This year, TAG joined the Alliance in calling upon NIH to double funding for microbicide research from its current $13 million a year level. Members of TAG accompanied the Alliance to a meeting with Dr. Anthony Fauci at the National Institute of Allergy and Infectious Diseases for this purpose. TAG has also worked to communicate the importance of this prevention strategy. In 1998 TAG sponsored a community forum in New York City with Dr. Polly Harrison from the Alliance. TAG has also pushed to have microbicide advocacy efforts featured at the National AIDS Treatment Advocates' Forum. TAG's new Antiviral Project Director, Yvette Delph, reports from a recent Washington forum.
The NIH "Microbicides 2000" conference was held in Washington, D.C., on March 13-16, 2000. The over 600 participants included 275 international registrants from 40 countries. The Office of AIDS Research (OAR) plans to publish the conference proceedings and post them on the Web (www.nih.gov/od/oar).
The 20-hour conference covered virtually the entire landscape on vaginal microbicides, from basic science and animal models to clinical trials and behavioral science. A major weakness, however, was inadequate attention to the rectal use of microbicides. There was a mere one-hour concurrent session on "non-vaginal microbicide use." No one would dispute the urgent need for women-controlled methods for the prevention of sexually transmitted infections (STIs), including HIV, and the pressing need to expedite research in this area and to get a safe, effective product on the market; however, failure to study the drugs in development for rectal use ignores the many women who practice rectal intercourse and the men who have sex with men.
Michael Gross of ABT Associates, Inc. noted that HIVNet VPS2 found a 32% prevalence of at least one act of anal intercourse in the preceding six months among 1,400 high-risk women using audiocomputer-assisted self interviewing. We have to assume that any topical vaginal microbicide that is marketed will be used rectally. Rectal safety and efficacy studies of topical microbicides should be done concurrently with vaginal studies.
Ashley T. Haase, of the University of Minnesota Medical School, looked at the early stages of SIV infection following vaginal inoculation. On Day 1, there was no evidence of viral replication. By Day 3 there was some viral replication limited to the cervix, which increased 7-fold by Day 7. By Day 12, viral replication had spread systemically except for the central nervous system (CNS). In early infection, T-cells seem to be the predominant cells supporting viral replication. Macrophages are not infected in large numbers, but they play a crucial role in priming T-cells so that they are activated and go on to become infected and replicate virus. The infection of quiescent CD4 T-cells helps to maintain an unbroken chain of transmission. Haase concluded that there may be a narrow window of opportunity after initial inoculation for preventing the systemic spread of the virus.
Ronald Roddy and Zeda Rosenberg of Family Health International provided an overview of microbicides currently in development. There are six products undergoing in vitro screening, twenty-five in rabbit vaginal irritation studies, twenty-eight in animal toxicology, about twenty in Phase I clinical trials, three in Phase II, and four in Phase III: Nonoxynol-9 (N-9) sponge, N-9 film (VCF), N-9 gel (Advantage-S and Conceptrol) as well as five completed Phase III trials since 1990.
Products in development include:
There were several reports of N-9 causing vaginal and rectal inflammation and raising concerns that such inflammation may impair the mucosal barrier function -- enhancing rather than reducing transmission of infectious organisms. Deborah Anderson of Harvard Medical School noted that daily vaginal application of Conceptrol (N-9 100mg) for three days resulted in sloughed epithelial cell sheets and a dramatic influx of polymorphonuclear cells two days after the last N-9 application. She reported findings from a study of N-9 induced cytokine release from normal vaginal and cervical epithelial cell cultures. The findings suggest that N-9 induces vaginal inflammation via IL-1a, which acts on neighboring cells to activate NF-KB, which in turn triggers the typical inflammatory cascade.
Gregg N. Milligan of Children's Hospital Medical Center (Cincinnati) used a mouse model to examine the influence of N-9 application on infiltration of inflammatory cells into the vagina. The number of white blood cells (WBCs) was four-fold greater at 4 hours and continued to increase significantly (p<0.05) by 8 hours in N-9 treated mice compared with placebo controls. Application of preparations containing 4% N-9 resulted in greater numbers of infiltrating WBCs than did preparations with lower concentrations of N-9. Up to 50% of the infiltrating WBCs were macrophages, and there was no significant increase in lymphocytes. The vaginal inflammatory response began to resolve by 24 hours after a single N-9 treatment.
David Phillips of the Population Council (New York) presented a study comparing the effects of rectal application of N-9 (KY-Plus and Foreplay) and two non-N-9 containing formulations in each of four subjects. Rectal lavages collected thirty minutes after the application of N-9 revealed sheets of epithelium. This was not seen in any of the baseline or non-N-9 lavages, nor in the lavages at 10-14 hours after N-9 application.
Connie Celum of the University of Washington also looked at the toxicity of rectal N-9 and found minimal epithelial toxicity at the 52.5 mg dose, but sampling was done several hours after N-9 insertion. This would suggest that N-9 may cause rapid mucosal exfoliation which is fully repaired within 14 hours. More studies need to be done with larger numbers of subjects.
William Donohue of the Magee-Women's Research Institute presented a poster of a study of the susceptibility of ten strains each of Lactobacillus, Neisseria gonorrhoea and Trichomonas vaginalis to thirty minutes of exposure to N-9. All ten strains of Lactobacillus and 7/10 of Neisseria survived, and all ten of Trichomonas were killed.
Several participants expressed concern about the wisdom of continuing N-9 clinical trials, especially one funded by UNAIDS, until the safety of N-9 as a microbicide has clearly been established. Echoing these concerns, Lut van Damme of the Institute of Tropical Medicine in Belgium noted that of five completed N-9 studies, two were observational studies that suggested a protective effect. However, there were three randomized, controlled trials (RCTs): one in Kenya in 1985 which showed that N-9 was harmful; one in Kenya in 1988 of STDs only, which failed to show any effect (the study was too small to analyze the effect on HIV transmission); and one in Cameroon in 1997 which showed no effect on gonococcal or chlamydial transmission. Christine Rouzouix (Hôpital Necker-Enfants Malades, France) and Robert Coombs (University of Washington) dealt with the male and female genital compartments, respectively, noting that viral load in blood plasma correlated with viral load in seminal plasma (RR = 0.56, <0.0001) and in the female genital tract (RR = 0.6, p<0.01). Steven Taylor presented a poster of a study comparing seminal antiretroviral drug concentrations with concurrent blood concentrations. Indinavir reaches concentrations in semen that are not significantly different from blood concentrations, whereas ritonavir and saquinavir seminal concentrations are <5% those in blood. Nevirapine semen levels were >60% of corresponding blood levels. Lamivudine (3TC) concentrations in semen were 5-10-fold higher than those in blood and stavudine (d4T) had similar seminal and blood concentrations -- although several patients on d4T had seminal and blood concentrations that were below the limit of detection of the assay.
Finally, some of the issues related to the design and conduct of microbicide trials included: the difficulty collecting data relating to compliance; the dilemma over whether analysis should be conducted based on compliance levels; the difficulties posed by the use of a placebo, since any product used intravaginally may have an effect and the production of placebo formulations can prove challenging; and the use of other STIs as surrogates for HIV. Some of the ethical concerns included: the effect of microbicide use on male condom use; how best and how intensely to counsel about condom use; the need to promote the use of the male condom in trials of the female condom -- although both can not be used simultaneously; the meaning and extent of informed consent; whether male partners should be asked to consent; whether and, if so, how antiretroviral therapy should be provided for women found to be HIV-positive at screening or for seroconverters; and the impact of microbicide research on research on other barrier methods (condom, diaphragm, cervical caps).
This article was written by the most recent addition to the TAG staff, Yvette Delph, who became the new Antiviral Project Director in January 2000. A medical doctor and native of the Caribbean, Yvette has worked extensively in HIV/AIDS and Women's Reproductive Health. She comes to TAG from the National Minority AIDS Council, where she was the Director of Treatment Education, Training and Advocacy. Please see www.treatmentactiongroup.org for more information on Yvette.
|Summary of Selected Papers Presented at the Microbicide 2000 Meeting|
|Focus of Study||Conclusion(s)||Author|
|Prevalence of anal intercourse among "high-risk" women (in the HIVNet VPS2 study, N=1,400)||Thirty-two percent of the women were determined to have had at least one act of anal intercourse within the preceding 6 months.||Gross M|
|Early stages of SIV replication within the vagina||In early infection, T-cells appear to be the cells which support viral replication. Systemic spread not immediate.||Haase A|
|Nonoxynol-9 induced vaginal inflammation||N-9 appears to induce vaginal inflammation via interleukin-1a, which acts on neighboring cells to activate NF-KB.||Anderson D|
|Nonoxynol-9 effect on infiltration of inflammatory white cells (study in mice)||Number of WBCs increased 4-fold at four hours compared to controls, and continued to increase.||Milligan G|
|Comparison of rectal lavage after N-9 and non-N-9 lubricants||Sheets of epithelium were observed in the two groups given the N-9 containing lubricants (KY-Plus and Foreplay) but not in those not containing N-9.||Phillips D|
|Comparison of epithelial toxicity of rectal N-9||Minimal toxicity was found at the 52.5 mg dose, but questions remain over the timing of the sampling.||Celum C|
|Susceptibility of various vaginal microbes to N-9 (Lactobacillus, Neisseria gonorrhoea, Trichomonas vaginalis)||Only the Trichomonas vaginalis were reliably killed||Donahue W|
|Review of five N-9 clinical studies||The three randomized controlled studies of the group concluded that N-9 was either harmful (Kenya 1985) or had no effect (Kenya 1988, Cameroon 1997).||van Damme L|