World-wide, many new potential microbicides are being tested in clinical trials; their effect on the genital epithelium is an important safety outcome. The interpretation and documentation of epithelial findings should be standardized to optimize the validity of these trials.
PHOTO ATLAS FOR MICROBICIDE EVALUATION
The Photo Atlas for Microbicide Evaluation1,2 describes the wide spectrum of epithelial appearances found during clinical examination and colposcopy in microbicide clinical trials. It can be used as a reference document or for training purposes. More than 3000 copies have been distributed at international conferences and by mail. The 6 x 9-inch booklet containing 88 pages and the CD-ROM version are available upon request.
The Photo Atlas starts with a comprehensive review of male and female genital anatomy with drawings and photographs. This is followed by a step-by-step guide to procedures for the clinical examination and specimen collection of female and male study participants. The evaluation of cervical mucus and vaginal discharge are discussed in relation to the menstrual cycle, and photographs are shown of normal variation. The documentation section describes how to describe and characterize lesions, and sample case record forms are provided. More than 90 photographs are shown with their description and coding in the photography section.
During routine examination in microbicide trials, colposcopy is usually performed without the application of 3% acetic acid, thereby making it difficult to distinguish between normal and dysplastic epithelium. However, women are usually screened for the presence of cervical dysplasia, and a normal Pap smear result is often an eligibility criterion for enrollment in microbicide safety studies.
Epithelial findings seen during colposcopy include normal variations related to age or parity. Such findings need to be recognized to ensure that they are not misinterpreted as potentially clinically significant findings or lesions. The interpretation of cervical findings is especially challenging because the appearance of the transformation zone may show considerable variation. Normal variation may be misinterpreted and can result in an overestimated prevalence of cervical lesions, resulting in biased study results. For example, ectopy could be misinterpreted as erythema and Nabothian cysts could be misinterpreted as papules (Fig. 1).
An ongoing microbicide safety study in Thailand3 is investigating the frequency of lesion types that are not seen by naked-eye examination, but are identified by colposcopy. This investigation may provide an insight into the significance of lesions first identified by colposcopy and the added value of performing colposcopy in the safety evaluation of candidate microbicides.
The colposcopy manual from the Contraceptive Research and Development Program (CONRAD) and the World Health Organization in 20004 recommends recording the number of findings, their location, size, and types, and whether they persist or progress. The types of finding are defined by the status of the epithelium and blood vessels. Lesions with epithelial disruption, e.g. abrasions and ulcers, are most likely to enhance HIV acquisition5 and transmission6 and are therefore especially important to report. However, lesions with intact epithelium are frequently identified and their clinical significance is not well established. The descriptive coding of lesions by the integrity of epithelium and blood vessels does not distinguish between a substantial number of lesions with intact epithelium (see Table 1). Photographing lesions is an important part of the documentation process and will provide material for training and quality assurance.
The additional coding of lesion types facilitates the categorization of lesions. First of all, some lesions may appear to have a higher likelihood of facilitating HIV acquisition or transmission than others. Second, lesions might be caused by a sexually transmitted infection (STI), such as vesicles and condylomata, and may be important in the evaluation of the effect of microbicides on STI acquisition. Third, epithelium may become disrupted over the natural history of the lesion, as could occur with vesicles or papules (Fig. 2), thereby increasing the risk of HIV acquisition and transmission. Fourth, the significance of some findings in HIV acquisition or transmission remains unclear, for example petechial hemorrhage of the cervix (Fig. 3). Finally, the additional coding of lesion types enables the categorization of clinically relevant lesions after trial completion, as more knowledge about the significance of lesions may become available.
In addition, the coding of blood (Fig. 4), slough, and crust (Fig. 5) on the surface of genital ulcers, may provide helpful information in describing them.
The interobserver variation of the interpretation and documentation of genital lesions may bias study results, which could be reduced by conducting regular training sessions during the study, thereby improving quality assurance. However, interobserver variation will probably not bias study results if study staff examine a similar number of participants across study groups.
NOISE OR SIGNAL
Findings cannot be interpreted as related or unrelated to product use during clinical examination,4 but can only be interpreted as abnormal or normal. An abnormal finding is not necessarily caused by the use of a product, but could be related to sexual activity or tampon use.7 The correlation of genital lesions with product use will be evaluated after the trial by comparing incident lesions between the candidate microbicide and placebo groups. Adding a third group of women using no product to the design of a relatively small microbicide safety study may provide an insight into whether the placebo is facilitating or preventing the occurrence of genital lesions.
Efforts will continue to standardize colposcopy8 until more accurate methods become available to assess the safety of candidate microbicides. An updated edition of the Photo Atlas could include photographs of genital lesions from participants residing in other parts of the world that could provide a wider variety of lesions. In addition, photographs of conditions caused by STIs could provide guidance for interpretation and documentation. Also, including photographs of neoplastic lesions that warrant referral for evaluation might be useful. Furthermore, an electronic version or supplement of an updated Photo Atlas could include a self-administered test to estimate the interobserver variation among clinicians performing colposcopy, which could be used as a quality indicator for assessing safety in microbicide clinical trials.
This research was supported in part by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention, National Center for HIV, STD and TB Prevention administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the CDC.
1. Bollen LJM, Kilmarx PH, Wiwatwongwana P. Photo Atlas
for Microbicide Evaluation. Bangkok: Thailand MOPH - U.S. CDC Collaboration; 2002.
2. Alliance for Microbicides Development.
3. McLean C, Kilmarx PH, Van De Wijgert J, et al. Clinical trial of microbicide safety and acceptability among HIV-infected women in northern Thailand. Microbicides 2004 Conference, London, United Kingdom, March 2004 [Abstract 02577_2].
4. Contraceptive Research and Development Program (CONRAD), International Working Group on Microbicides (IWGM) and the Joint United Nations Program on HIV/AIDS (UNAIDS). Manual for the standardization of colposcopy for the evaluation of vaginal products: update 2000.
5. Arlington: CONRAD; 2000. van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet
6. Ghys PD, Fransen K, Diallo MO, et al. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in Abidjan, Côte d'Ivoire. AIDS
7. Fraser IS, Lahteenmaki P, Elomaa K, et al. Variations in vaginal epithelial surface appearance determined by colposcopic inspection in healthy, sexually active women. Human Reprod
8. World Health Organization and CONRAD. Manual for the Standardization of Colposcopy for the Evaluation of Vaginal Products. Geneva and Arlington: WHO and CONRAD, 2004 (WHO/RHR/04.02 and CONRAD/2004.1).
Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
Genital findings; microbicide clinical trials; photo atlas