RECENT SYPHILIS OUTBREAKS among men who have sex with men and other high-risk populations challenge the national goal of syphilis elimination and underscore the need for efficacious and easily administered treatments for incubating syphilis in exposed sex partners. 1-6 Effective identification, notification, and prophylactic treatment of asymptomatic but potentially infected partners are key to preventing disease progression and the infection of future generations of partners.
A single dose of intramuscular (IM) benzathine penicillin (2.4 million units) has long been the treatment of choice for incubating syphilis in exposed sex partners, because its high efficacy and single-dose administration ensure that patients receive adequate treatment. 7 The requirement of IM injection and the risk of serious reactions, however, have meant that benzathine penicillin therapy must typically be administered by qualified personnel in a clinical setting. When sex partners of persons with early syphilis are located in the field by disease intervention specialists (DISs), they are generally referred for evaluation and presumptive treatment. Patient nonadherence to referrals may allow some cases of incubating syphilis to go untreated. 8,9 The availability of an effective, single-dose alternative to benzathine penicillin that can be administered at the time of referral may enhance the ability to prevent new infections and the sequelae associated with untreated infections.
Animal and human trials indicate that azithromycin may be an effective drug for treatment of early syphilis. 10-14 Additionally, a single 1-g dose of azithromycin has been shown to be effective in treating incubating syphilis in exposed sex partners of persons with early syphilis. 15 The ultimate potential of treatment with azithromycin as an alternative to standard penicillin therapy for incubating syphilis will be contingent on the drug's efficacy and its cost.
In this study we estimated the direct costs and efficacy of azithromycin therapy in comparison with the standard course of IM benzathine penicillin treatment. The cost and cost-effectiveness analyses were conducted from two perspectives: public sexually transmitted disease (STD) programs and the broader healthcare system. Providers in public STD programs typically diagnose and treat early syphilis but not late-stage infections or the associated sequelae. Thus, we considered two perspectives, because change in the treatment models may effect different outcomes and recommendations at the STD program and healthcare system levels. The cost and morbidity estimates generated by this model may assist STD programs, health systems, and individual providers in deciding if azithromycin treatment is an appropriate alternative to standard benzathine penicillin treatment for incubating syphilis.
Methods
We employed a decision-analysis model constructed with DATA 3.5 software (TreeAge Software, Williamstown, MA) to estimate the associated costs and relative effectiveness of azithromycin treatment in comparison with standard penicillin therapy. We compared two alternative prophylactic treatment approaches for exposed sex partners located by DISs in the field: (1) a penicillin referral strategy and 2) an azithromycin field treatment strategy. Under the first approach, partners exposed to early syphilis located in the field by DISs are referred to an STD clinic for evaluation, testing, and presumptive treatment with IM benzathine penicillin. Under the second approach, the exposed partners are referred for further evaluation but are administered a 1-g oral dose of azithromycin in the field at the time they are initially located, with DIS observation of the treatment.
The analysis was limited to consideration of those partners who are located by DISs in the field. While more expensive than benzathine penicillin, azithromycin has a potential advantage in cost and disease prevention, stemming from the ability of DISs to administer treatment outside the clinic setting. For sex partners who present to the clinic for evaluation and treatment without DIS intervention, the determining factor in drug selection may be largely drug cost; in this context, IM benzathine penicillin therapy retains a clear cost advantage.
For both strategies, our starting point was the partners of patients with early syphilis. The structure of the decision tree is shown in Figure 1. We restricted our analysis to partners for whom patients provided sufficient information to make notification feasible. We controlled for the possibilities that partners may refuse treatment or referral for treatment. We assumed that treatment failure was possible for patients infected with syphilis. We did not incorporate any of the rare adverse effects for either penicillin or azithromycin therapy. 16,17 We assumed that if partners developed syphilis and sought care during the infectious stage, DISs would initiate an investigation of the partners' recent sex partners.
The primary outcome was the number of averted cases of primary or later-stage syphilis. The cost analyses incorporated the direct costs associated with the tracing and location of exposed partners, the evaluation and prophylactic treatment of located partners, and the evaluation and treatment of sequelae resulting from nontreatment or inadequate treatment. As appropriate, cost estimates incorporated a share of STD program overhead costs, proportionate to the time spent by DISs on each element of the partner notification process. Indirect costs arising from lost productivity due to healthcare visits or to complications of untreated syphilis were not considered.
Probability estimates were compiled from published studies. Where published estimates differed, we choose conservative baseline values such that our findings would favor the standard IM benzathine penicillin referral strategy. Sensitivity analyses considered the entire range of published estimates. When a reasonably broad range of published probability estimates was unavailable, we conducted sensitivity analyses with estimates of 50% to 150% of baseline values. The only value held fixed throughout the study was the estimate of IM benzathine penicillin's efficacy in aborting incubating syphilis, which we maintained at 100%, reflecting the extensive clinical experience in use of the drug for incubating syphilis and to give analytical preference to the standard penicillin-referral approach to treatment. 18,19
The one published study evaluating the efficacy of 1-g single-dose azithromycin therapy in aborting incubating syphilis showed the treatment to be 100% effective. 15 Nonetheless, we conservatively chose a 90% level as the baseline estimate for the efficacy of azithromycin. The 90% value falls within the 95% exact probability confidence interval (78-100%) and is below 94%, the estimated median of the confidence interval range for the drug's efficacy. We conducted one- and two-way sensitivity analyses over the entire confidence interval range.
Published estimates of the rates of infection among sex partners of persons with early syphilis vary widely, from <10%19 to 67%. 20 Intermediate estimates of infection rates range from 30% to 62%. 8,20-26 We adopted 30% as our baseline value and varied the estimates through the range of published figures.
Estimates for the probability that an identified partner would initially consent to testing and treatment (0.95) and that the partner would ultimately adhere to testing and treatment recommendations (0.87) were drawn from a recent large-scale study of partner notification. 27 The likelihood that an untreated or inadequately treated partner would seek medical care for symptoms of early syphilis was estimated at 0.49. 28 Using data from the National Health and Social Life Survey, we derived an estimate of 0.18 for the likelihood that persons seeking treatment would choose an STD clinic for care rather than another healthcare facility. 29 For those not receiving treatment for early syphilis, we utilized estimates from a study of the likelihood of progression to and treatment for late syphilis and its sequelae. 28
In our analysis of the STD program perspective, we considered all direct medical costs that would be incurred by a given provider in locating and treating a partner of a patient with early syphilis. These costs included those of the index patient interview to identify recent sex partners, the records search to determine if any of the exposed partners had already sought testing and treatment, the field visits to locate exposed partners, the evaluation and testing of those exposed, and the presumptive treatment with penicillin or azithromycin. Penicillin treatment costs comprised the public-sector cost of the drug and the labor time and overhead costs required for the IM injection in an STD program clinic. Azithromycin treatment costs accounted for only the drug cost, because the administration of treatment was incidental to the DIS field visit, for which the cost had already been accounted. Where infected partners were untreated or inadequately treated, we included costs of treatment for early syphilis and DIS investigation of these partners' recent sex partners. The healthcare system perspective included all costs in the STD program perspective, plus those associated with treatment of syphilis in care settings other than STD clinics, as well as the costs attributable to long-term sequelae of untreated syphilis.
The values for the costs were drawn from multiple published sources. All cost figures were converted to 2001 U.S. dollars with use of the Consumer Price Index for all urban consumers (CPI-U). 30 We utilized the 2001 public-sector price of the 1-g sachet formulation of $11.50 and wholesale prices for a 1-g dose ranging from $17.32 for the sachet formulation to $27.89 for tablets. 31 The spectrum of azithromycin drug prices was considered in sensitivity analyses, because the lower, negotiated public-sector prices may not be available to all purchasers and the tablet formulation may be preferred by some providers. We estimated the public-sector cost of standard IM benzathine penicillin therapy to range from $18.64 to $22.22. 31-33 This cost incorporated the medication cost and the direct costs of an STD clinic visit for administration of the therapy.
The direct costs of treating early syphilis, as well as the long-term sequelae of the disease, were estimated for those partners for whom the treatment was not successful or was refused. For partners not receiving timely, effective treatment, we included costs of treatment for late syphilis and its sequelae. We estimated the costs of treating early syphilis on the basis of recommendations of the Centers for Disease Control and Prevention for benzathine penicillin therapy, with two follow-up visits for evaluation and treatment. 7 These treatment costs were assumed to be borne by the public STD program or by other private and public providers, proportionate to the likelihood of a client seeking treatment at particular venues. Treatment costs for early syphilis were assumed to be uniform across all venues. Cost estimates for treatment of long-term complications of untreated syphilis were obtained from a study of the direct medical costs of syphilis that included treatment and expected long-term-care costs associated with late-stage syphilis, including rare neurologic and cardiovascular manifestations, discounted at 3%. 28
We did not include the costs attributable to an increased risk of HIV infection and transmission associated with syphilis or the costs resulting from the increased occurrence of congenital syphilis in children born to infected women. We assumed that all long-term sequelae would be treated by providers outside of STD clinics. A summary of all cost and probability estimates used in the model is presented in Table 1.
Results
Despite the baseline assumption of an efficacy rate of just 90%, field treatment with azithromycin was more effective in averting cases of syphilis among exposed partners than was referral for standard penicillin treatment, because a portion of partners do not adhere to referrals for treatment. Of each sex partner located in the field, 5.4% of the penicillin referral group would be expected to develop early syphilis, versus 4.5% of the azithromycin treatment group. If the efficacy of azithromycin is greater than the 90% baseline value we employed, the attributable number of averted cases of syphilis increases accordingly.
In addition to averting more cases of syphilis, azithromycin was also the lower-cost therapeutic approach from both the healthcare system and STD program perspectives. Using the baseline estimates for all variables, we found that the expected healthcare system cost for treating in the field a sex partner located in the field with directly observed administration of oral azithromycin was $299.12, versus an expected cost of $314.19 for referral for treatment with IM benzathine penicillin. Thus, use of azithromycin offers the healthcare system a cost savings of 4.8%. Field treatment with azithromycin was also cost saving from the STD program perspective: the cost was $251.06 for azithromycin therapy, versus $256.70 for treatment with penicillin. The percentage cost savings of 2.2% was lower than that from the healthcare system perspective. The difference in savings reflects the fact that public STD programs typically do not treat the late-stage manifestations of the disease and that the incidence of these manifestations is lower than with the penicillin-referral approach.
Sensitivity Analysis
We conducted one- and two-way sensitivity analyses on all variables in the model, with the exception of the efficacy of benzathine penicillin in the treatment of incubating syphilis, which was held constant at 100%. The variables that had the most impact on the model were the price of azithromycin, the efficacy of azithromycin, the probability of transmission between index patient and sex partner, and the probability that a client would adhere to a referral for prophylactic treatment with IM penicillin. Variation in the values of other probability and cost estimates did not affect the preferred strategies in the model.
From the STD program perspective, azithromycin remained cost-saving at public sector pricing of $11.50 at efficacy levels as low as 75%. If the efficacy of azithromycin dropped below the 75% level, referral for penicillin therapy became the lower-cost treatment strategy. From the healthcare system perspective, azithromycin was cost-saving at efficacy levels of 86% or higher. When we considered syphilis cases averted, field treatment of azithromycin was more effective than referral for penicillin therapy as long as the efficacy of azithromycin was 87% or higher. Below this threshold, the standard referral approach resulted in more cases of syphilis averted. Notably, if the efficacy of azithromycin was assumed equal to that of penicillin (at 100%), the field treatment strategy resulted in just 1.6% of located partners progressing to early syphilis, versus a rate of 5.4% for the penicillin referral strategy.
As the public-sector price of azithromycin increases, the cost savings of field treatment with azithromycin decreases from both the STD program and healthcare system perspectives. Because averted cases of syphilis result in savings from averted medical costs (from both perspectives), the interaction of the cost of azithromycin and its predicted efficacy was critical to determination of total costs associated with the field treatment strategy (Figure 2A). At the wholesale price of $17.32 for the sachet formulation of azithromycin, the field treatment strategy remained the lower-cost treatment approach from the STD program perspective at efficacy levels of at least 90%. The tablet formulation of azithromycin, with a wholesale price of $27.89, was not cost-saving, even if 100% efficacy was assumed. From the healthcare system perspective, however, drug cost was less important than predicted efficacy level in determining the optimal treatment strategy (Figure 2B). Thus, at the $17.32 wholesale price for the sachet formulation, the field treatment strategy was of lower cost when efficacy levels exceeded 87%; the even more expensive tablet formulation of azithromycin was cost-saving if efficacy levels achieved a minimum of 90%.
Varying the probability of disease transmission (from index patient to exposed partner) did not substantially alter the preferred treatment strategies, although the cost differences between the two treatment strategies declined as we considered lowered estimates of transmission probability. High rates of adherence to treatment referral, however, did affect the preferred treatment strategy. If adherence to treatment referral reached 92%, referral for penicillin treatment became less costly from a healthcare system perspective. In contrast, rates of adherence below the baseline estimate of 87% only increased the advantage of the azithromycin field treatment strategy, both in terms of cost and in terms of the number of syphilis cases averted. The rate of adherence did not have an appreciable impact on the optimal strategy from the STD program perspective; field treatment remained the preferred strategy under all values of adherence with referral for treatment.
Discussion
Observed treatment with azithromycin appears preferable from both disease prevention and cost standpoints when an exposed partner is located in the field. Because of problems with adherence to referrals for treatment, field treatment with azithromycin may be especially advantageous in outbreak contexts with high-risk populations, such as men who have sex with men or those who trade sex for drugs or money. The azithromycin field treatment strategy was, under most assumptions, cost-saving from both the STD program perspective and the healthcare system perspective. The cost savings associated with the administration of azithromycin in the field result primarily from the increased likelihood that those with incubating syphilis will receive curative treatment, thus decreasing the number of early syphilis cases expected to develop. The cost savings to be realized from field treatment with azithromycin are smaller from the STD program perspective than from the healthcare system perspective, because STD programs do not typically bear the costs associated with late-stage manifestations of the disease, such as neurosyphilis.
Sensitivity analysis demonstrated that the findings were not appreciably affected through a reasonable range of assumptions about the efficacy of azithromycin. The optimal choice of treatment strategies for STD programs was sensitive to the price of azithromycin; at wholesale pricing for the more expensive tablet formulation, field treatment with azithromycin ceased to be cost-saving for STD programs, although it remained cost-saving from the healthcare system perspective. This may be a barrier to implementation of azithromycin treatment for providers who do not use the sachet formulation of azithromycin.
Ongoing studies are evaluating the efficacy of 2-g dosing of azithromycin for treatment of primary and secondary syphilis and 1-g dosing for incubating syphilis. Should the higher dose be required to effectively treat incubating infections as well, field treatment with azithromycin may no longer be cost-saving from the STD program perspective without significant price discounting, although it may remain cost-saving from the healthcare system perspective. Increased treatment costs would need to be evaluated against any efficacy advantages.
Among the limitations of the study was the limited data on the efficacy of azithromycin in aborting incubating syphilis infection. We applied conservative baseline estimates of the efficacy of azithromycin, despite evidence indicating that its efficacy may approach 100%. If the efficacy of azithromycin is significantly higher than our baseline estimate of 90%, the cost savings of the field treatment will be underestimated. Ongoing studies should provide needed additional data to predict the value of the drug for treatment of incubating syphilis.
Also of importance in the context of recent syphilis outbreaks among men who have sex with men will be data on the efficacy of azithromycin for treatment of incubating disease in those dually infected with HIV. Reports of increased rates of treatment failure among HIV-infected persons to whom benzathine penicillin was administered for early syphilis 34 raise the possibility of diminished drug efficacy for incubating syphilis. If the efficacy of either or both drugs is lessened by coinfection with HIV, the relative cost-effectiveness of the treatment approaches may shift, and increased follow-up management may be merited.
In this study we did not consider the effects of averted cases of HIV infection or congenital syphilis resulting from more efficient treatment of exposed partners. Inclusion of these outcomes and the associated costs would increase the cost savings associated with the azithromycin field treatment strategy. Finally, estimates of treatment expenditures were based on public-sector costs, which may underestimate private-sector and societal costs. Because the azithromycin field treatment strategy averted more cases of syphilis, however, this limitation would bias the findings toward an underestimation of the attributable cost savings and further strengthens the case for the field treatment strategy.
The ability of DISs to offer an oral observed treatment in the field may significantly increase the numbers of exposed partners receiving timely prophylaxis for incubating syphilis. The recent outbreaks of syphilis among men who have sex with men and other groups have demonstrated the need for rapid and flexible responses to treatment in both the public and private sectors. Field treatment with azithromycin may provide an added tool in containing these outbreaks and may facilitate efforts to eliminate syphilis in the United States.
References
1. Chen J, Kodagoda D, Lawrence A, Kerndt P. Rapid public health interventions in response to an outbreak of syphilis in Los Angeles. Sex Transm Dis 2002; 29: 277-284.
2. Centers for Disease Control and Prevention. Resurgent bacterial sexually transmitted disease among men who have sex with men: King County, Washington, 1997-1999. MMWR Morb Mortal Wkly Rep 1999; 48: 773-777.
3. Centers for Disease Control and Prevention. Outbreak of syphilis among men who have sex with men: Southern California, 2000. MMWR Morb Mortal Wkly Rep 2001; 50: 117-120.
4. Kahn R, Heffelfinger J, Berman S. Syphilis outbreaks among men who have sex with men: a public health trend of concern. Sex Transm Dis 2002; 29: 285-287.
5. Taking Action to Combat Increases in STDs and HIV Risk Among Men Who Have Sex with Men, 2001. Atlanta: Centers for Disease Control and Prevention, May 15, 2002.
6. Bronzan R, Echavarria L, Hermida J, et al. Syphilis among men who have sex with men (MSM) in Miami-Dade County, Florida. In: Program and Abstracts of the 2002 National STD Prevention Conference. San Diego, CA: March 4-7, 2002.
7. Centers for Disease Control and Prevention. 2002 Guidelines for Treatment of Sexually Transmitted Diseases. MMWR Morb Mortal Wkly Rep 2002; 51: 1-80.
8. Cates W Jr, Rothenberg RB, Blount JH. Syphilis control: the historic context and epidemiologic basis for interrupting sexual transmission of Treponema pallidum. Sex Transm Dis 1996; 23: 68-75.
9. Cowan FM, French R, Johnson AM. The role and effectiveness of partner notification in STD control: a review. Genitourin Med 1996; 72: 247-252.
10. Hook EWIII, Martin DH, Stephens J, Smith BS, Smith K. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002; 29: 486-490.
11. Gruber F, Kastelan M, Cabrijan L, Simonic E, Brajac I. Treatment of early syphilis with azithromycin. J Chemother 2000; 12: 240-243.
12. Lukehart SA, Fohn MJ, Baker-Zander SA. Efficacy of azithromycin for therapy of active syphilis in the rabbit model. J Antimicrob Chemother 1990; 25 (Suppl A): 91-99.
13. Mashkilleyson AL, Gomberg MA, Mashkilleyson N, Kutin SA. Treatment of syphilis with azithromycin. Int J STD AIDS 1996; 7 (Suppl 1): 13-15.
14. Verdon MS, Handsfield HH, Johnson RB. Pilot study of azithromycin for treatment of primary and secondary syphilis. Clin Infect Dis 1994; 19: 486-488.
15. Hook EWIII, Stephens J, Ennis DM. Azithromycin compared with penicillin G benzathine for treatment of incubating syphilis. Ann Intern Med 1999; 131: 434-437.
16. Handsfield HH, Dalu ZA, Martin DH, Douglas JM Jr, McCarty JM, Schlossberg D. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis 1994; 21: 107-111.
17. Waugh MA. Open study of the safety and efficacy of a single oral dose of azithromycin for the treatment of uncomplicated gonorrhoea in men and women. J Antimicrob Chemother 1993; 31 (Suppl E): 193-198.
18. Alexander L, Schoch A, Mantooth WB. Abortive treatment of syphilis. Am J Syph Gonor Vener Dis 1949; 33: 429-436.
19. Moore MB, Price EV, Knox JM, Elgin LW. Epidemiologic treatment of contacts. Public Health Rep 1963; 78: 966-970.
20. Idsoe O, Guthe T, Christiansen S, Krag P, Cutler JC. A decade of reorientation in the treatment of venereal syphilis. Bull World Health Organ 1954; 10: 507-561.
21. Schroeter AL, Turner RH, Lucas JB, Brown WJ. Therapy for incubating syphilis: effectiveness of gonorrhea treatment. JAMA 1971; 218: 711-713.
22. Kohl KS, Farley TA, Ewell J, Scioneaux J. Usefulness of partner notification for syphilis control. Sex Transm Dis 1999; 26: 201-207.
23. von Werssowetz A. The incidence of infection in contacts of early syphilis. J Vener Dis Inform 1948; 29: 132-137.
24. Stamm LV. Biology of Treponema pallidum. In: Holmes KK, Sparling PF, Mardh P-A, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999: 467-472.
25. Schober PC, Gabriel G, White P, Felton WF, Thin RN. How infectious is syphilis? Br J Vener Dis 1983; 59: 217-219.
26. Klingbeil L, Clark E. Studies in the epidemiology of syphilis. J Vener Dis Inform 1941; 22: 1-6.
27. Peterman TA, Toomey KE, Dicker LW, Zaidi AA, Wroten JE, Carolina J. Partner notification for syphilis: a randomized, controlled trial of three approaches. Sex Transm Dis 1997; 24: 511-518.
28. Chesson HW, Rein D, Kassler WJ, et al. Direct medical costs of syphilis in the United States: the potential for a cost-saving national elimination program. In: Proceedings of the 1998 National STD Prevention Conference, Dallas, Texas. 1998.
29. Laumann EO, Gagnon JH, Michael RT, Michaels S. The Social Organization of Sexuality. Chicago: The University of Chicago Press, 1994.
30. Consumer Price Index, All Urban Consumers (CPI-U). Washington, DC: U.S. Department of Labor, Bureau of Labor Statistics, November 16, 2001.
31. 2001 Drug Topics Red Book. Montvale, NJ: Medical Economics Company, 2001.
32. Begley CE, McGill L, Smith PB. The incremental cost of screening, diagnosis, and treatment of gonorrhea and chlamydia in a family planning clinic. Sex Transm Dis 1989; 16: 63-67.
33. Engelgau MM, Woernle CH, Rolfs RT, Greenspan JR, O'Cain M, Gorsky RD. Control of epidemic early syphilis: the results of an intervention campaign using social networks. Sex Transm Dis 1995; 22: 203-209.
34. Augenbraun MH, Rolfs R. Treatment of syphilis, 1998: nonpregnant adults. Clin Infect Dis 1999; 28 (Suppl 1): S21-S28.