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3
Biomedical Interventions
Stuart Berman, M.D., Sc.M., and Mary L. Kamb, M.D., M.P.H.
Biomedical interventions for STD are not new. In fact, the 19th century discoveries related to syphilis in large part presaged the biomedical model of intervention. Three major discoveries at the dawn of the 20th century set the stage for subsequent medical advances: the identification of Treponema pallidum as organism responsible for syphilis; a complement fixation blood test that could diagnose the presence of the organism; and the identification by Paul Ehrlich of an arsenical, salvarsan (though not the magic bullet hoped for), that could kill the organism (1). Subsequently, the availability of penicillin and the publication of Surgeon General Thomas Parran’s “Shadow on the Land” contributed to the national effort to control syphilis transmission, supported by the National Venereal Disease Control Act (1938), the model for modern public health interventions based on the biomedical model. However, as this book demonstrates, the array of available interventions aimed at preventing and controlling sexually transmitted infections (STIs) now include many other nonmedical approaches. Nevertheless, in many ways biomedical interventions are still the critical mainstay of prevention, and new biomedical approaches are constantly being evaluated and added to the armamentarium.
In considering biomedical interventions, we have found that the Anderson-
May equation, R = bcd, serves as a useful framework (2). In this construct, R, the reproductive number, is the average number of secondary cases associated with an index case; b is the measure of transmissibility, given exposure; c is the average number of susceptibles exposed during the period of infectivity; and d is the average period of infectivity. Although biomedical interventions may affect any of these transmission parameters, two of these, d—duration of infectivity, and b—transmissibility, are most directly affected and are the focus of this chapter. Some aspects of c are addressed by biomedical interventions (e.g., vaccines); however, this parameter is primarily affected by sexual behaviors that are addressed elsewhere in this book.
Reducing d—Duration of Infectivity
Reducing duration of infection (i.e., affecting d) is the most obvious and historically most common means by which biomedical interventions reduce transmission. Case identification and prescribed antibiotic treatment of STD
Behavioral Interventions for Prevention and Control of Sexually Transmitted Diseases.
Aral SO, Douglas JM Jr, eds. Lipshutz JA, assoc ed. New York: Springer Science+ Business Media, LLC; 2007.
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infection clears infection and renders the index case noninfectious—achieving “prevention” by reducing the period of infectivity, and thus reducing prevalence. Although case identification and treatment is the biomedical intervention that probably comes to mind first, there are a variety of other biomedical approaches that can reduce duration of infectivity. STD screening of asymptomatic populations can identify unrecognized infections and allow treatment of cases that would otherwise have been missed. “Mass treatment” of an entire at-risk population—regardless of symptoms or behavioral risks—is a strategy that aims to reduce STD prevalence in the entire community. In addition to prescribed treatment approaches, nonprescribed approaches such as traditional therapies and folk remedies have been used to attempt to reduce symptoms and eliminate disease (and thereby infectivity).
The various approaches and contexts by which biomedical interventions affect d are addressed here primarily for the curable STDs targeted by national control programs, typically for syphilis, gonorrhea, and chlamydia. However, some therapeutic approaches aimed at viral STDs such as herpes simplex virus (HSV) and human immunodeficiency virus (HIV) may also affect duration of infectivity, and these are commented on as relevant.
Case Identification and Prescribed Antibiotic Treatment
There are few more established, fundamental biomedical interventions than the antibiotic treatment of infectious disease. In fact, the landmark paper in 1944 promoting use of penicillin to treat syphilis (a disease that was already a public health priority) and gonorrhea was among the first published applications of the drug (3,4). The availability of this powerful and effective antibiotic therapy was a revolutionary advance that changed medical management of STDs and other communicable diseases forever, as antibiotic treatment not only prevented adverse consequences in the individual, but also affected disease transmission, incidence, and prevalence.
Gonorrhea
Classically, antibiotic treatment was primarily provided to those persons presenting with symptoms; in terms of gonorrhea, male urethritis was the typical presenting complaint, and was one of first demonstrated uses for penicillin (5). The treatment was highly effective—symptoms were relieved and in addition, infection was cured; the reduction in infectivity could be clearly demonstrated by microbiologic culture. In fact, treatment of gonococcal urethritis with an appropriate antibiotic has been demonstrated to eliminate infectivity in a matter of hours (6). Treatment for gonorrhea has been observed to be so effective that some experts recommend that only therapies with greater than 95% efficacy would meet an acceptable standard of care (7). However, maintaining that rate of efficacy has been challenging since N. gonorrhoeae has proved quite nimble at acquiring antimicrobial resistance (8). In fact, evolving antibiotic resistance over time has resulted in substantial changes in the antibiotic regimens recommended for treatment of gonorrhea. As resistance emerged to penicillin and tetracycline, these drugs were no longer sufficiently effective, and have ceased to be recommended in most national STD guidelines (9). Currently, as an increasing percentage of N. gonorrhoeae strains have demonstrated resistance to quinolone antibiotics, this class of drug treatment is also becoming less relevant even in the United States. As of 2005, resistance has
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reached high enough levels in certain settings or subpopulations that quinolone use for gonorrhea is no longer recommended in several western states including Hawaii and California, or among men who have sex with men regardless of location (10,11). In such situations, cephalosporins are the primary treatment recommended for gonorrhea, and although clinical failures have been reported and low levels of resistance to some cephalosporin preparations have been observed (12), resistance has not as yet been documented to ceftriaxone. If widespread antimicrobial resistance to ceftriaxone were to develop, gonorrhea treatment options would be severely limited (13).
Although antibiotic treatment of gonorrhea has been observed to be highly effective at the individual level, the broader public health benefit of treating symptomatic disease—primarily males who present with urethritis—is less obvious. The community trial conducted in Mwanza, Tanzania, during the early 1990s found that increased access to and quality of symptomatic STD treatment was associated with a 49% reduction in prevalence of male symptomatic urethritis compared with control communities, although prevalence of gonorrhea among women attending antenatal clinics in the treatment and control communities did not differ (14). Furthermore, evidence from mathematical models has demonstrated the importance of providing prompt treatment to men and women with symptoms (15). Given reports of increasing delays in obtaining services in genitourinary medicine clinics in Britain, modelers evaluated the public health impact of such compromise. The models indicated that when disease incidence is elevated, if access is limited a “vicious” cycle can be set in motion, whereby “inadequate treatment capacity leads to many untreated infections, generating further high incidence and high demand and thus maintaining the inadequacy of services” (15). Additionally, other data support the concept that compromises in treatment efficacy can also have population-level public health impact, as at least one gonorrhea outbreak was attributed to prevalence of antibiotic resistant gonorrhea (16).
How effective is case identification and treatment of gonorrhea in controlling disease prevalence? In the United States, rates of gonorrhea disease did not decline dramatically until three years after a national gonorrhea control program, with broadly applied culture-based screening for gonorrhea among women, was launched in 1972 (17). Rates of gonorrhea continued to decline over the next 25 years, although the relative contributions of behavior change, partner notification, and screening are unknown (Fig. 1). However, some experts estimated that the gonorrhea prevention program—which relies primarily on antibiotic treatment—had shortened duration of gonorrhea infectivity by 70% (18).
Syphilis
Assessing the role of case identification and treatment regarding prevention of syphilis transmission is somewhat more challenging than for gonorrhea. As is the case for gonorrhea, studies that document the effectiveness of penicillin are historic—before the era of randomized trials. But, additionally, evidence of antimicrobial efficacy is challenging to gather since the causative agent of syphilis, Treponema pallidum, cannot be readily cultured (19), and thus outcome measures of efficacy have not been based on assessing microbiologic cure as is done for treatment of gonorrhea. Instead, assessments of efficacy have relied upon the imperfect approach of following serologic titers (20). Despite
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Rate (per 100,000 population)
500
400 300 200 100
0
1941 46 51 56 61 66 71 76 81 86 91 96 2001
Figure 1 Rates reported for gonorrhea, prevalence in the United States, 1941–2004.
the difficulties in accurately assessing treatment efficacy for a disease with such an unpredictable course, and one that can result in complications years later following long periods of latency, clinical experience is consistent in suggesting that antibiotic treatment for syphilis has been highly effective (21).
Another area of contrast between syphilis and gonorrhea is that treatment recommendations for syphilis have been remarkably consistent since 1944. Penicillin was quickly adopted as the treatment of choice for syphilis when early studies demonstrated that the antibiotic was rapidly treponemicidal (22). (The arsenic-derived drug salvarsan also killed the treponeme but had many side effects associated with it. Interestingly, Alexander Fleming was one of the few physicians administering salvarsan; that experience encouraged him to search for other antimicrobials, leading to discovery of penicillin (23)). In fact, after longer-acting penicillin formulations were available in the 1950s, there have been minimal changes in drug treatment schedules for syphilis (21). T. pallidum has remained exquisitely sensitive to penicillin, and resistant strains have never been identified. This may be related to fact that the T. pal- lidum genome is quite limited (24); the organism has very few genes and a very limited metabolic repertoire (19,25). However, strains of the organism that demonstrate antibiotic resistance to azithromycin have been identified (26), and such resistance can compromise effectiveness of a drug (27) whose efficacy otherwise appears comparable to that of benzathine penicillin (28).
As noted, from the earliest clinical studies it was apparent that acute lesions of syphilis resolved promptly after penicillin treatment (5). Since the lesions of early syphilis are very infectious, effective treatment should theoretically shorten duration of infectivity. However, the lesions associated with early syphilis are also self-limited and of short duration, and this, coupled with the lower infectiousness of later stage syphilis, has limited the impact of treatment (outside or early syphilis) on disease transmission. Importantly, early treatment also prevents the development of subsequent stages or relapses of syphilis, when individuals may become infectious again. Therefore, the earlier in the course of syphilis that treatment is provided, the greater is the reduction in duration of infectivity and the greater the prevention benefit (29). In sum, reduction in duration of infectivity is greatest—and the contribution to prevention greatest—when syphilis is treated in primary stage (29).
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The contribution of syphilis treatment to prevention would seem to vary by gender and perhaps by sexual orientation. Females with syphilis are less likely to be diagnosed with primary stage lesions than heterosexual males (30), probably because the primary chancre is classically painless and may go unnoticed, or the primary lesion may occur on the cervix where it is not easily observed without a speculum examination. Similarly, it is assumed that the occurrence of rectal and pharyngeal lesions among men who have sex with men (MSM) are less likely to be noticed than penile lesions (31) and thus MSM are less likely to present with primary stage lesions than are heterosexual males. (Note: such gender differences also exist with regard to treatment of gonorrhea and chlamydia; males are more likely to present with incident, symptomatic infection, whereas infections among women, are more likely to be diagnosed by screening.)
Some evidence indicates that providing primarily symptomatic treatment for syphilis (manifested as genital ulcer disease) could have a population effect, shown by the Mwanza community trial of enhanced syndromic case management discussed earlier(14). In this study, in which the symptomatic treatment provided to those with genital ulcers included penicillin, syphilis seroprevalence was 29% lower in the intervention communities than in the comparison communities. Prevalence of active syphilis was also 38% lower in the intervention than in the comparison communities, although differences did not achieve statistical significance at p < 0.05. In that trial, no differences in syphilis prevalence were observed among pregnant women receiving antenatal care in the intervention and control communities (14).
Historically, however, treatment for syphilis was not provided primarily to reduce acute symptomatology or even reduce transmission; the primary objective was to prevent the long term complications (32). Soon after the U.S. national program to control syphilis was established in 1938, rapid treatment centers were set up to screen and identify infected individuals; this occurred even prior to penicillin availability. With a national program already in place, provision of penicillin treatment began to be implemented broadly, and treatment was not limited to just those seeking symptomatic care.
Although the population-level impact of the syphilis control program was quite effective, it is difficult to tease out how much of this was related to penicillin treatment as opposed to other control strategies. As noted earlier, penicillin treatment was initiated in 1944 as part of a national STD control program that already included syphilis screening. By 1956, reported incidence of primary and secondary syphilis in the United States had fallen to 3.9 per 100,000 from a rate of 70.9 a decade earlier (Fig. 2) (33). As the national program evolved, aggressive locating and treatment of exposed sexual partners was emphasized in the 1950s, and has continued to the present. The limitations of antibiotic treatment alone began to be observed as syphilis has become less common in the general population, and more concentrated in “core groups” (subpopulations with high STI prevalence and high rates of partner change). At the turn of the 21st century, after achieving historic low syphilis prevalences, Sweden, Canada, the United Kingdom, and the United States have all begun to see a resurgence in disease rates (34–37).
Chlamydia
Chlamydia is the third bacterial STD for which there is a national control program in the United States, and that program’s structure is similar to that of the
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Cases (in thousands)
600
P&S
Early Latent
480
360 240 120
0
Total Syphilis
1941 46 51 56 61 66 71 76 81 86 91 96 2001
Figure 2 Rates reported syphilis, prevalence in the United States, 1941–2004.
national gonorrhea control program. Historically, men presented to care for treatment of symptomatic urethritis; when this was caused by something other than gonorrhea, it was termed non-gonococcal urethritis (NGU). Typical studies found that C. trachomatis caused 30–50% of NGU in heterosexual males (38). However, the purpose of NGU treatment was to provide symptomatic relief; specific etiologic diagnoses were rarely made, and evidence of microbiologic cure following treatment typically was not available. Subsequently, clinical studies have demonstrated that the antibiotics used to provide symptomatic relief for NGU—typically a week’s course of tetracycline—were effective treatment for chlamydia infection, eradicating the organism in over 95% of cases among males, and over 90% among females in trials of up to 21 days of follow-up (39). Clinical entities, such as mucopurulent cervicitis, were identified which were regarded as manifestations of chlamydia infection among women corresponding to NGU (40); such entities warranted antimicrobial treatment for chlamydia. Until the availability of azithromycin, treatment involved multiple-day regimens (41). However, although a single-dose regimen is associated with greater adherence, there is thus far little evidence supporting enhanced treatment effectiveness of this approach compared with multiple dose regimens (42,43).
It is not yet clear whether or not antibiotic treatment efficacy for chlamydia is compromised by antimicrobial resistance. Some anecdotal evidence supports the existence of clinically relevant antimicrobial resistance; however, substantial uncertainty exists about the relevance of such evidence, and the appropriateness of the methodologies used for assessing resistance (44). Treatment efficacy has become an issue, however. As data have accumulated from follow-up evaluations of women treated for chlamydia, it is apparent that approximately 5–10% of women “successfully” treated for chlamydia (i.e., women who have negative chlamydia tests at approximately one month after treatment) test positive for chlamydia some months later (45,46). Such infections have typically been assumed to result from exposure to an infected partner (reinfection); however, prevalence frequently seems unassociated with such exposure (46,47), suggesting biologic persistence. Subclinical persistence is a characteristic of the organism (48), independent of any formal antimicrobial resistance.
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Antibiotic treatment, which effectively cleared chlamydia infection, was clearly associated with decreased transmission on an individual level, especially in light of evidence that duration of chlamydia infection is quite long (probably over a year in women) (49). However, there are little available data to assess the population impact of treatment of symptomatic chlamydia infection. Effective symptomatic treatment for male urethritis, whether gonococcal or non-gonococcal, was standard care and widely available for years prior to the implementation of a national chlamydia prevention program. Nevertheless, prior to program implementation, chlamydia prevalence among young women in clinical settings was typically 10% or more (50,51), suggesting that symptomatic treatment had limited effect on community prevalence (Fig. 3). Supporting this, the Mwanza, Tanzania, community trial found little impact on prevalence of chlamydia among pregnant women, although, as noted earlier, prevalence of symptomatic urethritis among males was lower in intervention communities (14).
The impact of the U.S. national program on chlamydia transmission has become increasingly difficult to determine. In 1988, the beginning of the national infertility prevention program was launched and was subsequently implemented across the United States; it focused primarily on screening among young women. Screening programs were first implemented extensively in the Pacific northwestern states (Washington, Idaho, Alaska, and Oregon), and were observed to have apparently a substantial prevention effect as, from 1988 to 1994, prevalence among 15–24-year-old women declined from 15.1% to 5.7% (34,51) in those states. Similar declines were noted in other regions as their screening programs were implemented (50). However, neither national nor regional chlamydia prevalence has continued to decline over time, and prevalence may have in fact been increasing in some locales. Other countries (52) have also experienced increases in rates of chlamydia despite ongoing program activities. It is possible that limited screening coverage (52,53) or limited treatment of partners (54) explain some of the waning declines in chlamydia rates. Other mechanisms have also been hypothesized. Brunham (55) postulates that existing chlamydia control activities resulted in shortened duration of infection, which interfered with development of the immunologic protection that has been observed with repeated chlamydia infections. This would increase the number of susceptibles, permitting increases in incidence and re-infection rates. This is a complicated scenario, and is still only conjecture. Of note, this hypothesis would not apply to gonorrhea, since there is little evidence that gonococcal infection is associated with any subsequent immunologic protection.
Viral STDs
The role of treatment as an STD prevention strategy by means of reducing infectivity is also relevant for the viral STDs. For example, antiviral therapies have been shown to be associated with a 20-fold decrease in genital shedding of HSV-2 compared with placebo, and measured by culture (relative risk = 0.05) (56). Consistent with this finding, Corey demonstrated that, among discordant couples, provision of acyclovir (500 mg/day) to symptomatic partners was associated with a 48% reduction in HSV-2 incidence compared with placebo among the uninfected partners (57). Such an approach has obvious benefit on the individual level; however, it is as yet unclear whether sufficient numbers of HSV-2 infected individuals will utilize the approach to produce a population-level impact.