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Marvellous microbicides
FEATURE
FEATURE
Marvellous microbicides Intravaginal gels could save millions of lives, but first someone has to prove that they work . . . reventing AIDS is theoretically simple: encourage mutual monogamy or consistent condom use. But experts warn that if responsibility for protection stays with men, these interventions will produce only small gains in the fight against AIDS. The majority of women in some parts of sub-Sarahan Africa are in immediate danger of contracting HIV. But these women are powerless to protect themselves because most are dependent on men for economic security, and are often unable to negotiate safe sex. If a method of HIV prevention were available that women could administer themselves, the situation could rapidly become very different. Alan Stone, chairman of the International Working Group on Microbicides believes that microbicides —topical agents that stop the HIV virus being transmitted during intercourse— are the only realistic option. “There is absolutely nothing else on the horizon that could make a large-scale impact”, he says. But there is a problem with these products: none has yet successfully completed clinical trials. So, to all intents and purposes, the theory remains unproven. 2004, therefore, is a crucially important year. Several
P
compounds are poised to start phase III testing and the badly needed proof that this approach works may soon become a reality. These trials are the culmination of nearly 20 years of work, but the huge weight of expectation on positive outcomes illustrates just how desperate researchers working in this area have become. It has taken a momentous effort to get to this stage. Starved of funding for several years, microbicide research was initially marginalised by an AIDS community that pinned most of its hopes on a vaccine. “18 years ago, people were saying we’d have a vaccine in 2 years”, recalls Robin Shattock, a microbicide researcher at St George’s Hospital Medical School in London. Now, however, it is widely acknowledged that this goal is still years away. Other misconceptions are vanishing too. For example, Stone says, “people now realise how difficult it is to create a durable response to condom promotion campaigns”. Another blow to microbicide research came when alarming findings from trials of the first candidate agent, nonoxynol-9, were revealed. According to Tim Farley, who is based at the department of reproductive health and research at WHO, nonoxynol-9 was an
Panos Pictures
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
It is difficult to achieve a lasting response from condom promotion campaigns
1042
ideal potential microbicide because it was already a registered spermicide, and in-vitro studies pointed to its effectiveness against HIV. If human tests confirmed anti-HIV activity, “it would have been easy to scale up production and roll it out”, he explains. But results from a trial of around 900 sex workers in South Africa, Thailand, Benin, and Côte d’Ivoire—announced to an expectant audience at the AIDS 2000 conference in Durban, South Africa— showed that a gel containing nonoxynol9 (known as COL1492) had actually facilitated viral transmission. Researchers found out later that the compound’s detergent properties made it just as effective at destroying human cells as viral particles. And by damaging the epithelial lining of the vagina, it helped give the virus easy access to the body. Since the disappointment of nonoxynol-9, microbicides have been struggling to regain credibility. Gita Ramjee, director of South Africa’s HIV Prevention Research Unit, who worked on the COL1492 trial and has since continued with microbicide research, says it has been quite a task getting microbicides back on the health agenda. She thinks the South African government in particular “became really anti-microbicides” after the Durban AIDS conference. The issue was compounded by the fact that Ramjee’s group contributed the greatest number of seroconverters to the trial. Now, pressure to achieve good results and to ensure absolute safety of the products under evaluation is high. “They want an assurance that should the product be inefficacious, or increase the risk of HIV, then there should be some kind of liability coverage”, explains Ramjee. Opinion is turning, however. Several large funding bodies have pledged millions to microbicide research during the past few years. Among the first was the UK government’s Overseas Development Administration (now called the Department for International Development). It donated seed funds for small research projects in the early 1990s, and then, in 2002, pledged another £16 million. In May, 2002, the Rockefeller Foundation also made microbicides a priority and established the International Partnership for Microbicides (IPM) to accelerate the discovery, development, and accessibility of microbicides. The Bill & Melinda Gates Foundation, which in March last year pledged US$60 million to IPM, is the latest organisation to become a donor.
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
FEATURE
WHO is also backing microbicide research. For the first time, a section on microbicides will be included in this year’s World Health Report. “We see this as a high priority and we are delighted at the attention and work that is going on”, said WHO spokesman Tim Farley. Shattock, who is also chairman of IPM’s Research and Development Advisory Committee, believes the reason for this change of heart is disenchantment with current progress. “People are seeing major hurdles to developing an effective vaccine and they are suddenly realising that microbicides could be out there making a difference now.” Although momentum is increasing, without proof of concept, microbicide advocates face an uphill struggle. This year’s phase III trials are crucial. But clinical testing of microbicides is fraught with Few women are able to negotiate condom use problems. First, because it would be unethical not to promote condoms earnings targets, some women take among participants, the trials must be risks. Even though investigators took very large. Researchers have to bank on great care to explain the randomisation the fact that very few women will be process, many women chose to believe able to negotiate condom use every that their gel was the one that worked. time, so at least some people in each “That’s the sad part about this whole arm will be using the microbicide or thing; women become so desperate that control gel alone. A second problem is they just hope to God that what they’ve compliance. “Even if the product is got inside them will protect them”. very efficacious, if people aren’t using it And it is difficult to change these properly, you won’t show any efficacy”, misperceptions. says Shattock. Third, it is essential that the product “In the remotest part of Thailand is acceptable to the local population in you can buy a bottle of Coke. We which the test is being done. “One of want microbicides to be the cultural differences here in subavailable like that” Sarahan Africa is that people practise dry sex, which means they do not like a lot of vaginal fluid”, explains Once the trials get off the ground, it Ramjee. This observation raised will still be a long time before concerns that an intravaginal gel—the microbicides are available. Ramjee formulation used for all microbicides predicts it could be 3 years before there that are in clinical trials at the are any meaningful results. And moment—might not appeal to some worryingly, some experts believe that women. But fears proved unfounded. the first microbicides are unlikely to be Although a few women complained effective. that the gel seemed to leak on first use, “The ones that are going into trials they soon adapted. now are the oldest things people have During her preparation for the been working on—some of them were forthcoming clinical trials, Ramjee started 18 years ago”, says Shattock. learnt just how important the idea of And that was before much was known microbicides is to some women. about the biology of AIDS. Although According to sex workers she researchers have learnt lessons from interviewed in previous microbicide nonoxynol-9—so none of the products studies, sex with condoms fetches a are damaging—poor efficacy could still much lower price. So, to achieve threaten the hard-won support.
But Ramjee argues that even a minimally effective microbicide would have a huge impact on women. Calculations done by a group from the London School of Hygiene and Tropical Medicine in London indicate that even if a microbicide were 40% effective and only 30% of people used it, 6 million lives would be saved globally over 3 years. Regardless of their effectiveness, Stone believes that microbicides will not reach everyone who needs them unless large pharmaceutical companies get involved. “In the remotest part of Thailand you can buy a bottle of Coke. We want microbicides to be available like that . . . and the big companies know how to do this”, he says. Until now, however, they have been firmly sitting on the fence. Concerns about legal liability and the assumption that most people who need microbicides will not have the money to pay, are the main reasons for their reluctance to support microbicide research, according to the Global Campaign for Microbicides. “When you look at it from the companies’ perspective”, says Stone, “these are logical business decisions.” But he is sure that once microbicides have been shown to work, private money will not be far behind. If the first phase III trials are successful, it will help to smooth the way for a new generation of more specific agents targeting individual stages in the virus’s life cycle. Other avenues of research involve different delivery formulations. For instance, sustained-release products such as vaginal rings, which could carry a month’s dose at a time, are being explored. The more specific compounds will probably have a higher chance of success in the short term, but may be more prone to resistance mechanisms. “I think the way the field will probably go after this is to look at combinations”, says Shattock. Stone is worried that, because funds for microbicides are limited, some researchers will start arguing for money to be set aside for the next generation of microbicide products, and that this could delay or disadvantage current trials. “Every day we’re not doing something, people are getting infected and dying . . . we’ve just got to get these products out there”, he says. Reuters
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Hannah Brown
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1043
FEATURE
Marvellous microbicides Intravaginal gels could save millions of lives, but first someone has to prove that they work . . . reventing AIDS is theoretically simple: encourage mutual monogamy or consistent condom use. But experts warn that if responsibility for protection stays with men, these interventions will produce only small gains in the fight against AIDS. The majority of women in some parts of sub-Sarahan Africa are in immediate danger of contracting HIV. But these women are powerless to protect themselves because most are dependent on men for economic security, and are often unable to negotiate safe sex. If a method of HIV prevention were available that women could administer themselves, the situation could rapidly become very different. Alan Stone, chairman of the International Working Group on Microbicides believes that microbicides —topical agents that stop the HIV virus being transmitted during intercourse— are the only realistic option. “There is absolutely nothing else on the horizon that could make a large-scale impact”, he says. But there is a problem with these products: none has yet successfully completed clinical trials. So, to all intents and purposes, the theory remains unproven. 2004, therefore, is a crucially important year. Several
P
compounds are poised to start phase III testing and the badly needed proof that this approach works may soon become a reality. These trials are the culmination of nearly 20 years of work, but the huge weight of expectation on positive outcomes illustrates just how desperate researchers working in this area have become. It has taken a momentous effort to get to this stage. Starved of funding for several years, microbicide research was initially marginalised by an AIDS community that pinned most of its hopes on a vaccine. “18 years ago, people were saying we’d have a vaccine in 2 years”, recalls Robin Shattock, a microbicide researcher at St George’s Hospital Medical School in London. Now, however, it is widely acknowledged that this goal is still years away. Other misconceptions are vanishing too. For example, Stone says, “people now realise how difficult it is to create a durable response to condom promotion campaigns”. Another blow to microbicide research came when alarming findings from trials of the first candidate agent, nonoxynol-9, were revealed. According to Tim Farley, who is based at the department of reproductive health and research at WHO, nonoxynol-9 was an
Panos Pictures
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
It is difficult to achieve a lasting response from condom promotion campaigns
1042
ideal potential microbicide because it was already a registered spermicide, and in-vitro studies pointed to its effectiveness against HIV. If human tests confirmed anti-HIV activity, “it would have been easy to scale up production and roll it out”, he explains. But results from a trial of around 900 sex workers in South Africa, Thailand, Benin, and Côte d’Ivoire—announced to an expectant audience at the AIDS 2000 conference in Durban, South Africa— showed that a gel containing nonoxynol9 (known as COL1492) had actually facilitated viral transmission. Researchers found out later that the compound’s detergent properties made it just as effective at destroying human cells as viral particles. And by damaging the epithelial lining of the vagina, it helped give the virus easy access to the body. Since the disappointment of nonoxynol-9, microbicides have been struggling to regain credibility. Gita Ramjee, director of South Africa’s HIV Prevention Research Unit, who worked on the COL1492 trial and has since continued with microbicide research, says it has been quite a task getting microbicides back on the health agenda. She thinks the South African government in particular “became really anti-microbicides” after the Durban AIDS conference. The issue was compounded by the fact that Ramjee’s group contributed the greatest number of seroconverters to the trial. Now, pressure to achieve good results and to ensure absolute safety of the products under evaluation is high. “They want an assurance that should the product be inefficacious, or increase the risk of HIV, then there should be some kind of liability coverage”, explains Ramjee. Opinion is turning, however. Several large funding bodies have pledged millions to microbicide research during the past few years. Among the first was the UK government’s Overseas Development Administration (now called the Department for International Development). It donated seed funds for small research projects in the early 1990s, and then, in 2002, pledged another £16 million. In May, 2002, the Rockefeller Foundation also made microbicides a priority and established the International Partnership for Microbicides (IPM) to accelerate the discovery, development, and accessibility of microbicides. The Bill & Melinda Gates Foundation, which in March last year pledged US$60 million to IPM, is the latest organisation to become a donor.
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
FEATURE
WHO is also backing microbicide research. For the first time, a section on microbicides will be included in this year’s World Health Report. “We see this as a high priority and we are delighted at the attention and work that is going on”, said WHO spokesman Tim Farley. Shattock, who is also chairman of IPM’s Research and Development Advisory Committee, believes the reason for this change of heart is disenchantment with current progress. “People are seeing major hurdles to developing an effective vaccine and they are suddenly realising that microbicides could be out there making a difference now.” Although momentum is increasing, without proof of concept, microbicide advocates face an uphill struggle. This year’s phase III trials are crucial. But clinical testing of microbicides is fraught with Few women are able to negotiate condom use problems. First, because it would be unethical not to promote condoms earnings targets, some women take among participants, the trials must be risks. Even though investigators took very large. Researchers have to bank on great care to explain the randomisation the fact that very few women will be process, many women chose to believe able to negotiate condom use every that their gel was the one that worked. time, so at least some people in each “That’s the sad part about this whole arm will be using the microbicide or thing; women become so desperate that control gel alone. A second problem is they just hope to God that what they’ve compliance. “Even if the product is got inside them will protect them”. very efficacious, if people aren’t using it And it is difficult to change these properly, you won’t show any efficacy”, misperceptions. says Shattock. Third, it is essential that the product “In the remotest part of Thailand is acceptable to the local population in you can buy a bottle of Coke. We which the test is being done. “One of want microbicides to be the cultural differences here in subavailable like that” Sarahan Africa is that people practise dry sex, which means they do not like a lot of vaginal fluid”, explains Once the trials get off the ground, it Ramjee. This observation raised will still be a long time before concerns that an intravaginal gel—the microbicides are available. Ramjee formulation used for all microbicides predicts it could be 3 years before there that are in clinical trials at the are any meaningful results. And moment—might not appeal to some worryingly, some experts believe that women. But fears proved unfounded. the first microbicides are unlikely to be Although a few women complained effective. that the gel seemed to leak on first use, “The ones that are going into trials they soon adapted. now are the oldest things people have During her preparation for the been working on—some of them were forthcoming clinical trials, Ramjee started 18 years ago”, says Shattock. learnt just how important the idea of And that was before much was known microbicides is to some women. about the biology of AIDS. Although According to sex workers she researchers have learnt lessons from interviewed in previous microbicide nonoxynol-9—so none of the products studies, sex with condoms fetches a are damaging—poor efficacy could still much lower price. So, to achieve threaten the hard-won support.
But Ramjee argues that even a minimally effective microbicide would have a huge impact on women. Calculations done by a group from the London School of Hygiene and Tropical Medicine in London indicate that even if a microbicide were 40% effective and only 30% of people used it, 6 million lives would be saved globally over 3 years. Regardless of their effectiveness, Stone believes that microbicides will not reach everyone who needs them unless large pharmaceutical companies get involved. “In the remotest part of Thailand you can buy a bottle of Coke. We want microbicides to be available like that . . . and the big companies know how to do this”, he says. Until now, however, they have been firmly sitting on the fence. Concerns about legal liability and the assumption that most people who need microbicides will not have the money to pay, are the main reasons for their reluctance to support microbicide research, according to the Global Campaign for Microbicides. “When you look at it from the companies’ perspective”, says Stone, “these are logical business decisions.” But he is sure that once microbicides have been shown to work, private money will not be far behind. If the first phase III trials are successful, it will help to smooth the way for a new generation of more specific agents targeting individual stages in the virus’s life cycle. Other avenues of research involve different delivery formulations. For instance, sustained-release products such as vaginal rings, which could carry a month’s dose at a time, are being explored. The more specific compounds will probably have a higher chance of success in the short term, but may be more prone to resistance mechanisms. “I think the way the field will probably go after this is to look at combinations”, says Shattock. Stone is worried that, because funds for microbicides are limited, some researchers will start arguing for money to be set aside for the next generation of microbicide products, and that this could delay or disadvantage current trials. “Every day we’re not doing something, people are getting infected and dying . . . we’ve just got to get these products out there”, he says. Reuters
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Hannah Brown
THE LANCET • Vol 363 • March 27, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1043