Martin, David H. MD
First, I want to thank the American Sexually Transmitted Disease Association Awards Committee for bestowing this great honor upon me. Of critical importance to every successful academic career is outstanding mentors, and I had two. Karl Johnson, my mentor at the Middle America Research Unit in Panama beginning in 1970, guided my early research efforts that were focused on laboratory and field work with Venezuelan equine encephalitis virus. The second was King Holmes, my fellowship mentor at the University of Washington, who redirected my focus from arboviruses to sexually transmitted diseases. King taught me to think critically; covered my early papers with red ink, thus teaching me how to write scientifically; and inspired me by his exuberant enthusiasm for STI research. He has supported my career continuously over the last 3 decades. I also am indebted to those who trained with me at the University of Washington and who became supportive colleagues and friends over the years. These include Bob Jones, Bob Burnham, David Eschenbach, and the late Walter Stamm. Others with whom I have worked closely and who also came out King’s training program include Tom Quinn, Hunter Handsfield, Ned Hook, and Jeanne Marrazzo. Julie Schachter taught me much of what I know about chlamydial infections, and Charlotte Gaydos has been a wonderful consultant and colleague over the years. Finally, I want to recognize my greatest supporter, my spouse of 42 years, Jane, an expert in HIV clinical care in her own right and a former American Social Health Association board member without whom I could not have accomplished anything.
In trying to decide what to speak to you about at this meeting, I considered the diseases and organisms that I have worked on at various times over the last 35 years including Chlamydia trachomatis (CT), chancroid, Mycoplasma genitalium, and the genitourinary tract microbiome. Because STI prevention is the focus of this biannual meeting and there are no prevention programs focused on the latter three entities, I would like to focus today on the progress of the US CT prevention program (also known as the Infertility Prevention Program, or IPP) and offer some thoughts about what we might do in the future to better control this important sexually transmitted pathogen. I will review the principles of STI prevention to place the IPP program in context, and I will offer my thoughts on better approaches to CT control. I will briefly touch on CT vaccine development, and finally, I will focus on the critical importance of better sexual health education to the ultimate success of both current and future Chlamydia prevention programs.
The importance of the May and Anderson Formula (Ro = βcD) to the understanding of STI epidemiology was very well described by Bob Brunham1 in his 2005 Parran Award Lecture. Ro represents the reproductive rate of an infection in a population and correlates with changes in prevalence over time. β represents the infectivity of the organism; c, the rate of exposure to infected individuals; and D, the duration of infectivity. An understanding of the components of the formula is key to designing STI control strategies. Decreasing rates of new sex partner acquisition or “c” theoretically can be achieved through successful behavioral intervention programs. To some extent, this has occurred in the United States. The National Survey of Family Growth survey data show steadily decreasing rates of any sexual activity among adolescent boys and girls since the surveys were began in 1988.2 The infectivity of the organism, β, can be decreased through successful condom promotion programs or vaccination, but there is little evidence that the former has occurred and no vaccine candidates are yet available. Decreasing the duration of infectivity, D, is the primary approach we take to controlling STIs including CT in the United States through programs such as the IPP. The concept is that identifying those that are infected and treating them removes them from the pool of infected individuals in the population, thus decreasing the average duration of infection in the population.
Chlamydia trachomatis screening programs were not possible until the 1980s because CT, as an obligate intracellular organism, required inefficient cell culture systems for diagnosis. The first nonculture test for CT was the direct fluorescent microscopic assay using urethral and cervical secretions smeared on a slide, stained with CT-specific fluorescently labeled antibodies, and use of a fluorescent microscope to detect the tiny dots representing the elementary body form of the organism. A specialized microscope and an expert microscopist were required, but transport to the laboratory required no special conditions and results were available relatively rapidly. Using this assay, a pilot CT screening program was initiated in US Public Health Region X (the northwestern corner of the country) in 1988. The results were striking. Among 15- to 24-year-old women in family planning clinics from 1988 to 1992, CT infection rates dropped from 13% to 7%.3 Based on the results from this pilot project, Congress funded the IPP program in 1992. It was focused on family planning programs and was fully implemented nationwide by 1995. With the development of Gen-Probe’s direct CT gene probe assay, which could be automated for high-throughput testing, the Centers for Disease Control and Prevention (CDC) also began to push for increased CT testing in STI and prenatal clinics in addition to family planning clinics.
Other new tools of potential value to the CT screening and treatment program became available in the mid-1990s. The first was single-dose azithromycin for CT treatment.4,5 From a public health point of view, it was thought that directly observed single-dose treatment would significantly decrease treatment failure rates by eliminating noncompliance with multidose doxycycline therapy. The next breakthrough was the advent of nucleic acid amplification tests for CT and gonorrhea. These tests improved sensitivity of CT detection in urethral and endocervical secretions over that of culture, direct fluorescent microscopic assay, and the direct DNA probe test with specificities of 98% to 99%. Although this represented a significant advance, the truly exciting characteristic of nucleic acid amplification tests was that they retained sensitivity and specificity when used with urine and vaginal swab specimens, something that was not possible with previously available assays. For the first time, CT could be detected without the necessity of doing a pelvic examination in women and without inserting a swab into the male urethra. Urine testing, in particular, opened the door to expanded CT testing in populations not previously accessible including men and women in correctional facilities, job corps participants, military recruits, high school students, and so on.
Today, screening for CT is a thriving enterprise. In 2010, CDC reported that 130,000 men and 60,000 women were tested in US correctional facilities. In the same year, 30,000 men and 15,000 women were tested through the job corps program. According to the 2003 IPP program’s Report to Congress, 1.4 million women were screened nationwide in that year, and if anything, this program has continued to grow. Additional evidence of the successful uptake of CT screening is available from the Health Care Effectiveness Data and Information Set, a measure of health care quality in general medical clinics. Since 2000 when CT screening of sexually active women between the ages of 15 and 25 years was adapted as one of the Health Care Effectiveness Data and Information Set medical care quality measurements, screening rates of Medicaid recipients have increased steadily to more than 50% in 2008.
What have we accomplished with our steadily expanding CT screening and treatment program? Unfortunately, not much according to data published annually by the CDC.6 Since the initiation of the IPP nationally in the mid-1990s, the prevalence of CT in the family planning clients has changed little, if at all. In a recent analysis of data from the National Health and Nutrition Survey, Datta et al.7 reported that the prevalence of CT has declined in white women in the United states but not at all in African American women who have the highest rates on infection. Consequently, the average overall rate of CT infection in US women has declined relatively little. Based on these data, clearly screening efforts over the last 15 years in this country have not achieved what we had hoped for. An intriguing question is why the Region X data showed a major decrease in infection prevalence before the initiation of the national program. This is not to say that the IPP necessarily has failed; rates could be substantially higher than currently observed, but I think we can do better.
I believe that current clinic-based screening programs are missing the highest risk female population. Our work in New Orleans with high school–based CT screening programs showed that CT infection rates in African American girls in New Orleans peaked at 16 to 17 years of age, levels significantly higher than seen in the local family planning population.8 Others have confirmed these findings.9,10 Thus, there is a large reservoir of untreated women outside family planning clinics, STI clinics, correctional facilities, and job corps that are not being screened. Some of these women will eventually attend family planning clinics, so perhaps it is not surprising that CT prevalence as measured by the IPP has not changed substantially since the programs initiation. Thus, it seems self-evident that institution of school-based screening and treatment programs at least in high CT prevalence communities is a critical missing piece in the national CT prevention effort. Of course, calling for nationwide screening of high-risk high school students is easier said than done. Congress funded the IPP as a means of improving reproductive health in the US population for women self-identified as being sexually active. In the current political environment, similar support will be difficult to win for screening young women who are supposed to be celibate despite the extensive data that show that the majority are sexually experienced. Nevertheless, we should recognize the facts of the matter and push for best public health practices at all times in hopes that eventually reason will prevail.
Another problem is that we are not successfully addressing the male reservoir of infection. By far, most CT-infected males are asymptomatic and therefore do not seek screening and treatment.11 An important finding in the high school studies was that infection rates in boys lagged behind those in girls. In boys, CT prevalence rates appeared to peak in the 19- to 20-year-olds.9,12 Schillinger et al.11 reported results of screening more than 23,000 men between 1999 and 2003 in 4 US cities. The highest infection rates were in 20- to 24-year-old men. Girls choose sex partners who are on the average 2 to 3 years older than they are,13,14 which is consistent with the data showing that CT infection rates peak in women 16 to18 years of age, whereas the highest rates in men are in the 19- to 24-year-olds. Thus, the partners of CT-infected high school girls are often no longer in school and are more difficult to bring in for treatment. Moreover, high school screening programs miss a large proportion of infected males, thus leaving an untreated a reservoir for continued infection of susceptible young women. Gift et al.,15 in a recently published cost-effectiveness analysis, showed that screening and treating men in a high-risk environment would be more cost-effective than expanding current screening efforts to women in the general population. However, reaching this demographic is a difficult problem. Communities at high risk for STIs generally have high rates of incarceration among young males, and screening in correctional facilities has been demonstrated to yield high rates of CT infection.16,17 Therefore, targeting jails and juvenile detention centers in communities with school-based testing programs makes sense, and as noted above, such programs are well underway. However, even in communities such as New Orleans, which has among the highest incarceration rates among African American males in the United States, 85% of the population never has been incarcerated. Thus, innovative new approaches are needed to reach out to all young males.
Parallel screening in high schools, jails, and juvenile detention centers in high-risk communities would be a reasonable step forward but very likely will not be enough even if we offer screening to young males outside correctional facilities. The reason why is illustrated by data from a recent CDC-funded study in which we participated.18 The study was designed to test the hypothesis that the use of self-collected vaginal swabs at home directly mailed to the laboratory would result in greater numbers of CT-infected women being retested after treatment of a known infection. Women were recruited from STI and family planning clinics. In the STI clinic population, 27% of the women who were randomized to receive a self-collection vaginal swab kit returned the swabs and were tested compared with 19% of those randomized to return to the clinic for retesting, a significant improvement. Among the family planning women, 41% of the women randomized to self-collection were retested versus 21% of those randomized to clinic collection, an even higher success rate. The good news was that home testing significantly improved retesting rates, but the bad news, which I want to emphasize here, was that most women in both populations did not take advantage of the opportunity to retest themselves despite counseling at the time of treatment and repeated reminders that retesting was supposed to be done. This result starkly highlights a fundamental problem for CT prevention programs based on screening and treatment that will not be overcome by merely increasing testing opportunities. If young women and men do not have knowledge adequate to understand their own risk of disease acquisition and the importance of testing in mitigating that risk, any screening program that is dependent on self-initiated action has a high probability of failure. Therefore, I have come to the conclusion that the development of adequate sexual health education programs in US middle and high schools is the essential first step in improving the CT prevention efforts in this country. Adolescents and young adults need to take responsibility for their own health. They must understand the risk factors for STIs, and they have to believe that getting tested for STIs is an important part of their overall wellness agenda. Only with the appropriate sexual health knowledge will they be likely to use school-based health clinics or take advantage of other opportunities for STI screening such as the Johns Hopkins group’s Web-based “I Want the Kit” program.19
What is sexual health? As stated by Swartzendruber and Zenilman,20 sexual health is “an integrated care-delivery and prevention concept that recognizes sexual expression as normative and encompasses preventive and treatment services throughout the life span.” I highly recommend that all of you read this well-stated commentary. A recommended path forward with respect to sexual health education will be published soon from the CDC. Unfortunately, many areas in the United States that have the highest rates of CT, such as the South, have restrictive laws against sexual health education. This is an issue that we must overcome. The Web-based “Get Yourself Tested” program (http://www.itsyoursexlife.com/gyt/) is a recent step in the right direction, but my feeling is that it will be important to develop appropriate sexual health educational programs within our middle and high schools. I may be wrong because the significance of the social media phenomenon as an educational tool is hard for me to judge, but I suspect that information presented through the traditional educational system will be better retained.
What about the role of a CT vaccine? Recent observations in British Columbia and Europe indicate that despite comprehensive health care system–based CT screening programs, which resulted in major declines in CT prevalence rates, more recently, rates are rising. In British Columbia, the driving force behind this phenomenon appears to be increasing numbers of reinfections.21 The proposed explanatory hypothesis is that successful screening and treatment programs led to a decrease in the duration of infection in the population (“D” in the May and Anderson formula), which, in turn, led to an increase in “β,” susceptibility to infection, as a result of a decrease in the development of protective immunity induced by chronic CT infection. If true, the hypothesis suggests that, ultimately, the only way to control CT infections will be the development of a vaccine. It follows that CT prevention based on screening and treatment programs in the absence of very high rates of successful partner treatment will not achieve their goals. The latter may not be achievable despite increasing use of expedited partner treatment programs.22 Therefore, I agree that vaccine development is an important goal. A successful vaccine would prevent primary infection and reinfection and, if widely accepted, would likely be more successful than screening and treatment programs, regardless of whether the decreasing immunity hypothesis is true or not. However, in the absence of adequate sexual health education, a vaccine will not achieve the goal of controlling CT infection in this country. The HPV vaccine experience in the United States stands as evidence of this likely outcome.23 Unless the at-risk population and, in the case of adolescents, their parents believe that a preventive measure is in their best interest and worth the cost, neither screening and treatment or vaccination will successfully decrease the prevalence of CT infection.
In summary, improved sexual health education in middle and high schools should be the immediate goal of the US STI prevention program in general and for CT prevention specifically. While awaiting the development of a CT vaccine, we should focus on developing high school–based CT screening programs in high-risk communities.
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