Looking forward to 2004: microbicide and ARV prevention prospects

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Several would-be microbicides are due for large-scale clinical trials in 2004, testing two basic ideas about how to protect women from HIV through vaginal sex. More than 50 products are in the pipeline although there will never be funding to test them all fully. Increasingly, serious issues will have to be resolved concerning the process by which products are evaluated and, it is hoped, can be made available to all who need them.

Microbicides based on “sulphated polysaccharides”

The leading idea for a microbicide is now to use a gel containing a substance formed from a chain of modified sugar molecules to coat the surfaces of viral particles and/or cells and form a barrier to stop infection with viruses and bacteria. Animal studies suggest this might also block the passage of HIV-infected human cells from semen into a woman’s body. However, all of this must depend on getting the substance into the right place, in the right amounts, at the right time. This in turn depends on putting the active ingredient into a product that is acceptable both to women and their male partners.

The first and best known of these products is Carraguard, derived from seaweed, which is being developed and tested in South Africa (where full-scale trials are planned) and Thailand by the US-based not-for-profit organisation, the Population Council. Two more products – Emmelle and PRO 2000 are about to enter international trials in Africa, sponsored by the UK’s Medical Research Council. The Population Council is supported by the Bill and Melinda Gates Foundation and by USAID; the MRC by the UK’s Department for International Development. However, both will need substantially more money to complete their trials.

Microbicides for vaginal acidity

The other idea due to be tested is to neutralise the alkalinity of semen to preserve the vagina’s normal acidity, which limits the survival of HIV and other unwanted infections. A product called Buffergel is due to enter clinical trials next year (alongside PRO 2000), sponsored by the US-government funded HIV Prevention Trials Network.

Problems with trial design: whose needs come first?

Glossary

microbicide

A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

post-exposure prophylaxis (PEP)

A month-long course of antiretroviral medicines taken after exposure or possible exposure to HIV, to reduce the risk of acquiring HIV.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

For better or worse, the HPTN 035 trial has been downgraded from a three-arm Phase III trial including placebo, designed to show whether either of the products were at least moderately effective against HIV, to a large Phase II trial including a placebo and a condom-only arm likely to give only preliminary indications of effectiveness. The change was forced by the US Food and Drug Administration last summer. The FDA insisted that the study was designed to support product licensing leading to changes to the original design which added greatly to the cost and could not be delivered within available budgets.

Effects on non-HIV infections

As well as any findings on HIV, researchers will be looking to see if these products reduce rates of other sexually transmitted and other reproductive tract infections. Any such effect can only add to the usefulness of a microbicide against HIV, given the importance of other infections as a co-factor for HIV transmission. It is possible that findings of this could emerge from some of the preliminary trials, ahead of the large trials needed to measure effects on HIV transmission.

The need for a non-contraceptive microbicide

To the extent they are effective against HIV, most of these products are also likely to be contraceptive, although there are suggestions that Carraguard may not be. In any case, these microbicides are fundamentally different to the spermicide nonoxynol-9, the first product ever to be evaluated as a microbicide. Nonoxynol-9 acts as a detergent, breaking up the membranes of viral particles but also cells, which is why in the end it proved to be worse than useless against HIV.

The other crying public health need beyond having a microbicide that prevents HIV transmission, is for inexpensive and feasible methods of protecting women against HIV while allowing them to become pregnant. The ‘ABC’ prevention strategy – abstain, be faithful or use a condom – most seriously fails young married women who don’t know their own or their partner’s HIV status and want a baby even when they know their HIV status is different to their partner’s.

In Europe and North America, sperm washing and in-vitro fertilisation may be options, but these are too costly for other parts of the world.

A highly effective microbicide which targets HIV, including antiretroviral drugs and/or specific antibodies, might eventually be an alternative to sperm-washing. Products like this – some of which are soon to enter early safety trials - may also be more usable for anal sex than Carraguard, Emmelle or PRO 2000. An unanswered question about ARVs in microbicides is how much HIV testing will be needed, to avoid repeated use by HIV positive women and drug-resistance that could compromise their own or a child or a future partner’s treatment.

Antiretrovirals for HIV prevention

In the next year, three separate double-blind randomised trials – in gay men in San Francisco and Atlanta, Georgia, and in African and Asian women and men at high risk through heterosexual exposure – are supposedly due to test whether tenofovir can prevent sexual transmission of HIV.

Given the problems set out above, in relation to microbicide trials, the possibility of delays while trial sponsors, regulators, clinical investigators and ethical committees try to work out their respective positions must be a real one.

Nonetheless, once they get under way, these studies should give information on side effects of the drug, which may have been masked in combination therapy with other ARVs. Unless serious problems derail these trials, there could be major implications for sexual health services in Europe and North America and a big boost, probably in 2005, for the perceived efficacy of post-exposure prophylaxis, for which tenofovir is then likely to become the preferred option. Another important HPTN clinical trial, to launch in 2004, will evaluate short-course tenofovir as an alternative to nevirapine in preventing mother-to-baby transmission of HIV. Whether this will turn out to be good news for the company that makes it, or a major headache, will be particularly interesting to see.

Further information

Global Campaign for Microbicides

HIV Prevention Trials Network US-funded international collaborations

International Partnership for Microbicides

Microbicides 2004 conference website