Invited Commentary: Condom Effectiveness—Will Prostate-specific Antigen Shed New Light on This Perplexing Problem?

Markus J. Steiner1,, Paul J. Feldblum1 and Nancy Padian2,3,4

1 Family Health International, Research Triangle Park, NC.
2 AIDS Research Institute, University of California San Francisco, San Francisco, CA.
3 Center for Reproductive Health Research and Policy, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA.
4 Department of Epidemiology and Public Health Biology, University of California Berkeley, Berkeley, CA.

Received for publication August 17, 2001; accepted for publication June 27, 2002.

Abbreviations: Abbreviations: HIV, human immunodeficiency virus; PSA, prostate-specific antigen; STI, sexually transmitted infection.


    INTRODUCTION
 TOP
 INTRODUCTION
 EVIDENCE ON CONDOM EFFECTIVENESS
 MEASUREMENT CHALLENGES
 CAN PROSTATE-SPECIFIC ANTIGEN...
 REFERENCES
 
On July 20, 2001, the US National Institutes of Health released a controversial report summarizing a federal interagency workshop on the scientific evidence for condom effectiveness in preventing eight sexually transmitted infections (STIs) (1, 2). After reviewing 180 papers, the report concluded that correct and consistent use of condoms "significantly reduced the risk of HIV [human immunodeficiency virus] infection in men and women" (1, p. ii) and "could reduce the risk of gonorrhea for men" (1, p. ii). However, for all other STIs reviewed (gonorrhea in women, chlamydial infection, syphilis, chancroid, trichomoniasis, genital herpes, and genital human papillomavirus), "there was insufficient evidence from the epidemiologic studies ... to draw definite conclusions" (1, p. ii).

Does the absence of data demonstrating a protective effect against many STIs indicate that condoms do not work? Alternatively, may this absence simply reflect the particular challenges faced by researchers attempting to measure relevant exposures and behaviors in these condom studies? We argue the latter and congratulate Lawson et al. (3) and Macaluso et al. (4) for their novel approach to improving exposure measurement in condom-effectiveness research.


    EVIDENCE ON CONDOM EFFECTIVENESS
 TOP
 INTRODUCTION
 EVIDENCE ON CONDOM EFFECTIVENESS
 MEASUREMENT CHALLENGES
 CAN PROSTATE-SPECIFIC ANTIGEN...
 REFERENCES
 
Biologic plausibility as well as in vitro data support the proposition that the condom’s latex membrane should greatly reduce transmission of HIV. Two laboratory studies testing the permeability of intact latex condoms documented only minute amounts of HIV-sized particles passing through the latex condoms tested (5, 6). One group of authors used their in vitro results to calculate that the risk of HIV transmission is reduced 10,000-fold by the use of latex condoms (6). The National Institutes of Health panel concluded that intact condoms are essentially impermeable even to the smallest sexually transmitted virus, hepatitis B (1).

Despite convincing in vitro data that condoms provide an effective barrier against STI/HIV, results from in vivo studies have been inconsistent and unpersuasive for most STIs (1). Until recently, the debate over this lack of an association has centered on the methods of collecting data on sexual behavior, including condom use (713). Zenilman et al., for example, were among the first to argue that the failure to find an association between condom use and STIs (gonorrhea, chlamydia, syphilis, and trichomoniasis) was due to the poor validity of self-reported condom use data (7) and not to condom ineffectiveness.

However, with the release of the National Institutes of Health report (1), some are using these negative studies to argue that condoms do not work. At a press conference following the release of this report, a group of physicians claimed to be exposing "the fact that condoms are ineffective in preventing transmission of most STDs [sexually transmitted diseases], thus challenging the notion of ‘safe sex’ as championed by the CDC [Centers for Disease Control and Prevention]" (2, p. 232). They went so far as to demand the resignation of then–CDC Director Dr. Jeffrey Koplan for having "deliberately" misled the US public about condom effectiveness.


    MEASUREMENT CHALLENGES
 TOP
 INTRODUCTION
 EVIDENCE ON CONDOM EFFECTIVENESS
 MEASUREMENT CHALLENGES
 CAN PROSTATE-SPECIFIC ANTIGEN...
 REFERENCES
 
Those who trumpet condom ineffectiveness on the basis of a subset of negative studies reveal naiveté about the measurement challenges inherent in condom research. The main measurement challenges are twofold: 1) the validity of condom use data, and 2) the extent of exposure to infection.

Regarding the validity of condom use information, we cannot objectively measure consistency or correctness since condom use is an inherently private act that cannot be independently observed or verified. Social desirability bias (7, 10) in many contexts may lead to overreporting of condom use and is one of many biases that threaten validity (1, 14). Even with the collection of more "objective" measures such as collecting used condoms, the likelihood of participants misrepresenting their condom use can be considerable (e.g., claiming they used the condom throughout the whole act when they used it only briefly). Unfortunately, participants sometimes go to great lengths to subvert research protocols (15). All studies involving condoms are likely to share some overreporting of condom use, a form of nondifferential misclassification that tends to bias results to the null.

Regarding measurement of exposure to infection, we need to know whether the coital acts for which we are evaluating condom use carry an actual STI risk. Recent data suggest that self-reported condom use is a marker for sex with risky partners (10, 13). Higher self-reported condom use in relationships in which the STI risk is greater than in less-risky relationships will further underestimate the true protective effect of condoms.

Study design solutions for these measurement conundrums are limited. A randomized controlled trial in which only one group is assigned condoms would minimize confounding but is ethically unacceptable. A discordant-couple cohort design that ensures that every act presumably carries the risk of exposure is possible only with incurable STIs (e.g., HIV, genital herpes). For all other STI outcomes, we need improved measurement of both condom use and exposure status.

Improvements in data collection technology hold some promise to advance the accuracy of condom use measurements. Although new approaches, such as audio computer-assisted self-administered interviewing (ACASI), for measuring self-reported behaviors have been validated in related fields with clear biologic measures of exposure (e.g., metabolites of marijuana in urine (16)), if and how well these techniques might improve validity of reported condom use remains unknown. As a result, for trials failing to find an association between condom use and STI, including HIV, poor validity of self-reported condom use will always remain a plausible explanation.

Exposure indices also appear to be of limited value in measuring associations between condom use and STI. Efforts to develop simple STI risk assessment algorithms to identify infected persons, or reliance on behavioral surrogates in STI research, have been disappointing (13, 17). After failing to validate a behavioral scoring tool by using data from the Project Respect trial (18), Peterman et al. concluded that "researchers are unlikely to have enough information to adjust for the likelihood of infection in each partner of every person in a study" (13, p. 450).


    CAN PROSTATE-SPECIFIC ANTIGEN HELP?
 TOP
 INTRODUCTION
 EVIDENCE ON CONDOM EFFECTIVENESS
 MEASUREMENT CHALLENGES
 CAN PROSTATE-SPECIFIC ANTIGEN...
 REFERENCES
 
The female condom effectiveness analyses presented in this issue of the Journal circumvent the problem of measuring partner STI transmission risk by avoiding that outcome measure altogether (3, 4). The investigators chose a biologic outcome measure, prostate-specific antigen (PSA), that is detectable by using vaginal swabs after acts of unprotected vaginal intercourse in which ejaculation occurs (19, 20). PSA levels decline sharply after intercourse and return to background levels within 48 hours (20). Thus, most unprotected sex acts result in detectable exposure to PSA.

How good a proxy measure is PSA? PSA has a lower molecular weight than HIV (30 kDa vs. 120 kDa) and is hypothesized to migrate across barriers as readily as HIV (19). However, since urethral discharge may not contain PSA, this proxy measure may be better for pregnancy than for disease outcomes (i.e., condoms put on after intercourse has started may not prevent transmission of pathogens in discharge but would prevent transmission of PSA in ejaculate).

By comparing pre- and postcoital PSA levels and using two different detection thresholds, Macaluso et al. found PSA in 7–21 percent of coital acts reportedly protected by female condom use (4). Does this mean that 7–21 percent of the female condoms permitted vaginal deposition of PSA? In addition to the arbitrariness of these chosen thresholds, this association still relies on the validity of self-reported condom use, our first measurement challenge. We cannot exclude the possibility that some exposure of ejaculate occurred during acts not protected by the female condom despite the reporting of female condom use. Partial use of the female condom (e.g., removal prior to ejaculation) may have been reported as correct use of the device. In one study (21), partial use of male condoms has been associated with gonorrhea transmission; in another study (22), it has been shown to occur in 10 percent of sex acts in which condoms were used. Moreover, as Macaluso et al. point out, "swabs may have been contaminated with semen if the instructions for collecting the postcoital samples were not followed" (4, p. 295).

A similar, but much smaller study used PSA to evaluate the effectiveness of male latex, polyurethane, and natural-membrane condoms (19). These investigators detected PSA after 6 percent (3/50; 95 percent confidence interval: 1 percent, 16 percent) of coital acts protected by male condoms; excluding the three acts in which the condom slipped off the penis, the PSA transmission risk dropped to 2 percent (1/47; 95 percent confidence interval: 0.5 percent, 11 percent). No PSA transmission was detected after the 22 uses during which the latex condoms remained on the penis (0/22; 95 percent confidence interval: 0 percent, 15 percent). Because of a lack of data from a randomized controlled trial comparing male and female condoms, no conclusions should be drawn about the relative effectiveness of male and female condoms from these two observational studies that used different approaches to assess PSA transmission (3, 4).

Two practical applications of the PSA measure could facilitate condom development and help develop strategies to increase use. First, PSA may be useful for product approval studies in which a new condom is compared with an existing marketed device (20). While current US Food and Drug Administration written guidelines for approval of condoms made from new material require phase III pregnancy outcome studies (23), recent indications from the Food and Drug Administration are that these expensive and time-consuming studies may no longer be required (Collin Pollard, Chief, OB/GYN Devices Branch, personal communication, June 20, 2002). Although certainly not a perfect proxy measure for pregnancy and disease prevention, PSA testing would have advantages over using condom breakage and slippage as the primary outcome of interest since it does not rely on self-report of an outcome that may be difficult to detect by study participants. In addition, PSA outcome studies would readily allow a cross-over design in which each participating couple would serve as their own control by using both devices. This study design would provide a valid relative outcome and would not be threatened by the various measurement challenges discussed in this commentary.

Second, PSA may be useful in intervention studies that aim to increase the use of condoms. Because of the social desirability bias, studies in which self-reported condom use is the outcome may not be compelling. Studies with STI/HIV or pregnancy as an endpoint are more convincing but require large study sizes and long follow-up to produce a sufficient number of outcomes for statistically meaningful comparisons between study arms. In cohorts in which coital frequency is high, the presence of PSA would indicate whether a woman recently had engaged in unprotected intercourse. Investigators could thus evaluate randomized intervention trials by measuring PSA prevalence.

Condoms do not work unless used correctly and consistently. The misdirected debate over their efficacy can undermine overall condom use because potential users may lose confidence in the method. Condoms are the best STI/HIV prevention approach for sexually active persons who either have infected partners or do not know their partners’ infection status. Although messages directed at youth should empha-size delaying sexual initiation, most adults are sexually active, and STIs are relatively common. Thus, aggressive condom promotion must remain a key to reducing STI/HIV.


    ACKNOWLEDGMENTS
 
Support for this work was provided with funds from US Agency for International Development (USAID) cooperative agreement AID/CCP-A-00-95-00022-02.


    NOTES
 
Correspondence to Dr. Markus J. Steiner, Family Health International, P.O. Box 13950, Research Triangle Park, NC 27709 (e-mail: msteiner{at}fhi.org). Back


    REFERENCES
 TOP
 INTRODUCTION
 EVIDENCE ON CONDOM EFFECTIVENESS
 MEASUREMENT CHALLENGES
 CAN PROSTATE-SPECIFIC ANTIGEN...
 REFERENCES
 

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Related articles in Am. J. Epidemiol.:

Partner Characteristics, Intensity of the Intercourse, and Semen Exposure During Use of the Female Condom
M. Louise Lawson, Maurizio Macaluso, Ann Duerr, Glen Hortin, Karen R. Hammond, Richard Blackwell, Lynn Artz, and Amy Bloom
Am. J. Epidemiol. 2003 157: 282-288. [Abstract] [FREE Full Text]  

Efficacy of the Female Condom as a Barrier to Semen During Intercourse
Maurizio Macaluso, M. Louise Lawson, Glen Hortin, Ann Duerr, Karen R. Hammond, Richard Blackwell, and Amy Bloom
Am. J. Epidemiol. 2003 157: 289-297. [Abstract] [FREE Full Text]  

Macaluso et al. Respond to "Condom Effectiveness and Prostate-specific Antigen"
Maurizio Macaluso, M. Louise Lawson, Ann Duerr, and Glen Hortin
Am. J. Epidemiol. 2003 157: 301-302. [Extract] [FREE Full Text]