Microbicides take center stage among prospects for HIV prevention

London - Intravaginal microbicides currently represent the most promising strategy for allowing women to protect themselves against HIV transmission, according to Jonathan F. Weber, M.D., who spoke at the Annual Meeting of the European Academy of Dermatology and Venereology.

"At the moment, a vaccine able to prevent HIV infection by inducing sterilizing immunity is not even on the horizon as a clinical entity. Therefore, addressing the growing HIV epidemic mandates that we look at alternative biomedical methods for reducing an individual's risk of infection, and what is particularly needed are options that will empower women," says Dr. Weber, professor of genito-urinary medicine and communicable diseases, Imperial College School of Medicine, London.

"Condoms prevent HIV, but women have little control over their use. Considering there are about 4 million new heterosexually transmitted HIV infections per year, 50 percent of which involve women, development of a safe and effective vaginal microbicide is an invaluable HIV prevention method and an important research priority."

Ten vaginal microbicides working via one of three different mechanisms have entered clinical testing to date. Those agents act either by destroying the HIV envelope to disable the virus, blocking HIV entry into the host cell to prevent infection, or interfering with reverse transcription post cell entry. Three of those microbicides, naphthalene sulphonate (PRO 2000), cellulose sulphate and carageenan (Carraguard), have entered proof-of-efficacy phase 3 trials. The antiviral activity of all of those agents involves prevention of HIV binding to the receptor on the host cell surface.

Focus on naphthalene sulphonate

Since 1995, Dr. Weber has been involved in Britain's Microbicides Development Programme (MDP). The MDP is a consortium bringing together universities and nonprofit organizations in Britain and Africa for the purpose of developing vaginal microbicides to prevent HIV transmission. It is funded by the British government's Department for International Development through Britain's Medical Research Council and is administered by the MRC Clinical Trials United and Imperial College London. In January 2005, the MDP launched a double-blind, phase 3 study of naphthalene sulphonate.

Indevus, a Massachusetts-based biotechnology company, developed naphthalene sulphonate. Initial in vitro testing showed that it had superior activity compared with other candidate compounds against HIV-1 and HIV-2 along with activity against herpes simplex viruses, human cytomegalovirus and Chlamydia trachomatis.

Favorable results evaluating potential vaginal and penile irritation associated with an aqueous gel formulation containing up to 4 percent PRO 2000 were obtained in animal studies. In phase 1 and 2 testing involving sexually abstinent and sexually active healthy women, the PRO 2000 gel was well-tolerated and associated with good user acceptance, and it demonstrated favorable local and systemic safety with multiple dosing.

"It is important that the microbicide have activity against HIV at a concentration much lower than that which causes local inflammation, epithelial cytoxicity or depletion of lactobacilli, because integrity of the vaginal epithelial barrier and maintenance of the normal vaginal flora are thought to be important for mitigating HIV transmission risk," Dr. Weber explains.

Exposed males

Safety of exposed males has also been demonstrated in phase 1 testing. Efficacy testing in a rhesus macaque simian/HIV challenge model showed two intravaginal applications of naphthalene sulphonate gel provided in vivo protection against infection. A study in HIV-infected women showed the compound retained its activity against HIV. Other important characteristics of the compound are that it is easy to manufacture, has a reasonably long shelf life and does not adversely affect latex condoms.

Testing in Africa

The phase 3 study of naphthalene sulphonate is being conducted at eight sites in six sub-Saharan African countries. Based on initial feasibility studies that determined the regional incidence and prevalence of HIV infection, the phase 3 study has a sample size of 11,800 women. Enrolled subjects are being randomized into one of three groups to use one of two concentrations of the microbicide, 0.5 percentand 2 percent, or a placebo gel prior to intercourse. They will be followed for nine months. Participants are also receiving condoms and information on risk reduction. The trial is expected to last three or four years, and interim analyses are planned.

User-friendly depot

Research is also ongoing to develop a microbicide-impregnated vaginal ring that would provide sustained delivery.