Promising microbicides

Third World women's hope against infection by the human immunodeficiency virus may lie in emerging prevention methods such as the use of microbicides. But the research into them is severely underfunded.

THERE is some good news for women who face the risk of human immunodeficiency virus (HIV) infection. With several microbicides - which when applied locally can kill, neutralise or block HIV and other sexually transmitted diseases (STDs) - into final stages of trial or nearing release, women need no longer negotiate the use of protectives such as condoms. Unlike a condom, which must be worn by her partner, the microbicide - in the form of gels, creams, lubricants or even a ring, which gradually release the active ingredient - is used by the woman, who is biologically and sociologically more vulnerable to contracting HIV infection.

For many women, the most common HIV risk factor is being married. According to Pamela Norick, legislative and policy consultant with the International Health Development (IHD), Washington D.C., marriage is becoming a social hazard in India, where women can neither refuse sex nor demand protection. The same holds true for most of the world's women, who have little or no control over when or with whom they have sex. Citing World Health Organisation (WHO) statistics, she says that men are eight times more likely to transmit the virus than women, although the reverse is true when it comes to contracting the infection.

Addressing a group of 12 journalists from developing countries attending a seminar on reproductive health organised by the Population Reference Bureau in Washington D.C. in May, Norick said: "Forced to leave sexual decision-making to men, women are unable to negotiate condom use due to various factors, including violence, coercion and economic dependence. While gender-biased social norms often encourage men to seek multiple partners, women bear the burden of shame and stigma associated with the infection."

In this context, experts agree that prevention strategies that focus on abstinence, mutual fidelity and male condom use are meaningless for many Indian women. Women's hope may lie in emerging prevention methods such as use of microbicides, female condoms and cervical barriers.

How do microbicides work?

Microbicides kill or immobilise sexually transmitted infectious (STI) pathogens, form a barrier between the pathogen and the vaginal or rectal tissue, block the infection early on, prevent the pathogen from replicating once it has entered the cells, and boost the vaginal defence system. Norick says that microbicides protect both partners and that some can even prevent pregnancy. Most of them will eventually become available across the counter and inexpensively too.

"Six microbicidal products that scientists believe can effectively prevent the transmission of HIV are in advanced stages of being tested," says Norick. According to her, the products are undergoing efficacy testing in developing countries such as Botswana and India, where there is high HIV prevalence. But their availability across the counter would depend on the results of the efficacy tests. "Each product must undergo rigorous testing in both the laboratory and human clinical trials, to adhere to the guidelines set by the drug regulatory authorities, international and national. "If a reasonable level of effectiveness is documented in the large effectiveness trials now under way, the first microbicide may reach the market in the next three to five years," she adds.

The typical phase of effectiveness testing is about three and a half years and costs some $45 million. It involves 300 to 30,000 people.Norick also believes that the introduction of microbicides can have a major public health impact. "A microbicide with 60 per cent efficacy introduced in 73 low-income countries can avert 2.5 million HIV infections over three years in women, men and infants. This would lower the incidence rate of HIV with subsequent productivity benefits and large savings in health care costs," she says.

A potent vaccine for HIV/AIDS is still some time away, and the cocktail of antiretroviral (ARV) drugs remains comparatively expensive for the affected, largely poor. Thus there is a desperate need for alternatives, especially for women, among whom HIV infection is rising sharply in Africa and Asia.

The announcement by British scientists of trials in Africa of two gels has raised the hope that women will soon have a product to protect themselves from HIV infection. The United Kingdom's Department for International Development (DFID) is providing up to $23.5 million over five years for the microbicide development project. Clinical trials involving around 12,000 women in South Africa, Zambia, Tanzania, Uganda and Cameroon are to be taken up over the next three years. According to the DFID, if successful, the products would hit the market before 2010.

Microbicides are not the only method to stem the spread of HIV. According to Norick, no one strategy can be the magic bullet to kill the HIV virus. The most effective approach to combating HIV globally is to employ a combination of strategies that have the potential to prevent transmission, broaden coverage, and tighten the collective grip on the AIDS epidemic. "However, microbicides could be an integral part of this strategy," she says.

AND indeed, much is happening in the research and development of microbicides. For instance, one big hope is the seaweed-based microbicide - Carraguard, an initiative of the New York-based Population Council, an affiliate of the Rockefeller Foundation, which has given a grant of $20 million for microbicide research. Carraguard is made from carrageenan, a carbohydrate gel derived from seaweeds growing along the coasts of Chile and Nova Scotia (Canada). Carraguard is undergoing clinical trials.

Currently, 60 microbicides are in different stages of development across the globe. There are 14 microbicide product leads in the pre-clinical phase. Six product leads - cellulose sulphate, PMPA, PSS, CSIG, Acidiform, and DS - have completed phase I (initial safety trials). Three products - Carraguard, Lactobacillus crispatus, and PRO 2000 - have completed phase II (rigorous demonstration of efficacy and safety) trials. They have to go through phase IIIA (conducted on target population), phase IIIB (quality of life and marketing issues) and phase IV (post-marketing experiences of the target population) trials, according to Dr. Gita Ramjee of the Medical Research Council in Durban, South Africa.

Only two products have undergone large-scale phase III trials until now - both are Nonoxynol-9 based products, Conceptrol and Advantage 24. But the trials had to be given up because besides killing sperm and viruses, N-9 also killed vaginal wall cells and caused ulcerations, opening up an entry point for HIV. These trials were disappointing primarily because they were largely held in the sex workers' community (where the frequency of sexual intercourse is high) and lesions once formed inside the vagina can take two or three days to heal.

Among the more promising products, according to the Global Campaign for Microbicides (an amalgam of research institutions, pharma companies, governments and researchers interested in microbicide development), are Buffergel from Reprolect of Baltimore; Pro 2000 from Interneuron Pharma; Cellulose Sulphate from Polydex Pharmaceuticals; and Carraguard from the Population Council.

According to Norick, the cost of phase III clinical trials (in which stage several microbicides are), which must cover a large test population, can go up to $46 million, which incidentally, exceeds the U.S. government's total budget for microbicide research.

In India, phase I and II trials of Praneem, the neem-based poly-herbal microbicide being developed by the Pune-based National AIDS Research Institute (NARI), have shown encouraging results. According to Dr. Sanjay M. Mehendale, Deputy Director, NARI, Praneem has proved to be very effective in in-vitro studies and it is now being tested on high-risk groups and the general population. Subject to its viability, the microbicide could be available to Indian women in six or seven years. Buffer Gel, Pro 2000 and Carraguard are into phase III multi-centric trials in India.

The slow progress in microbicides is attributed to the lack of interest from drug majors, which do not see them as money-spinners and are hence not allocating funds for research. Microbicides are a public health good; its social benefits are high but economic incentive to private investment at this stage appears low. "Therefore," says Norick, "public funding is the best hope for now."

However, while the cost of developing a first-generation microbicide (with a global market size of $900 million by 2011) would have to be borne by public sector funding, an analysis by the Rockefeller Foundation suggests that the second-generation product could get to the market without public sector subsidy. And because of the increasing market size and the declining development cost, the third generation products may offer potential for significant returns - estimated at over $428 million (with sales of over $1.8 billion by 2020). "Of course," the Rockefeller Foundation report "Mobilisation for Microbicides" observes, "the real challenge is to mobilise interest around something that does not exist but has the potential to bring in high returns."

The National Institute of Health (NIH), the leading health-research funding agency in the U.S., has developed a strategic plan for the development of microbicides. The NIH's Fulvia Veronese, who was in India to attend an International AIDS conference in Chennai, said that with HIV vaccines still some time away, the growing involvement of the Rockefeller Foundation, the Melinda and Gates Foundation, USAID and the Global Microbicide Concerns augured well for accelerated development of a microbicide. Commendable is the effort of the International Working Group on Microbicides to get various key players - from the WHO to such local agencies as the AIDS Resource Centre at Dr. MGR Medical University in Chennai - involved.

The Global Campaign for Microbicides has mobilised $40 million in the past two years for research on microbicides. Persistent efforts by the Global Campaign for Microbicides have brought in 35 biotech companies, 44 non-profit research institutions and four public sector entities into the field.

The Global Campaign for Microbicides has involved stakeholders and policy-makers in discussions to get a major programme going in India. The Indian Council of Medical Research (ICMR) has a task force on microbicides. In terms of research, NARI, the ICMR's apex body on HIV/AIDS research, is actively involved in basic pre-clinical and clinical research trials of microbicide candidates. Other research institutions such as the NIPER (National Institute of Pharmacological Education and Research, Chandigarh) and the IRR (Institute for Research in Reproduction, Mumbai) are developing microbicide candidates for pre-clinical and clinical trials and are also participating in clinical trials.

According to Jayanti Pramanik of the IRR, trials of 6 per cent cellulose sulphate, a microbicide candidate product, are under way. Dr. K.V.R. Reddy, Head of Immunology at the IRR, is researching a possible microbicide candidate, Magainin-A (Mag-A), which has proven to be an effective contraceptive in pre-clinical animal-model studies. It also provides protection against most prevalent STI pathogens.

Dr. Alka Garg from the University Institute of Pharmaceutical Sciences, Punjab University, is conducting laboratory research with sulphonated hesperidin, a bioflavonoid found abundantly in the citrus species. It has a broad spectrum of anti-microbial activity, being an effective inhibitor of HIV, HSV-2, gonorrhoea and Chlamydia. It could also be a contraceptive as it inhibits the functional activity of sperm.

Acceptability studies by institutions, including NARI and the Delhi-based Programme for Appropriate Technology in Health (PATH), of microbicides in India show that people are interested and willing to use them.

People who have had the opportunity to use microbicides in trials have predominantly reported positive experiences. According to a study conducted in Tamil Nadu's Namakkal district by Dr. N. M. Samuel of the Experimental Medicine and AIDS Resource Centre of the Dr. MGR Medical University, 91 per cent of the women interviewed said they would use microbicides. According to a Women's Feature Service report, 60 per cent of the women interviewed in Chennai expressed their willingness to use a vaginal product to protect themselves from the infection.

The issue of the ethics of microbicide research and development, as in other medical trials, is often tricky and controversial. According to Dr. Gita Ramjee, in a microbicide - COL 1492 - multi-site study of 477 sex workers, several ethical concerns came to the fore, including the exclusion of some HIV-positive women from the study, lack of care and support to HIV seroconverters (those testing positive during the course of the trial), and the process of obtaining informed consent. According to her, informed consent is an ongoing process and there is a pressing need for repeated verification, monitoring (by independent agencies), and reiteration at every available opportunity. Sensitivity to cultural and moral values and the building of mutually respectful relationships between the research community and women undergoing trials emerged as significant concerns during the COL 1492 study.

"Complex ethical issues in clinical trials," she argues, "can only be resolved if developing countries come up with their own guidelines and researchers, community, and service providers work together - and not in isolation."

Issues pertaining to ethics in clinical trials, particularly of the informed consent process, remain as debatable in India as elsewhere in the world. The key challenges include whether to provide medical treatment and care to those who test HIV positive during trials and inducement to trial participants.

The ICMR has developed comprehensive guidelines on the ethical questions, which are being followed in microbicide clinical trials. But their complete implementation is the real challenge. The larger challenge, of course, is to ensure that the voices of the poor and vulnerable women are heard as the research progresses.

Researchers and policy-makers alike regret that research on microbicides, hailed as a powerful woman-controlled method, should remain severely underfunded and politically marginalised despite its enormous scientific and public health potential.

The Rockefeller Foundation and the Population Council are directing efforts to prove to the drug majors the feasibility of microbicides and show them that they are indeed potential money-spinners. Several microbicide candidates, such as Carraguard, are expected to emerge as a commercial product in the next five years, but the process can be accelerated only if pharmaceutical companies pitch in.