UNAIDS N-9 Data Under WHO, Industry Analyses

Condom manufacturers Ansell Healthcare and Carter-Wallace are standing by the inclusion of nonoxynol-9 as a spermicide in their products.

Despite the recent UNAIDS findings that N-9 is less effective than placebo in preventing HIV transmission, both companies plan to continue marketing condoms with the ingredient.

Ansell, manufacturer of Lifestyles condoms, will continue to offer condoms with and without N-9 as a spermicide. "The use of a condom with or without nonoxynol-9 remains the most effective prevention against the spread of sexually transmitted diseases including AIDS," the company said.

Carter-Wallace, the maker of Trojan condoms, suggested the UNAIDS study "has no scientific relevance to the use of nonoxynol-9 with condoms in the [U.S.]."

The firm said it had "not had the opportunity to review the new research...and therefore cannot fully comment on the validity of the study protocol or its conclusions." However, Carter-Wallace noted the N-9 doses tested in the COL-1492 study were significantly higher than "typical condoms containing a spermicidal lubricant."

"In addition, the study population, involving prostitutes who use nonoxynol-9 up to 20 times a day, is hardly reflective of typical use," the company observed.

The World Health Organization plans to host a conference at the end of 2000 or in early 2001 on the safety of N-9 as a spermicide or family planning method. The meeting, which likely will take place in Geneva, Switzerland, is being organized by WHO's Tim Farley, PhD.

Plans for the event follow the release of UNAIDS study results in July at the XIII International AIDS Conference indicating Columbia Labs' COL-1492 (Advantage-S), containing 52.5 mg of N-9, was significantly less effective than a placebo gel (Columbia's Replens) in preventing transmission of HIV when used by a cohort of sex workers (¹ (Also see "Nonoxynol-9 Spermicides May Need Review After Clinical Trial Results" - Pink Sheet, 17 Jul, 2000.)).

The upcoming conference will convene following complete analysis of the COL-1492 trial results.

Pending data could shed more light on the question of N-9 efficacy. Results of a USAIDS-funded Phase III study of N-9, led by Family Health International's Ron Roddy, PhD, are expected at the end of September.

The Centers for Disease Control & Prevention also has taken steps to address the issue of whether to continue N-9 use. In an Aug. 4 "Dear Colleague" letter, CDC said it would reevaluate its prevention guidelines, including correct condom use to prevent HIV/STDs as well as pregnancy, in light of the UNAIDS data (² (Also see "N-9 Study Results Lead CDC To Reevaluate HIV Prevention Guidelines" - Pink Sheet, 21 Aug, 2000.)).

Officials from the microbicide development community anticipate further movement away from research on N-9 products and movement toward new categories of microbicide products.

For example, Eastern Virginia Medical School's Contraceptive Research & Development Program, funded primarily by the U.S. Agency for International Development, has suspended development of new and existing N-9 products. In July, CONRAD received a $25 mil. donation from the Bill & Melinda Gates Foundation (Seattle) for microbicide research.

According to Alan Stone, PhD, chairman of the International Working Group on Microbicides, there are about six non-N-9 microbicidal products under development that are considered most promising because they have been shown to be active against HIV and HIV-infected cells in the lab and have proven non-irritating, even at high doses.

Examples of anti-HIV microbicides that have successfully undergone safety trials and are moving forward into larger clinical trials include PRO2000 Gel (naphthalene sulphonate oligomer), developed by Procept; Emmelle (dextrin-2-sulphate); and PC515 (carrageenan), a seaweed extract.

Most recently, Lexington, Mass.-based Interneuron Pharmaceuticals announced HIV-infected study subjects are being enrolled into a Phase I/II safety study of PRO2000 Gel. The trial, sponsored by the National Institute of Allergy & Infectious Diseases, was initiated in July 1999.

The NIAID two-part study aims to examine the safety of the ingredient's repeated application initially in HIV-negative sexually active women and subsequently in sexually abstinent, HIV-infected women.

The trial expects to enroll 12 HIV-positive patients by October. Initial data from approximately 50 HIV-negative women examined in the first phase of the study indicate PRO2000 is well-tolerated and does not cause mucosal lesions.

The study is being carried out at the University of Pennsylvania, Brown University-affiliated hospitals in Providence, R.I., the Center for Epidemiology Research of South Africa in Durban and the Chris Hani Baragwanath Hospital in Johannesburg.

Interneuron said Aug. 17 that "PRO2000 Gel is a leading candidate for testing in future clinical trials to assess the long-term safety and protective efficacy of the product." The ingredient also will be studied in a Phase II clinical trial to be funded by the European Union and conducted in Africa.

In an editorial slated to be published in the International Planned Parenthood Federation's August Bulletin, IWGM chairman Stone emphasizes that caution must be used in planning further studies of surfactant microbicides, especially in the case of spermicides that contain high doses of N-9.

Stone indicates the increased HIV infection seen in the N-9 arm of the UNAIDS study likely is due to the elevated occurrence of mucosal lesions observed in that group, which he believes were almost definitely caused by the microbicide.

He also believes new condoms probably ought not to be developed using N-9 as a spermicidal lubricant, but that earlier condoms manufactured with N-9 should not be discarded. Recently retired from the U.K. Medical Research Council, Stone has been in contact with major condom manufacturers about the issue and awaits their responses.

The National Institute of Child Health & Human Development shortly will release a request for applications in the area of microbicide development. The institute hopes to award the grants in the next year.

The initiative, led by NICHD, is a joint endeavor with NIAID and the NIH Office of AIDS Research. The project aims to encourage researchers who have novel ideas for microbicidal agents needing work on development, such as preclinical testing and formulation.

While grants targeting N-9 microbicidal products will not be encouraged explicitly in the RFA, it is possible NICHD could fund grants to develop products with a new formulation of N-9 that may be less irritating and more effective.