Editor of Citizen News Service (CNS). She is a J2J Fellow of National Press Foundation (NPF) USA. She received her editing training in Singapore, has worked earlier with State Planning Institute, UP and taught physics at India's prestigious Loreto Convent. She also authored a book on childhood TB (2012), co-authored a book (translated in three languages) "Voices from the field on childhood pneumonia" and a report on Hepatitis C and HIV treatment access issues in 2011. Email: shobha@citizen-news.org, website: http://www.citizen-news.org) 