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The next Phase III microbicide trials
The candidate microbicides which are now closest to publicly funded full-scale clinical trials are based on two principles, which may end up being combined in a single product.
BufferGel (produced by Reprotect LLC) is based on the observation that vaginal fluids are naturally acid, whereas seminal fluids are alkaline. HIV and other sexually transmitted infections (and also human sperm) are inhibited by the natural acidity of the vagina, so the idea of BufferGel is to maintain this (below pH 5) even in the presence of seminal fluid.
Following successful US phase I trials (Mayer) the US National Institutes of Health has sponsored preliminary international clinical trials of this product (and also PRO 2000, see below) through its HIV Prevention Trials Network. These have shown that it is at least as well tolerated as dextrin 2 sulphate and other credible candidate microbicides.
PRO 2000 (originally made by Procept but sold to Interneuron), dextrin 2 sulphate (Emmelle, made by ML Laboratories in the UK) and carrageenan (CarraGuard or PC515, backed by the New-York based Population Council) are three of the leading products in development, based on very large, stable polymers. Carrageenan is a natural product derived from seaweed; the others are also inherently easy and cheap to make.
These coat cell surfaces, preventing the binding of viruses or the entry of microbes into tissue. This activity has been confirmed in a range of laboratory studies using cell-cultures and there is evidence that PRO 2000 and dextrin 2 sulphate can protect female monkeys from vaginal infection with large quantities of HIV-related viruses (Lewis, Weber).
None of these products has the inflammatory problems that go with N9; Phase I and II clinical trials have shown that these products are all very well tolerated.
Their molecular size makes them unlikely to be absorbed into the bloodstream, which increases confidence in their safety.
Carrageenan is due to enter Phase III clinical trials during 2003 in Botswana and South Africa, sponsored by the Population Council with funding from the Bill and Melinda Gates Foundation among others (www.popcouncil.org).
In February 2002, the UK Department for International Development announced a grant of £16 million to extend previous microbicide research by the UK Medical Research Council. This is funding an international collaborative programme to take gel formulations of dextrin 2 sulphate and PRO 2000 into Phase III clinical trials. These are likely to start in 2003-2004 in Cameroon, South Africa, Tanzania, Uganda and Zambia.
Feasibility and acceptability studies
Microbicide researchers have taken a lead in addressing issues which need to be faced in all HIV prevention research but may be particularly acute when a new class of products is being assessed.
An evaluation of Carraguard trial volunteers' understanding of the information given to them, and of the voluntary nature of their participation has raised issues and provided insights that have implications well beyond microbicide research. Using focus group discussions and interviews, it was possible to identify a number of problems that trial participants had in understanding the aims of the trial, and to take action to remedy them. 'Informed consent is not a one-time event. Making informed consent meaningful requires a range of approaches and tools. Researchers must invest in ongoing assessment of the informed consent process and adapt it to meet the needs of study participants.' This also poses a challenge to the role of ethics committees (institutional review boards) which often do not play a role in trials once trial protocols have been approved (Friedland).
Another source of valuable information has come from interviewing women who did and did not choose to take part in a Phase II trial, to identify some of the factors that might determine the success of a Phase III trial in recruiting and retaining participants (de Kock).
A study within a Phase II clinical trial at two South African sites used audio computer assisted self-interview (ACASI) to ask participants if they had told the truth to interviewers. They were asked about the truth of what they had said about their behaviour and especially their use of condoms and the study products (placebo or microbicide gel) during the trial. All but 8% of the women preferred ACASI to being interviewed by a person, and more than half said they had not told a human interviewer the truth in answer to one or more of the questions they were asked. The bias of the previous direct interviews was towards understating the number of times women had sex, overstating their use of condoms, and understating the number of times they used gel without condoms (Norris Turner).
Similar evidence that participants in clinical trials don't always feel able to tell the whole truth to researchers is provided by a study of 35 women taking part in a microbicide trial in Kampala and seen on 169 occasions. Women recruited from STI clinics were excluded if they said they had never used condoms and they were also excluded if they did not use condoms consistently during a two-week run-in period before the clinical trial. Despite this selection, on two occasions, spermatozoa were detected; one women caught chlamydia and one woman became pregnant, despite all four saying they had consistently used condoms during sex (Pickering).
A review of 38 reported acceptability studies on microbicides found that most had interviewed individuals about hypothetical products, leaving significant gaps in knowledge about how couples would consider microbicides and how microbicide use might be seen in relation to other methods of contraception and/or HIV prevention. More work is needed with health care providers, key opinion leaders, couples, gay men, the married; more focus on processes - partner dynamics, sexual risk behaviour, dual protection, changes over time; 'uniform measures' (to make comparisons easier between studies); and looking at how microbicides would be promoted and integrated with other methods in 'real world' settings (Mantell).
A New York study interviewed 82 people involved in HIV/STI and/or pregnancy prevention counselling in four settings: family planning clinics, STI clinics, a hospital obstetrics/gynaecology service and AIDS service organisations. It found that while there was a lot of enthusiasm, it was based on expectations of a highly effective product. There was low awareness of and some confusion about research already carried out on N-9. When questioned about partially effective products, there was a wide variety of views as to their value (Hoffman).
Mathematical modelling has been used to assess the extent to which 'migration' from condom use to a presumed less-effective microbicide could occur, without an overall increase in the risk of HIV transmission in a population. The potential benefit of more widespread use of a less-effective method normally outweighs the risks of abandonment, by a comparatively small number of people, of a more highly effective method. This research was commissioned by the Rockefeller Foundation as part of a wider programme of support for microbicide-related policy development; there are implications for partially-effective vaccines, too (Foss).
Research on BufferGel
BufferGel had some effects on the natural microbial flora, cutting bacterial vaginosis but increasing the detectability of yeasts in the vagina. On balance, the researchers considered this more likely to be beneficial than harmful. While this paper does not discuss lactobacilli directly, the fact that lactobacilli are acid-tolerant means they should not be affected in the way that other more harmful bacteria apparently are (van de Wijgert 2001).
There are some questions about how long-acting BufferGel will be (see below).
Research on Carraguard (PC-515)
Studies in mice looking at duration of activity of Carraguard in preventing HSV-2 infection and showed it was active with no loss of effect for at least three hours. In contrast, both nonoxynol-9 and BufferGel lost activity within three hours. Carraguard was detectable in women in significant quantities up to 24 hours after application, and was bound to vaginal surfaces for at least 4 hours (Maguire).
Studies in mice also show that macrophages placed in the vagina of mice treated with Carraguard, compared to a placebo treatment, are less likely to reach their lymph-nodes. This suggests some ability to protect against infected cells as well as against free virus (Phillips).
Carraguard has been compared to methyl cellulose gel (a widely used lubricant) in controlled blinded studies involving 400 women at two sites in South Africa. Women were asked to insert 4ml of gel at least three times a week and before each act of sexual intercourse for up to 12 months. 'Signs and symptoms of genital irritation were rare in women using Carraguard or methyl cellulose placebo gel. Both gels appear safe for larger scale testing' (Coetzee).
A similar study has taken place in Thailand recruiting 165 HIV-negative women from family planning clinics and found a high level of acceptability for the gel and the applicator provided with it (Manopaiboon).
An important emerging issue in microbicide development is whether the use of microbicides can interfere with tests for sexually transmitted infections, leading to false negative results, for example, because bacteria or viruses are shielded from the antibodies used to detect them in samples. A team working on Carraguard in Thailand were able to give some preliminary reassurance that in practice such effects, while seen in some lab tests, did not seem to affect tests on clinical samples (Wasinrapee).
Researchers in South Africa asked women about their use of vaginal products in a Phase II trial and a survey for a Phase III trial in Gugulethu (near Cape Town) and Ga-Rankuwa (near Pretoria). They found that many of the women regularly wash and/or insert material into their vaginas (and almost all regularly wash their external genitalia). Reasons included cleansing (using water with or without soap, applied with a finger and/or towel), drying and/or tightening, medication, and menstrual hygiene. In particular, around 11% reported regularly cleansing their vagina before sex. In Gugulethu 63% preferred a dry/tight vagina compared to 10% in Ga-Rankuwa. 'Types of practices and preferences for vaginal lubrication vary by region and should be taken into account when studying microbicide acceptability. Educational messages should clearly state that women should not cleanse their vagina between microbicide insertion and use' (Jones).
Women in the Phase II trial were also asked about factors that might promote sharing of study gels, in the event of a larger scale trial. For example, would women accept being assigned to a 'no-gel' condom arm or seek gels from others? Results from this survey will be used in designing the Phase III trial that is planned (van de Wijgert 2002).
Researchers in Thailand have enrolled 55 heterosexual low-risk couples (out of 88 screened) in a double-blind placebo-controlled study, to generate data from men as well as women (Supawitkul, Yanpaisarn).
Research on PRO 2000
Cervico-vaginal lavage - carefully rinsing the cervix and vagina and then collecting the water for analysis - has been used to quantify the amount of PRO 2000 that remained in place, hours after administration. These tests showed how much PRO 2000 was present two hours after administration of 2g of a gel and about 12 hours after a 7th dose (7 doses in 6 days). This showed that either 0.5% or 4% PRO 2000 could achieve levels that would be protective in lab tests, 2 hours after administration.12 hours after the 7th dose, the 4% gel was also able to achieve this quite consistently. Studies of this kind are important to underpin the rationale for taking products into full-scale efficacy tests (Lacey).
Research on Emmelle (dextrin sulphate)
Dextrin sulphate gel has been assessed for safety in 80 sexually active HIV-negative women and 20 HIV-positive women. Controls (included in the 80) were 10 women who received a placebo gel and 20 women who were observed in the same way as the other women (with colposcopy and, in the UK, vaginal biopsies) but not asked to use any gel. In women using gels (with or without the microbicide) there was a higher frequency of inter-menstrual bleeding than in the group of 20 women who were simply observed. This has not yet been explained. There was no sign of any inflammation or toxicity (Low-Beer).
References
de Kock A et al. Expanded safety and acceptability (Phase II) of Carraguard™ microbicide gel trial: characterisation of participants and non-participants. XIV International AIDS Conference, Barcelona, abstract TuPeF5303, 2002.
Foss AM et al. Will shifts from condom to microbicide use increase HIV risk? Model projections. XIV International AIDS Conference, Barcelona, abstract WeOrD1319, 2002.
Hoffman S et al. What do health care providers think about microbicides? Views from five NYC agencies. XIV International AIDS Conference, Barcelona, abstract ThOrF1462, 2002.
Jones H et al. Vaginal product use by phase II microbicide trial participants in South Africa. XIV International AIDS Conference, Barcelona, abstract MoPeD3653, 2002.
Lewis M et al. Efficacy of PRO 2000 gel in a macaque model for vaginal HIV transmission. 8th Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 721, 2001.
Low-Beer N et al. A safety study of dextrin sulphate gel as a novel vaginal microbicide: data from HIV negative and positive women. XIV International AIDS Conference, Barcelona, abstract WeOrD1317, 2002.
Manopaiboon C et al. A year-long, randomized, controlled clinical trial of a carrageenan gel as a vaginal microbicide: Acceptability of gel and applicator use. XIV International AIDS Conference, Barcelona, abstract MoPeD3698, 2002.
Mantell JE et al. Improving the assessment of microbicide acceptability. XIV International AIDS Conference, Barcelona, abstract ThOrF1463, 2002.
Mayer K et al. Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States. Clinical Infectious Diseases 32: 476-482, 2001.
Norris Turner A et al. Telling the truth in microbicide trials: using audio computer assisted self-interview (ACASI) to assess the accuracy of self-reported behavioral data in a Phase II clinical trial. XIV International AIDS Conference, Barcelona, abstract LbPeC9028, 2002.
Phillips D. Carraguard™ prevents macrophage migration from the vaginal vault. XIV International AIDS Conference, Barcelona, published abstract F11893, 2002.
Pickering JM et al. Data on compliance with condom use in a cohort of women recruited into a Phase II Microbicide trial in urban Uganda. XIV International AIDS Conference, Barcelona, abstract MoPeD3646, 2002
Stafford M et al. A placebo-controlled, double-blind prospective study in healthy female volunteers of dextrin sulphate gel: a novel potential intravaginal virucide. Journal of AIDS 14: 213-218, 1997.
Supawitkul S et al. What about men? Enrolment characteristics and follow-up rates in a clinical trial of carrageenan microbicide gel use among heterosexual couples. XIV International AIDS Conference, Barcelona, published abstract D11309, 2002.
van de Wijgert J et al. Phase I trial of the topical microbicide BufferGel: safety results from four international sites. Journal of Acquired Immune Deficiency Syndromes 26: 21-27, 2001.
van de Wijgert JHH et al. Phase II microbicide trial participants' opinions about phase III trial methodology. XIV International AIDS Conference, Barcelona, abstract TuPeC4836, 2002.
Wasinrapee P et al. Do topical microbicides interfer with Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (NG) testing? XIV International AIDS Conference, Barcelona, abstract TuPeC4880, 2002.
Yanpaisarn S et al. Who knows what guys like? Gel and condom use in a clinical trial of a carrageenan microbicide gel among heterosexual couples. XIV International AIDS Conference, Barcelona, published abstract D11310, 2002.