Women randomised to microbicides currently being evaluated in the clinical efficacy studies, described at the Microbicides 2006 Conference recently in Cape Town, report that they do not always use the products as consistently as they should, and in one study, adherence to the microbicides has been lower without condoms than when condoms are being used.
Self-reported behaviour, particularly around microbicide and condom use (and sexual behaviour in general), is not always reliable but if these trends continue, it could make it more difficult for those studies to provide clear answers as to whether the products work or not. Numerous presentations at the Microbicides 2006 Conference focused on ways to improve acceptance, encourage longer-term adherence — and to verify whether the products are being used or not in the ongoing trials.
Gel and Condom Use During Follow-up in HPTN 035
Among participants assigned to gel, number of last vaginal sex acts reported by 422 participants
| With gel | Without gel | Total | |
| With condom | 82% | 18% | 70% |
| Without condom | 57% | 43% | 30% |
| Total | 74% | 26% | 100% |
“In the last sex acts of 422 participants, we only have 30% of sexual acts where there is no condom being used. If you look at adherence to gel, you’ll see that 74% of the sexual acts included gel. But one of the issues however, is that if we look at how well adherence to gel tracts with adherence to a condom. In women who used condoms, adherence to gel is very good (82%); however, of the women who did not use condoms, only 57% used the gel. So what we have is a situation in which even when the condom is not be used, we still have a problem with at adherence to gel,” he said.
The adherence issues in the MIRA study diaphragm study are even more complicated because the experimental arm has two components: the All-Flex diaphragm with Replens gel (a vaginal moisturiser). Overall, adherence in the study overall is lower than expected but if that weren’t trouble enough, women often don’t use the gel provided with the diaphragm. Participants in the trial reported using condoms at last sexual contact about 70% of the time (in both arms), while in the diaphragm and gel arm, only slightly more—76%—of the sex was covered by diaphragm, but the gel was only used in 50% of the last sex acts.
Confounding condoms
The investigators in the clinical efficacy trials of microbicides are in the awkward position of needing to encourage participants in their studies to use both the product to which they’ve been randomised (microbicide or placebo) and practice safer sex and use condoms — but the trials would have a better chance of reaching a clear conclusion about the effectiveness of the microbicide if people did not actually use the condoms.
According to Dr Elof Johansson of the Population Council, which is conducting the phase III trial of the microbicide, Carraguard, consistent condom use probably works better than the microbicide. ”“For ethical reasons we have to promote condom use within the trial. In my 35 years of experience working with clinical trials, I’ve never been in such a difficult situation were you have to promote another treatment that will work as good, and probably better, than the product you are testing. So we have to rely on non-compliance on the condom side and compliance on the gel.”
Yet just the reverse — better adherence to condoms than the microbicide — is being reported in some studies.
For example, in the Cellulose Sulfate trial in Nigeria, participants reported using a condom for 90% of sexual acts in the past week, but women reported using the microbicide less frequently for 83% of the sex acts in the past week. Reports from the Savvy Nigeria study are similar (88% using condoms, 78% using gel for sexual acts in the past week). Such high condom use rates, if true and sustained, would mean that very few women in the study may become infected — and that the trials may be too small to reach a clear conclusion.
And muddying the picture even further, women in HPTN 035, which compares Pro 2000 and BufferGel to a gel placebo or no gel, are reporting that they use the microbicide less frequently when they don’t use the condoms, which could confound the study’s ability to measure the effect of the microbicide.
According to the study’s protocol chair, Dr Salim Karim: “In many ways, we spend so much time within our trial promoting a highly efficacious prevention method in the form of condoms, and we have depended to some extent upon the fact that a condom will simply not be used on every occasion; and in those particular instances where condoms are not used, that we would have a high proportion of those women adhering to the gel. So in a way we are looking for two conflicting things, non-adherence to the condom and adherence to the gel and you can see the hazards and problems that that particularly poses.” See table.
Acceptability studies
Such low adherence could indicate that there is a problem with product acceptability in this setting, for both the diaphragm and for the gel.
Acceptability studies are usually conducted in the early stages of product development and clinical testing, in order to understand women (and men’s) preferences about a product, to help product developers find acceptable formulations, delivery mechanisms, and packaging designs. All of the current crop of microbicides had been extensively tested before proceeding into advanced stage trials, and in general, product acceptance has been high. These studies have been cross-sectional, however, and haven’t tracked temporal changes in adherence.
Even so, a number of acceptability studies presented at the conference suggested that could be room for improvement in the design of some of the products — especially the diaphragms, which are not widely available in many resource limited settings or familiar to the women there.
In one Brazilian study, 244 women and their male partners were asked to evaluate three delivery devises; plastic applicators (that are inserted into the vagina to deliver a set quantity of microbicidal gel), diaphragms and intravaginal rings. Most of the complaints were about the diaphragms.
More women in the study wanted to remove the diaphragm immediately after sex — but to be effective, diaphrams need to remain within the vagina for 6-24 hours after sex, depending upon the model. According to another study in Madagascar, women also want to remove the diaphragm after sex so that they can douche themselves. Note that this aspect of adherence may not be adequately addressed in many of the ongoing trials — and that douching could also interfere with the effectiveness of gel microbicide. In a pilot study of the MDP301 study, for example, in Uganda, “some women viewed gel use instructions (requirement not to wash inside the vagina until one-hour after sex) as difficult to follow over a long period of time.”
The design of the diaphragm could also be a problem. “Most of the women and about 60% of the men suggested changes for the diaphragm; mainly that it should be smaller, more flexible and have a thinner rim without a spring,” according to Ellen Hardy of the Universidade Estadual de Campinas in Sao Paulo, Brazil. In another study in couples with no previous experience using diaphragms in South Africa, Thailand, and Dominican Republic, complained that the All-Flex diaphragm was more difficult to handle, insert, and less comfortable than the SILCS diaphragm.
However, according to one poster, in the MIRA study, clinicians worked with the patient to determine the most comfortable, correct fitting diaphragm size — and only a few patients had serious problems with inserting the diaphragm.
And yet the study did note that although the Replens gel facilitated diaphragm insertion, the lubricant made the diaphragm difficult to handle — which could be one reason why adherence to the gel was lower. Other studies have also noted that “messiness” is a commonly reported problem associated with use of both diaphragms and gel.
Messiness or excessive wetness has frequently been cited as a drawback of some of the gels, and could be part of the problem with poor adherence in a number of the studies.
“Not surprisingly, gels increase lubrication” said the key note speaker on acceptability studies, Professor Joanne Mantell, a public health and social scientist from Columbia University, “but preferences regarding lubrication vary. Some studies show that women do not like a product that is too messy or drippy, although it is difficult to know what the underlying meaning is of excessive vaginal fluids.”
In fact, in the Brazilian study on delivery systems, “without meaning to, we obtained some information on the gel that we were using, that just came out, we didn’t ask it specifically,” said Dr Hardy. “They said that would like to use a smaller amount each time, and that this gel should be less fluid to prevent excessive lubrication or messiness.”
It should be pointed out that most of the various microbicides in advanced studies have specifically been designed to be less messy. Even so, the lubrication does not go unnoticed — including often, by the male partner. According to a comment made during one discussion of acceptance, regular male partner’s can tell “when something is different down there.”
While lubrication may be desirable for sex in Western society, in some African cultures, men prefer dry sex. Male partners may interpret too much lubrication, especially before sexual intercourse, as meaning that the woman is unfaithful, has an sexually transmitted infection or has poor vaginal hygiene. Several studies noted that regular male partners are occasionally problem for adherence in some studies — particularly if they were not informed of the woman’s participation or involved in the study from early on. (LINK)
But the acceptability or adherence problems in these studies could also simply be due to logistics, e.g., having access to and being able to insert the gel before sex occurs could be the issue. Several studies noted that storage and disposal of gel applicators and privacy needed to assemble the applicator and apply the gel in advance of sexual activity can be problematic in resource limited settings.
Product adherence in clinical trials is generally higher than when products are on the market, so getting to the bottom of these problems is crucial in order to anticipate problems in up-take and adherence that could occur and actually be worse once an effective product goes to market.
On-microbicide analyses
Such adaptability over the course of the study may overcome the adherence challenges faced in these studies — but in case it doesn’t always work, performing on treatment or on-adherence analyses could salvage the ability of these studies to determine whether the microbicides are effective in the subset of women who actually use the products.
But since self-reports are not always reliable, some of the studies are looking for more concrete evidence that the products have been used. In the MDP301 study they are looking at gel returns after a pilot study found that, if asked, women will return virtually all their used and unused applicators. This practice also allows the pharmacy staff to flag the participants whose gel use is low, who then receive intensive counselling to achieve overall higher gel adherence.
Counselling messages
One of the reasons why there is usually higher product use is because of high levels of staff support and the desire to please staff. But another possibility is that the staff counselling participants in the studies could be communicating the mixed messages about using the microbicides.
Although there’s only been a limited number of studies looking at the role of providers (from doctors to counsellors who are providing safe sex counselling), they’ve found that “providers say that they are reluctant to counsel people to use a ‘half-safe method’ especially when condoms offer a higher level of protection. The concept of harm reduction has not been incorporated into sexual risk reduction counselling in most settings, especially among family planning providers, who typically aim to promote the most effective contraceptive methods,” Prof Mantell said.
Preliminary indications are that this could at least be part of the problem. According to Dr. Karem, in HPTN 035, “the team’s initial exploration suggests that there may have been some misunderstanding of counselling messages among study staff and participants. So we’re looking at how to address this challenge and refine the kinds of messages that might be used to improve adherence to gel. Over the weekend before the conference, the protocol team got together to develop enhanced adherence counselling messages and scripts for immediate use at all the sites.”
Likewise, in the MIRA diaphragm study, they are focusing on the study staff, conducting in-person meetings trying to reinforce the importance of using the gel. They discuss how staff should respond to a patient who reports that either she or her partner does not want to use some/all products, stressing the importance of use for study results with role-playing and so on.
The proof is in the put-in
In the Carraguard study, however, they were concerned that an opened applicator may not necessarily have been inserted and used, so they developed to distinguish applicators that have been inserted into the vagina. The method uses a safe food dye powder used in the manufacture of chocolate that turns the applicator tip blue if it has been exposed to vaginal mucous — and can be easily and successfully performed by technicians at all the trial sites. The system does have limitations — sex may not have actually occurred afterwards or it may not have been the actual trial participant.
Said Dr Johansson, “we have developed a way of testing whether an applicator has been inserted into the vagina or not. We don’t know in whose vagina but we know if its been used.”
See Overview article.
Mantell J. Acceptabilityresearch: Outcomes & future direction. Microbicides 2006 Conference, Cape Town, key note address #1, 2006.
Manickum S et al. Challenges in introducing vaginal diaphragm among women in a phase lll HIV prevention clinical trial. Microbicides 2006 Conference, Cape Town, PB44, 2006.
Hebling EM, Hardy E, De Sousa MH. Devices for the administration of a vaginal microbicide: suggestions on how to make three devices more attractive. Microbicides 2006 Conference, Cape Town, OC6, 2006.
Hardy E, Hebling EM, De Sousa MH. Devices for the administration of a vaginal microbicide: use difficulties, adherence to use and preferred device. Microbicides 2006 Conference, Cape Town, PC23, 2006.
Kilbourne-Brook M et al. SILCS Diaphragm: acceptability of a single-size, reusable cervical barrier by couples in three countries. Microbicides 2006 Conference, Cape Town, PC33, 2006.
Wandiembe SP et al. Potential barriers to adherence to product use and cohort retention in microbicides efficacy trials. Microbicides 2006 Conference, Cape Town, OB9, 2006.
Kaganson N et al. Gel returns during phase III trials. Microbicides 2006 Conference, Cape Town, OB11, 2006.
Govender S. Evaluation of Microbicide Applicators to Determine Vaginal Use in the CarraguardTM Phase 3 Clinical Trial. Microbicides 2006 Conference, Cape Town, OB12, 2006.
Legardy-Williams J et al. Attitudes and Beliefs about Vaginal Cleansing among Women, Men, and Healthcare Providers in Antananarivo, Madagascar. Microbicides 2006 Conference, Cape Town, OC19, 2006.