Opportunities and challenges on the route to effective microbicides

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A plenary presentation at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco by Dr Robin Shattock from St George’s Hospital Medical School, London, UK, expressed cautious optimism about the development of microbicides. Dr Shattock reviewed recent scientific developments and set the scene for next month’s Microbicides 2004 conference in London, for which he co-chairs the Basic Science track committee.

A recurrent theme of his talk was the likely need for higher doses of active compounds to get clinical effects than was first suggested by cell culture studies. This means, among other things, that the scale of manufacturing and the costs of the final products will be bigger issues than people first hoped they might be.

Dr Shattock warned that leading candidate compounds based on 'polyanions', namely Pro 2000 and dextrin-2-sulphate (Emmelle), have only been tested in animal models against SHIVs which enter CD4+ T-cells using CXCR4 (X4) co-receptors. However, the HIV forms that first establish themselves in the body are usually those that infect macrophages, using CCR5 (R5) co-receptors. Work in cell cultures now suggests that higher doses of polyanions are needed to block infection when intermediate X4/R5 or R5 strains are used. Dr Shattock explained this in terms of electrical charge distribution on the envelope protein of the different virus strains. He called for the animal studies to be repeated, as a matter of urgency, using newer SHIV strains that include R5 versions of the V-3 loop. It wasn’t clear, though, if he would want current clinical trials to be modified, depending on the outcome.

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.

strain

A variant characterised by a specific genotype.

 

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

lymph nodes

Bean-sized structures throughout the body's lymphatic system, where immune cells congregate to fight infections. Clusters of lymph nodes are found in the underarms, the groin, and the neck.

culture

In a bacteria culture test, a sample of urine, blood, sputum or another substance is taken from the patient. The cells are put in a specific environment in a laboratory to encourage cell growth and to allow the specific type of bacteria to be identified. Culture can be used to identify the TB bacteria, but is a more complex, slow and expensive method than others.

More positively, the many different approaches to an effective microbicide offer a realistic prospect that at least something will work and could be widely available in a 6- to 12-year time frame. This should remain true, even if products currently entering clinical trials are not of public health value. The best strategy, he argued, given likely resources and capacity to run clinical trials, would be to look for 'best in class' prospects in different categories and seek to test up to five in parallel.

Apart from polyanions, large-scale clinical trials are already planned for BufferGel, which is designed to maintain vaginal acidity in a range that kills HIV (and sperm).

Dr Shattock also referred to imminent trials of Savvy (Biosyn Inc) - although the biggest of these seems to be a US trial focused on its potential use as a contraceptive. The fact that Savvy acts by disrupting membranes must raise questions, in the wake of the problems with nonoxynol-9 (discussed here on aidsmap) about its suitability for HIV prevention. That said, the safety margin claimed for Savvy is much higher than the safety margin for nonoxynol-9.

Dr Shattock’s group has pioneered the use of tissue culture systems to identify opportunities to block the earliest stages of HIV infection, particularly through vaginal sex. In recent years, such work has led to an understanding of the process which highlights the role of mobile dendritic cells and CD3+ T-cells in taking up virus which is then transferred to lymph nodes where it can infect other cells. This leads, in turn, to the use of blockers for DC-SIGN and mannose receptors as a specific approach to blocking this pathway.

Although 'explants' – tissues donated by women undergoing hysterectomies transplanted into immune-deficient mice – can help to show what might happen in normal mucosal tissues, Dr Shattock reported that even consensual penis-vagina sex commonly causes minor damage which would greatly increase the risk of HIV transmission. The risk of such damage is greater for anal sex, where the mucosal tissues are even more fragile. Globally, more women have anal sex than do men who have sex with men. Another major reason why intact vaginal tissue may not tell the whole story is the effect of infections, especially genital ulcerating diseases, and inflammation, which commonly disrupt membranes and draw in populations of cells that can be infected by HIV. Dr Shattock drew attention to a poster at the Retrovirus meeting showing that even Trichomonas, a common vaginal infection, is likely to boost the risk of HIV transmission in this way.

If products need to be effective after the virus has crossed vaginal, cervical or rectal membranes, then they may need to reach effective levels in surrounding tissues and in nearby (regional) lymph nodes.

The good news is that several antiretroviral drugs – PMPA (a version of tenofovir, Gilead) and the experimental non-nucleoside reverse transcriptase inhibitors UC781 (Biosyn, Inc) and TMC120 (Tibotec/Johnson & Johnson) – are looking very promising. It seems likely, based on what happens in cell cultures, that once taken up by vulnerable cells such drugs as UC781 can prevent HIV infection of those cells for many days.

Beyond gels, Dr Shattock reported work under way at Queens University Belfast to incorporate an NNRTI into a slow-release intravaginal ring, which a woman could insert and leave in place for a month or longer without being aware of its presence.

Dr Shattock was able to report positive preliminary findings about several other products in the pipeline, such as PSC-RANTES, which was presented at the IAS’s conference in Paris last year. Both PSC-RANTES and a topical monoclonal antibody had been shown, in separate studies, to block SHIV-162P3 infections in macaque monkeys. Cellulose acetate phthalate was also showing promise in recent animal studies. Dr Shattock welcomed and sought to encourage a trend to evaluate therapeutic products for their microbicidal potential.

Although Dr Shattock did not make the point, the distinction between a 'topical' agent and a drug which enters the body is increasingly blurred by such developments. A compound that is absorbed into the body will need to be monitored more carefully for its effects on different tissues, organs, and interactions with other drugs, than one which is not. This may make it harder to secure early non-prescription licensing for the new products, which is seen as vital for their widespread use.

Mathematical modellers at the London School of Hygiene and Tropical Medicine, led by Dr Charlotte Watts, were cited by Dr Shattock in answer to the perceived risk of replacing highly effective condoms with moderately effective microbicides. Recent work from the London School concludes that with a 50% effective microbicide, this problem is not significant unless condom use at baseline is in the region of 70%. If condom use in a population is under 20%, then people would be better off with the microbicide even if they abandoned condoms. Recent African surveys find condoms had been used for sex with regular partners on less than 7% of most recent occasions. However, this argument is unlikely to go away, as there must still be many questions about which 'populations' are of greatest importance for the transmission of HIV.

Further information

Microbicides on aidsmap

Microbicides 2004 conference site

Webcasts from the 11th Conference on Retroviruses and Opportunistic Infections

Looking forward to 2004: microbicide and ARV prevention prospects (aidsmap news)