Microbicide Mechanisms of Action
Clinical TrialsAntiretrovirals as microbicides: tenofovir
Partner: International Partnership for Microbicides
CONRAD, along with the International Partnership for Microbicides, has been granted a co-exclusive license in developing countries for tenofovir by Gilead Sciences. Monkey and rabbit pharmacokinetic studies were conducted prior to initiating a pharmacokinetic study in women in March, 2007. The clinical portion of this study was completed in April 2008. A male tolerance study of tenofovir gel was carried out in 2006. Clinical supplies are being manufactured under CONRAD’s supervision for a Phase IIb clinical trial in South Africa that is ongoing. For complete information on the tenofovir trial, please go to: www.caprisa.org
Antiretrovirals as microbicides: UC781
Partners: CDC and NIH
UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties, showing high potency alone and in drug combinations. CONRAD has licensed UC781 from Chemtura for development and public-sector marketing. Safety studies are underway in collaboration with CDC at Emory University in Atlanta and in Thailand. A male tolerance study was initiated by CONRAD at the California Family Health Council in Los Angeles, while a rectal safety study was launched at the University of California, Los Angeles, and a pharmacokinetic study which was conducted at the University of Pittsburgh.
Enhancing the predictive power of preclinical evaluation of microbicide efficacy
An improved rabbit vaginal irritation model that provides information on the proinflammatory potential of microbicide candidates has been developed. In combination with in vitro tests, this model has enhanced the predictive power of preclinical evaluation.
New markers of mucosal inflammation have been identified and assessed in preclinical studies and are currently being validated in clinical trials. Development of low-dose, multiple-challenge SHIV and high-dose RT-SHIV vaginal infection models in monkeys is underway. Progress has also been made toward establishing small-animal models that are susceptible to HIV vaginal infection, and which will be useful for the early evaluation of microbicide efficacy.
Testing the Virucidal Qualities of Traditional Remedies
CONRAD completed a trial of intravaginal lime juice which took place in response to reports of Nigerian women applying lemon or lime juice intravaginally around the time of intercourse, due to a belief that it would protect them against HIV and other sexually transmitted infections. Preclinical data suggested that lime juice might be an active virucide, but only in high concentrations that are likely to be cytotoxic. In this prospective clinical trial, women were randomized to apply either water or lime juice (25%, 50%, or undiluted) intravaginally twice daily for two six-day intervals, separated by a three-week washout period. During one interval, they applied their product using a saturated tampon and during the other by douche, in order to simulate, as much as possible, practices in the field. Among the observations were a dose dependent pattern of symptoms, gross physical examination findings, colposcopic findings of deep epithelial disruption, and changes in some inflammatory markers that were consistent with a compromised vaginal barrier function. The largest drop in pH was about one half of a pH unit, seen one hour after douching with 100% lime juice. It was felt that this brief reduction in pH was highly unlikely to be virucidal in the presence of semen, which transports HIV. The conclusion was that lime juice is unlikely to protect against HIV and may be harmful. Results from this careful prospective clinical investigation were reported at the Microbicides 2006 meeting in South Africa in order to reach a wide audience.
The significance of the menstrual cycle on colposcopic findings on the cervix
Partner: National AIDS Research Institute of the Indian Council of Medical Research
A study that investigated the effects of the menstrual cycle on colposcopic findings on the cervix was conducted in Pune, India, in collaboration with the National AIDS Research Institute of the Indian Council of Medical Research. It showed that the mean diameter of the largest visible blood vessel differed significantly between the estrogenic and progestogenic phases, and that such changes observed during the progestogenic phase in safety studies should be considered normal.
International conference on biomarker research
Partner: Alliance for Microbicide Development
In collaboration with the Alliance for Microbicide Development, CONRAD organized a conference in November 2006 that presented the state of the art in biomarker research applied to microbicide development. Almost 100 participants from industry, academia, and non-governmental and governmental organizations discussed biomarkers of semen exposure, cervico-vaginal inflammation and HIV infection. This conference was the first of its kind and helped to identify gaps in knowledge, as well as studies and possible collaborations to resolve these gaps.
Inflammatory markers
A study of inflammatory markers in women using vaginal products was begun at two sites. Women are being randomized to use 14 days of twice-daily applications of a hydroxyethylcellulose-based “universal” placebo, 6% cellulose sulfate, or 4% nonoxynol-9 (Conceptrol®) gel. New safety endpoints are being studied that include soluble and cellular markers of inflammation in cervico-vaginal lavage fluid, biopsy specimens, and cytobrush specimens, as well as changes in pH, vaginal microflora, colposcopic findings, histopathological measures, and antiviral activity of the CVL supernatant. The degree of correlation between different methods of clinical assessment being used in the trial will be determined, as will the degree of correlation between the results of this clinical study and the results of the preclinical assessment of the same compounds.