Dear Editor,

In their editorial (Sexually Transmitted Infections 2004;80:331-33) Kevin Fenton and Helen Ward give a positive and detailed overview of the Government's policy on chlamydia screening in England. This could have been balanced by a more critical assessment of the challenges.

The alarming rise in chlamydia rates in Sweden, where opportunistic screening has been in place nationally since 1988, should be seen as a warning about the problems of this approach. Failures in chlamydia control activities might well have contributed to these trends [1]. Experience from the USA, where annual screening in family planning clinics takes place, is mixed: chlamydia prevalence has decreased in six regions and increased in four [2].

While the first year of screening has demonstrated feasibility, the underlying problem remains: no randomised controlled trial has ever shown that opportunistic screening controls chlamydia transmission or reduces reproductive tract morbidity in women in the long term [1,3]. The United Kingdom National Screening Committee states that, “evidence from high- quality randomised trials that the screening programme is effective in reducing mortality or morbidity” is essential before a programme can be introduced (http://www.nsc.nhs.uk/). For chlamydia, the randomised trial cited to demonstrate effectiveness and justify the current programme examined a completely different approach: systematic, register-based screening [4], which the Chief Medical Officer’s advisory group on Chlamydia trachomatis rejected as being impractical [5]. The Chlamydia Screening Studies (ClaSS) project (page 342-48 in this issue) and Department of Health study will answer some operational questions but do not provide evidence of effectiveness. A randomised trial is therefore required if the large bill for opportunistic screening is not to be accompanied (as in Sweden) by persistent uncertainty about exactly what is responsible for changes in chlamydial prevalence and reproductive morbidity.

Even assuming opportunistic chlamydia screening is shown to be effective, the major challenge is ensuring comprehensive and equitable coverage. Primary care has been dealing with this issue for many years, for example in screening to reduce cardiovascular risk, where the target population are older and arguably more accessible. From January to March 2004, the ten programme areas screened 7,672 people in all non- genitourinary medicine settings. This equates to an average 3,000 tests per area per year: a level of coverage that unlikely to have a substantial impact on chlamydia transmission. Furthermore, no general practice is obliged to provide any local or national enhanced service so, if vulnerable patients from hard pressed practices in deprived areas cannot access screening in their own practice, the inverse care law will be proven once again, and inequalities in health will widen.

It is not too late for cluster-randomised trials to be incorporated into the phased roll out of screening in this country to determine the most effective strategy for chlamydia screening and provide the evidence base that is essential for any national screening programme.

References

(1). Low N. Current status of chlamydia screening in Europe. Eurosurveillance 2004;8:5.

(2). Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2002 Supplement, Chlamydia Prevalence Monitoring Project. 2003. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.

(3). Stephenson J, Hopwood J, Babiker A, Copas A, Vickers M. Recent pilot studies of chlamydia screening. Sex Transm Infect 2003;79:352.

(4). Scholes D, Stergachis A, Heidrich FE, Andrilla H, Holmes KK, Stamm WE. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med 1996;334:1362-6.

(5). CMO's Expert Advisory Group on Chlamydia trachomatis. 1998. London, Department of Health.

Dear Editor,

Ogilvie et al. have published a well-designed meta-analysis of the diagnostic accuracy of self collected vaginal specimens for human papillomavirus (HPV) detection, in which they conclude that self-sampling may be an appropriate alternative for low resource settings or in patients reluctant to undergo pelvic examinations.[1] However, we have a number of remarks on the pooled sensitivities and specificities they present.

First, it is not an optimal strategy to choose clinician-collected vaginal specimens as the reference standard to compare self-sampled specimens to, since it is the concordance of self-sampling with presence of HPV-DNA in the cervical epithelium which determines the usefulness of vaginal sampling as a screening test for cervical cancer. It would have been more accurate to assess sensitivity and specificity compared to a cervical specimen, sampled in a standardized way by a clinician, as the golden standard.

Second, if guidelines for self-sampling are made, the accuracy of HPV- detection in a single sample must be maximized. A number of factors that may affect detection of HPV have been suggested in literature and are currently under further investigation. Short term fluctuations in prevalence of HPV within the menstrual cycle have been described.[2] Hormonal fluctuations within a menstrual cycle may affect HPV detection since progesterone causes deeper exfoliation of cervical and vaginal epithelium, where HPV assemblance takes place, whereas estrogens promote exfoliation of only the superficial layers, which does not allow maturation of the parabasal cells that is required for HPV assembly and release.[3,4]

Furthermore, vaginal penetration by coitus [4] could mechanically remove HPV infected cells, as could hygienic tampon use or vaginal douching. In case of unprotected intercourse, false positive tests could result from detecting HPV-DNA from the male partner.[4] Few empirical data confirm the latter theoretical considerations so far. It has been insufficiently examined to what extent vaginal lubricants, spermicidal cream or other intimate products, or even antibiotics, which affect the vaginal micro-climate or pH, could have an impact on HPV detection.

Finally, we observed in a small study that recent vaginal infections resulted in discordance of HPV detection between vaginal and cervical samples.[5] Indeed, it is conceivable that a vaginal infection speeds up the discharge of exfoliated (HPV-infected) cervical cells, thereby shortening the period of time these cells are present in the vagina. It is clear that at least some of these factors will affect sensitivity and/or specificity of vaginal self-sampling, and it is advisable to establish their effect on accuracy of vaginal sampling before practice recommendations are made.

References

1. Ogilvie GS, Patrick DM, Schulzer M, Sellors JW, et al. Diagnostic accuracy of self collected vaginal specimens for human papillomavirus compared to clinician collected human papillomavirus specimens: a meta- analysis. Sex Transm Infect 2005;81:207-12.

2. van Ham MA, Melchers WJ, Hanselaar AG, Bekkers RL, et al. Fluctuations in prevalence of cervical human papillomavirus in women frequently sampled during a single menstrual cycle. Br J Cancer 2002;87:373-6.

3. Ferenczy A, Wright TC Jr. Anatomy and histology of the cervix. In: Kurman R, ed. Blaustein’s Pathology of the female genital tract. 5th ed. New York, NY: Springer; 2002.

4. Harper DM, Longacre MR, Noll WW, Belloni DR, Cole BF. Factors affecting the detection rate of human papillomavirus. Ann Fam Med. 2003;1:221-7.

5. Baay M, Verhoeven V, Wouters K, Lardon F, et al. The prevalence of the human papillomavirus in cervix and vagina in low-risk and high-risk populations. Scand J Infect Dis 2004; 36:456-9.

Dear Editor

Replicating methods and comparing results across studies are critical for the resolution of scientific controversies. In a recent report, Niccolai et al. demonstrated that condoms were effective in preventing chlamydia among STD clinic patients with known exposure to C. trachomatis.(1) We were pleased to see the authors apply the methodology that we first presented for estimating condom effectiveness against chlamydia and gonorrhea in 2001 (2,3) and published in the American Journal of Epidemiology last year.(4) Their findings confirm the importance of restricting the study population to persons with known STI exposure (i.e., sexual contacts of infected persons) to reduce confounding on condom effectiveness estimates against bacterial (4) and viral (5,6) infections.

By focusing their analysis on chlamydia alone, Niccolai et al. underscore the need for disease-specific estimates of condom effectiveness. Focusing on a single disease is important because, although condoms should protect against all infections transmitted via the male urethra (including gonorrhea and chlamydia) (7), other factors, such as transmission efficiency, are disease-specific and may influence the magnitude of the protective effect. We would like to clarify for the readers, however, that the methodology we described will also allow for disease-specific estimates of protection when multiple infections are evaluated among persons with known exposure. As we noted ((4), p. 243)), the key point is that infections diagnosed among study participants must be identical to those of the participants’ infected partner. (For example, the relationship between condom use and risk for gonorrhea should be assessed only among participants exposed to gonorrhea, likewise for chlamydia). Maintaining this algorithm, we combined estimates for chlamydia and gonorrhea after observing the disease-specific point estimates (0.38 and 0.47, respectively) were neither appreciably nor significantly different from each other ((4), p. 245)). Thus, application of this methodology need not be limited to a single infection.

Niccolai et al.’s study represents the most recent application of this methodology for estimating condom effectiveness among persons with known STI exposure, and, encouragingly, provides independent confirmation of the validity of this approach and of our earlier findings. This work adds to an increasing body of evidence (4,8,9) suggesting that studies confounded by important differences between consistent users and inconsistent or nonusers (e.g., degree of STI exposure) tend to underestimate the protective effect of condoms against bacterial STI. Studies limited to individuals with known STI exposure are likely to estimate the protective effect of condom use more accurately. Given that such studies can be conducted using secondary analyses of existing trial data (4,8) as well as routinely collected clinic data (1,9), we encourage investigators to adopt similar methodologies to reduce confounding when evaluating condom effectiveness.

Finally, restricting the study population to sexual contacts of infected persons likely has many applications for STI research beyond assessment of condom effectiveness. This methodology for reducing confounding also may provide clearer insight into an array of potential causative and preventive factors for STI, where studies are subject to the same sources of confounding that have plagued condom effectiveness research.

References

1. Niccolai L., Rowhani-Rahbar A, Jenkins H, et al. Condom effectiveness for prevention of Chlamydia trachomatis infection. Sex Transm Inf 2005;81:323-5.

2. Warner L, Newman D, Peterman T, et al. Uncontrolled confounding: a methodologic problem in evaluating condom effectiveness for prevention of sexually transmitted diseases. 2001 National HIV Prevention Conference, Atlanta, GA, August 12-15.

3. Warner L, Newman D, Peterman T, et al. Project RESPECT Study Group. Studying condom effectiveness for sexually transmitted disease (STD) prevention: the importance of knowing partner infection status. 2002 National STD Prevention Conference, San Diego, CA, March 4-7.

4. Warner L, Newman DR, Austin HD, et al. Condom effectiveness for reducing transmission of gonorrhea and chlamydia; the importance of assessing partner infection status. Am J Epidemiol 2004;159:242-51.

5. Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev 2001;(3):CD003255.

6. Wald A, Langenberg AG, Link K, et al. Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 2001;285:3100-6.

7. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;51(No. RR-6).

8. Warner L. Macaluso M, Austin HD, et al. Application of the case- crossover design to reduce unmeasured confounding in studies of condom effectiveness. Am J Epidemiol 2005;161:1-9.

9. Shlay J, McClung MW, Patnaik JL, et al. Comparison of sexually transmitted disease prevalence by reported level of condom use among patients attending an urban sexually transmitted disease clinic. Sex Transm Dis 2004;31:154-60.

Disclaimer: The findings and conclusions in this letter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Dear Editor,

The engaging editorial by Cassell and Low (STI 2005 Aug; 81(4):285-6) is timely and highlights a critical issue in the debate about the effectiveness of screening as an intervention for genital chlamydial infection. The authors correctly note that ecologic studies are limited in their inference but have a role to play in suggesting areas for further research. The authors hypothesize that targeting only women, inferior intervention coverage, incomplete follow-up of partners, and irregular screening frequencies have played a role in the subsequent rise of incident chlamydial infections in Sweden and elsewhere, and infer that the current efforts in England are headed for similar failure.

However, the authors fail to appreciate the time and resources required to achieve the standard alluded. What proportion of the population has to be screened, how frequently does screening need to occur within that population, and what level of follow-up for partners have been under considerable debate recently, and the authors make no suggestion as to answers to these questions.

I contend that if chlamydia screening was given the appropriate resources and commitment from the start which would guarantee sufficient levels of uptake, ensure regular screening during the principal at-risk time (adolescence to young adulthood), treat a high proportion of the most recent partners, and sustain this effort for a minimum of three years, then the direct impact of this intervention would be certainly known. Completed work soon to be published suggests that if 50% of all sexually active women aged 16-24 years were screened (coverage) at least 4 times over these years (frequency) with at least 20% of partners successfully treated (good partner follow-up), reductions in prevalence up to 75% from baseline would occur within 3 years not only in the targeted populations, but those not targeted as well (through a 'herd immunity' effect).

The government has only recently committed itself to this effort with significant resources targeted in their public health white paper (Department of Health, Nov 2004), after years of debate and discussion. It would be unwise to suggest failure for a programme that has yet to be given the commitment necessary to see it a success.