INCREASES IN SYPHILIS INFECTIONS, predominantly among men who have sex with men (MSM), have raised concerns that human immunodeficiency virus (HIV) incidence may also be increasing in this population. Since 1998, outbreaks of syphilis among MSM have been documented in many cities across the United States,1–9 as well as internationally.10,11 Syphilis facilitates HIV transmission, and possible increases in sexual risk behavior accompanying the outbreaks of syphilis may also contribute to sustained or increasing HIV incidence among gay men. Only limited studies to date have examined the potential impact of syphilis outbreaks on the HIV epidemic, either by evaluating trends in syphilis morbidity and incident HIV infections in select populations of MSM or by assessing incidence of HIV among MSM diagnosed with early syphilis. We review these findings and related epidemiologic evidence for why HIV incidence among MSM may or may not be increasing during syphilis outbreaks and conclude with implications for HIV prevention.
Evidence and Potential Explanations for Why HIV Incidence Among MSM May Be Increasing
A very concerning aspect of the ongoing syphilis outbreaks is that about 50% to 60% of gay/bisexual men with early syphilis are HIV infected, with the coinfection rate varying by city and phase of the outbreak.1–8 Because syphilis is a cofactor in HIV transmission, and HIV infection affects the clinical presentation of syphilis, high syphilis and HIV coinfection rates within the sexual networks of MSM may enhance the spread of both sexually transmitted diseases (STDs).12 Syphilitic ulcers disrupt the epithelial and mucosal barriers, easing the passage of HIV, and inflammation and recruitment of CD4+ cells to the site of ulceration may further increase the probability of HIV transmission. In addition, by activating host immune cells and altering levels of cytokines and transcription factors, syphilis infection may enhance HIV replication.13 HIV can be detected in the exudate of genital ulcers from HIV-infected persons.14 As has been shown for other sexually transmitted diseases,15,16 syphilis may increase HIV viral load in HIV-infected persons,17,18 and persons with higher HIV viral load are more likely to transmit HIV to their sexual partners.19 HIV-infected individuals with early syphilis are also more likely than persons without HIV to have multiple chancres,20 thus enhancing the opportunity for transmission of both STDs.
The potential for HIV transmission during syphilis outbreaks is also substantial because of high rates of sexual risk behavior among HIV-infected and uninfected men who acquire syphilis. MSM syphilis cases frequently report having a large number of sexual partners, often anonymous and met over the Internet, and having sex under the influence of drugs.2–4,21 For example, in an outbreak of syphilis in southern California, 33 (50%) of 66 MSM reported having had anonymous sex, and 26 (40%) reported using illicit drugs, frequently methamphetamine.2 A cross-sectional study of 1318 MSM at the San Francisco municipal STD clinic during 2002–2003 found that factors significantly associated with the increased risk of early syphilis infection included nonwhite race (OR = 1.8), HIV infection (OR = 4.2), methamphetamine use (OR = 3.6), especially with Viagra (OR = 6.1), stronger affiliation with the gay community (OR = 2.9), and meeting recent partners on the Internet (OR = 2.0).22 Furthermore, a case-control study of 88 MSM with primary and secondary syphilis and 176 uninfected controls in New York City in 2001 found that cases were significantly more likely than controls to be HIV infected (OR = 7.3), to have intentionally practiced unprotected anal sex (“barebacked”) (OR = 2.6), and to have had annual income over $30,000 (OR = 2.7).23 Analyses limited to HIV-positive men in this study also revealed that somewhat greater percentage of syphilis cases (n = 42) compared with controls (n = 27) reported unprotected anal intercourse (UAI) at sex clubs and bathhouses (61% versus 37%) and methamphetamine use in the prior 6 months (36% versus 19%)23 (P > 0.05 for both), which might indicate that syphilis is a marker of recent risk behavior among HIV-infected men.
Consistent with these behavioral data, preliminary studies using the serologic testing algorithm for recent HIV seroconversion (STARHS)24 have suggested high HIV incidence in men who have early syphilis. HIV-infected persons who test reactive with the sensitive enzyme immunoassay (EIA) and nonreactive with the less sensitive EIA are considered recently HIV infected (mean seroconversion period of 170 days) by STARHS. Of 74 men who were diagnosed with primary or secondary syphilis at the San Francisco municipal STD clinic during 2002–2003 and who accepted confidential HIV and STARHS testing, 16 (22%) were HIV positive, and 4 had recent HIV infection based on STARHS results (corroborated by prior HIV-negative tests), with resultant estimated HIV incidence of 13.9% per year (95% CI, 0.3–27.5).25 Furthermore, testing of anonymous remnant sera of 212 men with early syphilis diagnosed at publicly funded STD clinics and other public sites in Los Angeles County revealed that 74 (35%) of these men were HIV positive, 15 appeared to be recently HIV infected based on STARHS results alone, and 12 were considered recently HIV infected based on STARHS results and self-reported HIV testing history, with resultant incidence of 17% per year (95% CI, 12%–22%).26 These 2 aforementioned studies lack comparison groups (HIV-infected men without syphilis from the same clinic populations), provide relatively imprecise incidence estimates, and may be limited, respectively, by potential self-selection bias (persons who seek HIV testing may differ in HIV risk from those who do not27) and by incomplete HIV testing histories. However, their preliminary findings suggest frequent HIV transmission in proximity to syphilis acquisition (before, after, or concurrently) in these MSM populations and are consistent with other studies indicating that a substantial proportion of recently and acutely HIV-infected persons have genital ulcer disease or other STDs and can be identified at the STD clinics.28–31
The ongoing syphilis outbreaks and increases in gonorrhea and chlamydia among MSM in some localities32–34 may be markers of resurgence in unsafe sex behaviors and may foreshadow increases in HIV incidence among gay/bisexual men and their partners. Serial cross-sectional surveys and surveillance data for MSM in some cities suggest that sexual risk behaviors in some MSM populations may indeed be increasing,35–41 although temporal trends inferred from serial cross-sectional data may not always be valid due to potential changes in sampling frame. For example, recent surveys conducted by the STOP AIDS Project in gay venues and in the streets of gay neighborhoods in San Francisco found that the percentage of HIV-positive MSM reporting UAI with other men in the previous 6 months increased from about 38% in 1998 to 54% in 2003.38 However, among MSM seeking anonymous HIV testing in San Francisco, the proportion reporting UAI with another man showed no consistent temporal trend from 1998 through 2003.38 In Seattle-King County, prevalence of reported sexual risk behavior among MSM at publicly funded sites has also increased during 1996–2002; for example, the proportion of MSM at HIV testing sites who reported insertive UAI in the prior 6 months increased from about 36% to 47%, and the proportion of MSM as the STD clinic who had >5 partners in the prior 2 months increased from about 8% to 15% during this period.34 Finally, among sexually active MSM diagnosed with AIDS in Los Angeles County, the proportion reporting 10 or more sex partners in the prior 6 months increased from 10% in 2000 to 25% in 2003, whereas the proportion reporting UAI with a man at last sexual intercourse increased from 11% in 2000 to 26% in 2003.39
The erosion in safe sex behaviors and possible increases in HIV incidence may be related to a myriad of factors, including adverse trends in substance use, particularly methamphetamine and Viagra,22,23,42 “HIV prevention fatigue” among gay men,43,44 improvements in health and survival in the era of highly active antiretroviral therapy (HAART), and possibly to HAART-related treatment optimism and reduced fear of death from AIDS.35,37,45 As a result of HAART, there has been a steady increase in the number of persons living with HIV/AIDS in the United States,46 many of whom continue to lead sexually active lives after HIV diagnosis and may continue to engage in unprotected sexual intercourse.42,47–50 Analyses of trends in HIV diagnoses in 29 states that conducted name-based HIV/AIDS surveillance during 1999–2002 (which did not include New York, California, or Texas) revealed that the number of MSM newly diagnosed with HIV infection increased 17% from 9988 in 1999 to 11,686 in 2002.51 The increase in new HIV diagnoses among MSM in these states may reflect increase in HIV testing, increase in HIV incidence, or both.
Evidence and Potential Explanations for Why HIV Incidence Among MSM May Not Be Increasing
Although recent HIV incidence data for MSM are sparse, the available data collected in San Francisco, Los Angeles, and Seattle suggest that HIV incidence among MSM may not be increasing. To investigate potential change in HIV incidence among MSM during syphilis outbreaks in San Francisco and Los Angeles, data from public HIV counseling and testing centers and municipal STD clinic were analyzed.25 In San Francisco, the incidence of HIV infection among MSM who tested for HIV at anonymous HIV-testing sites and the STD clinic did not appear to increase during 1998–2002, a period when the syphilis epidemic escalated in the city. HIV incidence was the highest in 1999 at both sites; in 2002, it was 2.4% per year at the anonymous HIV-testing sites (n = 1280) and 4.0% per year at the STD clinic (n = 1544) (Figure 1). In Los Angeles, the number of MSM newly diagnosed with HIV infection at the county testing sites also did not change appreciably during the syphilis outbreak.25 Furthermore, among MSM who tested for HIV at publicly funded HIV testing sites in Seattle–King County, estimated HIV incidence ranged from 2% to 4% during 1997–2004, with no consistent trend over time,34,52 and reported cases of HIV among MSM in this jurisdiction also remained stable.34 However, possible changes in both HIV testing patterns and practices (frequency of repeat testing, increasing use of oral HIV antibody testing) and shifts in the number and sexual risk characteristics of MSM seeking testing may affect temporal trends in HIV incidence and new HIV diagnoses,25,34,38 so these trends need to be interpreted cautiously. Nonetheless, these findings of level trends in HIV incidence in select populations of MSM in these US cities are, in general, corroborated by findings from studies of MSM in European cities affected by the outbreaks of syphilis.41,53–56
One possible explanation for why no increases in HIV incidence have been noted during syphilis outbreaks is that a relatively small fraction of MSM have been infected with syphilis to date in these metropolitan areas (e.g., less than 5% in San Francisco during recent outbreaks25), and half or more of these MSM already have a longstanding HIV infection. Therefore, even if the remaining susceptible men with syphilis acquire HIV at high rates, the absolute number of new HIV infections among them may be too small to markedly affect the overall trends in HIV incidence among MSM. In addition, HIV incidence among MSM in the last several years may be systematically lowered because of widespread use of HAART and associated population-level reductions in HIV viral load and infectiousness of HIV-positive persons.57 Of note, one small study suggests that HIV-infected men with syphilis who are virologically suppressed on HAART may not have an increase in plasma HIV viral load at the time of syphilis.17
Another explanation for possible stable trends in HIV incidence during the syphilis outbreak is that MSM may select sexual partners and alter sexual practices (occurrence and type of sex, use of condoms) according to the HIV-serostatus of their partners23,38,42,47,48,58 to reduce the risk of HIV transmission. The risk of HIV transmission from an HIV-infected partner to uninfected partner through unprotected receptive anal intercourse (estimated at 0.8% per contact) is approximately 10 times greater than the risk of HIV transmission through unprotected insertive anal intercourse and possibly as much as 100 times greater than the risk of transmission through unprotected oral sex.59,60 Analyses of risk behavior among 2491 HIV-positive MSM interviewed as part of multisite CDC’s Supplement to HIV/AIDS Surveillance (SHAS) project during May 2000 to December 200247 found that 31% of men reported being abstinent within the first year of HIV diagnosis, and 35% reported having only 1 steady male sexual partner during this period. Furthermore, at the last sexual encounter, sexually active HIV-positive MSM had oral sex more frequently than anal sex (85% versus 68%); they were significantly more likely (OR = 1.7) to have had insertive anal intercourse with partners who were HIV-positive than partners who were of HIV-negative or unknown HIV serostatus and were significantly more likely (OR = 3.3) to use condoms for insertive anal intercourse with HIV-negative partners than HIV-positive partners.47 In another study of MSM who were evaluated at a public health STD clinic in Seattle during October 2001 to March 2003, both HIV-infected and -uninfected MSM tended to chose partners of concordant HIV serostatus and engage in behaviors with lower risk of HIV transmission with partners of unknown or discordant HIV serostatus; for example, the 1365 HIV-negative men reported unprotected receptive anal intercourse more frequently with HIV-negative partners (31%) than partners of unknown HIV status (17%) or partners who were HIV positive (2%) in the past 12 months.42 Finally, STOP AIDS Project surveys in San Francisco have found that, although increasing proportions of MSM, particularly HIV-infected MSM, have reported UAI during 2001–2003, decreasing proportions have reported a partnership where HIV transmission could occur in the same period.38
The few studies of MSM with syphilis corroborate some degree of “HIV serosorting” and a shift toward safer sex behaviors. A case-control study of MSM with syphilis in New York City found that both HIV-infected and HIV-uninfected participants, regardless of syphilis infection, more frequently reported having HIV- seroconcordant than HIV-serodiscordant partners in the past 6 months; nevertheless, over 50% of HIV-negative and HIV-positive men had partners of unknown HIV serostatus, and a substantial minority reported unprotected sex with these partners.23 In addition, of primary and secondary syphilis cases among MSM in Chicago during 2000–2002, 20% reported oral sex as the only sexual exposure during the period when they likely acquired syphilis.5 Although unprotected oral sex is not an uncommon route for syphilis transmission due to oral syphilis lesions,61 and underreporting of unprotected anal sex by these men is possible, these findings raise the possibility that MSM may engage in unprotected oral sex as a strategy to reduce the risk of HIV transmission.
Limitations of Available Data
Our ability to draw conclusions about trends in HIV incidence among MSM during the syphilis outbreaks is limited by lack of adequate data. The few HIV incidence data and most behavioral data available are skewed toward large metropolitan areas with large gay populations and toward men who access HIV testing services in the public sector. It should also be noted that San Francisco and Los Angeles have mature HIV epidemics, but outbreaks of syphilis have occurred more widely, including in medium-size cities,9 where HIV prevalence among gay men, and gay men with syphilis, is likely lower. In these smaller cities, there may be more HIV-uninfected susceptible men who may have different risk behaviors and different trends in HIV incidence compared with men in the larger metropolitan areas.62–64
The available data must also be interpreted cautiously because of several key limitations. First, in the ecological analysis,25 the overall P&S syphilis morbidity data were reported from both private and public providers, but HIV incidence (San Francisco) and HIV diagnoses (Los Angeles) could be examined only for select populations at publicly funded HIV testing sites. Therefore, although we found level trends in HIV incidence and new HIV diagnoses among MSM who tested for HIV at public sites in the 2 cities, these findings may not apply to many men who test for HIV in the private sector or men who have not tested65 and thus may not represent the overall incidence trends for MSM in these cities. Of note, data from the National Health Interview Survey in 2002 indicate that, nationally, fewer than 25% of HIV tests are performed in public source sites, including AIDS clinic/counseling/testing sites and public health department clinics, whereas over 40% are performed by private doctors or health maintenance organizations.66 Second, the preliminary studies suggesting high HIV incidence among men diagnosed with early syphilis in San Francisco and Los Angeles may be limited by possible self-selection bias and incomplete HIV testing histories, respectively, and lack appropriate comparative data for men without syphilis. Third, STARHS methodology may misclassify persons with longstanding HIV infection as recently infected and vice versa24,26 and may overestimate HIV incidence in populations of HIV-infected persons with AIDS and on HAART, but it has been shown to produce estimates consistent with those obtained by other epidemiologic methods.67
Synthesis of Data Regarding HIV Incidence During Syphilis Epidemics
With the limited existing data, we cannot say whether HIV incidence has been increasing among MSM during syphilis outbreaks in the United States (Table 1). We do know that, to date, syphilis outbreaks have been concentrated among urban MSM, the majority of whom are HIV infected. Although MSM are more likely to have unprotected sex with partners of the same HIV serostatus, a significant subset engages in UAI with multiple partners of unknown or discordant HIV status, especially under the influence of disinhibiting substances, such as methamphetamine. Incidence of HIV infection among MSM coinfected with syphilis appears to be very high (13% and 17% per year in 2 studies). However, because MSM with syphilis represent a small fraction of all MSM in the cities and the majority of them are already HIV infected, the number of new HIV infections among MSM with syphilis and their sexual partners may be too small to markedly affect the overall trends in HIV incidence among gay and bisexual men. In San Francisco, Los Angeles, and Seattle, no consistent appreciable increase or decrease in new HIV infections in select MSM populations at public HIV testing sites has been documented during 1999–2002 (through 2004 for Seattle). Nonetheless, the variety of indirect data, including reported increases in sexual risk behavior, rates of STDs, and new HIV diagnoses, suggests that HIV incidence in some MSM populations might be increasing or might increase in the near future. It is possible that syphilis epidemics are sentinel events indicating increased sexual risk behavior and that increases in HIV incidence may lag behind increases in sexual risk behavior and syphilis morbidity.
Implications for HIV Prevention
High rates of HIV infection in syphilis cases among MSM clearly indicate that comprehensive and integrated HIV/STD prevention and control efforts are needed to halt the spread of syphilis and reduce HIV transmission. Syphilis prevention and control efforts by the local health departments and collaborating agencies have been described in detail in other papers in this supplement; here we focus the discussion on some key HIV prevention strategies.
Early detection of HIV and STDs and prompt treatment of major curable STDs are 2 essential components of comprehensive HIV prevention programs.68 In 2002, the CDC published guidelines for screening of MSM for HIV and other STDs.69,70 These guidelines state that health care providers should assess sexual risk of all male patients, including gender of patients’ sexual partners, provide HIV and STD screening when indicated, and counsel patients to reduce their risk of acquisition and transmission of HIV and STDs. Sexually active MSM should be screened at least annually for HIV infection (if HIV negative or previously not tested), syphilis, as well as gonorrhea and chlamydia at various sites.69 More frequent HIV and STD testing (every 3–6 months) may be indicated for MSM at highest risk, including those who acknowledge having multiple or anonymous sexual partners, history of STDs (including syphilis), or having had sex in conjunction with illicit drug use. Persons should be routinely offered an HIV test at the time of syphilis diagnosis. As described in other papers in this supplement, to increase testing for syphilis and HIV in the gay community, local health departments in collaboration with community-based organizations have employed a variety of strategies, including conducting health promotion campaigns to increase awareness of syphilis and the need for testing among gay men, educating private providers about STD screening guidelines, and increasing clinical and HIV and STD testing services in the community.
Furthermore, to address gaps in HIV prevention programs, the CDC launched Advancing HIV Prevention (AHP) Initiative in April 2003,71 which aims to reduce barriers to early HIV diagnosis and to increase access to and use of quality medical care, treatment, and prevention services for HIV-infected persons. Increased HIV testing and early diagnosis of HIV infection are important goals because once persons become aware that they are HIV positive, they tend to substantially reduce high-risk sexual behavior.50 One of the strategies of the AHP initiative includes implementing new models for diagnosing HIV infection outside of medical settings, which may include conducting outreach and screening for syphilis and HIV (often using a rapid HIV test) in areas and venues frequented by gay men, including men’s community centers, sex clubs/bathhouses, and adult bookstores. Another key strategy of the AHP initiative is to prevent new HIV infections by working with persons diagnosed with HIV and their partners. CDC recommends that medical providers deliver brief HIV prevention messages tailored to patients’ individual risk, reinforce safer sex behaviors, refer selected patients for more intensive HIV/STD risk-reduction interventions, and facilitate partner counseling and referral services (PCRS).70 More intensive interventions (multisession risk-reduction counseling, support groups, prevention case management) may be indicated for HIV-positive and -negative MSM diagnosed with syphilis because acquisition of syphilis indicates ongoing unsafe sex behaviors. All persons newly diagnosed with HIV should be linked to appropriate medical, behavioral, and psychosocial services to help them adapt and maintain safer sex behaviors and thus prevent acquisition of STDs and HIV transmission to their sexual partners.
In conclusion, limited available data suggest that HIV incidence among some MSM in San Francisco, Los Angeles, and Seattle-King counties is not increasing but not declining, either. Further studies of HIV incidence, sexual risk behavior, and substance use among MSM at public and private sites and in larger and smaller cities varying in maturity of HIV epidemic are needed to better understand recent trends in HIV incidence among gay and bisexual men across the United States, to promptly identify possible increases in HIV incidence in any sociodemographic and risk subgroups of MSM, and to appropriately target HIV prevention efforts using effective interventions.72,73 Recently launched HIV incidence surveillance74 will provide valuable data on HIV incidence among men and women in the United States. In addition, larger studies utilizing STARHS and pooled HIV RNA testing (for detecting acute HIV infections before HIV seroconversion)75 in men with and without early syphilis from the same clinical populations would be useful to clarify both the extent of HIV transmission associated with the syphilis outbreaks and the timing of HIV and syphilis acquisition in dually infected persons. Pooled HIV RNA methodology for screening high-HIV-incidence populations, including STD clinic patients with syphilis, should also be further evaluated as a promising HIV prevention strategy as it helps to identify persons with acute HIV infection who have a high likelihood of transmitting HIV.29 In summary, ongoing comprehensive and integrated HIV/STD research, prevention, and control efforts are needed in order to halt syphilis transmission and resurgence in unsafe sex behaviors and to reduce HIV incidence among MSM and their sexual partners in the United States.
1. 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.
2. 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.
3. Centers for Disease Control and Prevention. Primary and secondary syphilis among men who have sex with men: New York City, 2001. MMWR Morb Mortal Wkly Rep 2002; 51:853–856.
4. Centers for Disease Control and Prevention. Internet use and early syphilis infection among men who have sex with men: San Francisco, California, 1999–2003. MMWR Morb Mortal Wkly Rep 2003; 52:1229–1232.
5. Centers for Disease Control and Prevention. Transmission of primary and secondary syphilis by oral sex: Chicago, Illinois, 1998–2002. MMWR Morb Mortal Wkly Rep 2004; 53:966–968.
6. Bronzan R, Echavarria L, Hermida J, Burns T, Fox K. Syphilis among men who have sex with men in Miami-Dade County, Florida. In: Program and abstracts of the 2002 national STD prevention conference; March 4–7, 2002; San Diego, CA.
7. D’Souza G, Lee JH, Paffel JM. Outbreak of syphilis among men who have sex with men in Houston, Texas. Sex Transm Dis 2003; 30:872–873.
8. Ciesielski CA, Flynn J. HIV infection among men with infectious syphilis in Chicago, 1998–2000. In: Proceedings of the 9th conference on retroviruses and opportunistic infections; February 24–28, 2002; Seattle, WA.
9. Centers for Disease Control and Prevention. Primary and secondary syphilis: United States, 2002. MMWR Morb Mortal Wkly Rep 2003; 52:1117–1120.
10. Nicoll A, Hamers FF. Are trends in HIV, gonorrhoea, and syphilis worsening in Western Europe? BMJ 2002; 324:1324–1327.
11. Stolte IG, Dukers NH, de Wit JB, Fennema JS, Coutinho RA. Increase in sexually transmitted infections among homosexual men in Amsterdam in relation to HAART. Sex Transm Infect 2001; 77: 184–186.
12. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect 1999; 75:3–17.
13. Bentwich Z, Maartens G, Torten D, Lal AA, Lal RB. Concurrent infections and HIV pathogenesis. AIDS 2000; 14:2071–2081.
14. Plummer FA, Wainberg MA, Plourde P, et al. Detection of human immunodeficiency virus type 1 (HIV-1) in genital ulcer exudate of HIV-1-infected men by culture and gene amplification. J Infect Dis 1990; 161:810–811.
15. Mole L, Ripich S, Margolis D, Holodniy M. The impact of active herpes simplex virus infection on human immunodeficiency virus load. J Infect Dis 1997; 176:766–770.
16. Cohen MS, Hoffman IF, Royce RA, et al. Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1: AIDSCAP Malawi Research Group. Lancet 1997; 349:1868–1873.
17. Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in HIV-infected patients with new syphilis infections. AIDS 2004; 18:2075–2079.
18. Dyer JR, Eron JJ, Hoffman IF, et al. Association of CD4 cell depletion and elevated blood and seminal plasma human immunodeficiency virus type 1 (HIV-1) RNA concentrations with genital ulcer disease in HIV-1-infected men in Malawi. J Infect Dis 1998; 177:224–227.
19. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1: Rakai Project Study Group. N Engl J Med 2000; 342:921–929.
20. Rompalo AM, Joesoef MR, O’Donnell JA, et al. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis 2001; 28:158–165.
21. Wong W, Kent CK, Kohn RP, Klausner JD. Incidence of primary and secondary syphilis among HIV-infected men in San Francisco, 2001. In: Program and abstracts of the 40th meeting of the Infectious Disease Society of America; October 24–27, 2002; Chicago, IL.
22. Wong W, Chaw J, Kent C, Alpers L, Klausner J. Risk factors for early syphilis among men who have sex with men seen in an STD clinic, San Francisco 2002–2003. In: Program and abstracts of the 2004 national STD prevention conference; March 8–11, 2004; Philadelphia, PA.
23. Paz-Bailey G, Meyers A, Blank S, et al. A case-control study of syphilis among men who have sex with men in New York City: association With HIV infection. Sex Transm Dis 2004; 31:581–587.
24. Janssen RS, Satten GA, Stramer SL, et al. New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes. JAMA 1998; 280:42–48.
25. Centers for Disease Control and Prevention. Trends in primary and secondary syphilis and HIV infections in men who have sex with men: San Francisco and Los Angeles, California, 1998–2002. MMWR Morb Mortal Wkly Rep 2004; 53:575–578.
26. Taylor MM, Hawkins K, Gonzalez A, et al. Use of the serologic testing algorithm for recent HIV seroconversion (STARHS) to identify recently acquired HIV infections in men with early syphilis in Los Angeles County. J Acquir Immun Defic Syndr 2005; 38:505–508.
27. Weinstock H, Dale M, Linley L, Gwinn M. Unrecognized HIV infection among patients attending sexually transmitted disease clinics. Am J Public Health 2002; 92:280–283.
28. Pilcher CD, Price MA, Hoffman IF, et al. Frequent detection of acute primary HIV infection in men in Malawi. AIDS 2004; 18:517–524.
29. Pilcher CD, Fiscus SA, Nguyen TQ, et al. Detection of acute infections during HIV testing in North Carolina. N Engl J Med 2005; 352:1873–1883.
30. King JB, Samuel M, Kent C, Klausner J. Recent early syphilis, chlamydia and gonorrhea among men who have sex with men increase risk for recent HIV seroconversion: San Francisco 2002–2003. In: program and abstract of the 2003 national HIV prevention conference; July 27–30, 2003; Atlanta, GA.
31. Pao D, Fisher M, Hue S, et al. Transmission of HIV-1 during primary infection: relationship to sexual risk and sexually transmitted infections. AIDS 2005; 19:85–90.
32. Fox K, del Rio C, Holmes KK, et al. Gonorrhea in the HIV era: reversal of trends among men who have sex with men. Am J Public Health 2005; 91:959–964.
33. Sexually Transmitted Disease Prevention and Control Services. San Franisco Department of Public Health: San Francisco monthly STD report, November 2004 data. Available at: http://www.dph.sf.ca.us/Reports/STD/STDMONTH.pdf
. Accessed May 26, 2005.
34. HIV/AIDS Epidemiology Unit, Public Health–Seattle and King County, and Infectious Diseases and Reproductive Health Assessment Unit, Washington State Department of Health. HIV/AIDS epidemiology report: first half 2004: vol. 64, 2004. Available at: http://www.metrokc.gov/health/apu/epi/1st-half-2004.pdf
. Accessed May 26, 2005.
35. Katz MH, Schwarcz SK, Kellogg TA, et al. Impact of highly active antiretroviral treatment on HIV seroincidence among men who have sex with men: San Francisco. Am J Public Health 2002; 92:388–394.
36. Chen SY, Gibson S, Katz MH, et al. Continuing increases in sexual risk behavior and sexually transmitted diseases among men who have sex with men: San Francisco, Calif, 1999–2001, USA. Am J Public Health 2002; 92:1387–1388.
37. Rietmeijer CA, Patnaik JL, Judson FN, Douglas JM Jr. Increases in gonorrhea and sexual risk behaviors among men who have sex with men: a 12-year trend analysis at the Denver metro health clinic. Sex Transm Dis 2003; 30:562–567.
39. Wohl AR, Johnson DF, Lu S, et al. Recent increase in high-risk sexual behaviors among sexually active men who have sex with men living with AIDS in Los Angeles County. J Acquir Immun Defic Syndr 2004; 35:209–211.
40. Dodds JP, Mercey DE, Parry JV, Johnson AM. Increasing risk behaviour and high levels of undiagnosed HIV infection in a community sample of homosexual men. Sex Transm Infect 2004; 80:236–240.
41. Elford J, Bolding G, Davis M, Sherr L, Hart G. Trends in sexual behaviour among London homosexual men 1998–2003: implications for HIV prevention and sexual health promotion. Sex Transm Infect 2004; 80:451–454.
42. Golden MR, Brewer DD, Kurth A, Holmes KK, Handsfield HH. Importance of sex partner HIV status in HIV risk assessment among men who have sex with men. J Acquir Immun Defic Syndr 2004; 36:734–742.
43. Wolitski RJ, Valdiserri RO, Denning PH, Levine WC. Are we headed for a resurgence of the HIV epidemic among men who have sex with men? Am J Public Health 2001; 91:883–888.
44. Stockman JK, Schwarcz SK, Butler LM, et al. HIV prevention fatigue among high-risk populations in San Francisco. J Acquir Immun Defic Syndr 2004; 35:432–434.
45. Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and sexual risk behavior: a meta-analytic review. JAMA 2004; 292: 224–236.
47. Centers for Disease Control and Prevention. High-risk sexual behavior by HIV-positive men who have sex with men: 16 sites, United States, 2000–2002. MMWR Morb Mortal Wkly Rep 2004; 53:891–894.
48. Wolitski RJ, Parsons JT, Gomez CA. Prevention with HIV-seropositive men who have sex with men: lessons from the Seropositive Urban Men’s Study (SUMS) and the Seropositive Urban Men’s Intervention Trial (SUMIT). J Acquir Immun Defic Syndr 2004; 37:S101–S109.
49. Weinhardt LS, Kelly JA, Brondino MJ, et al. HIV transmission risk behavior among men and women living with HIV in 4 cities in the United States. J Acquir Immun Defic Syndr 2004; 36:1057–1066.
50. Marks G, Crepaz N, Senterfitt JW, Janssen RS. Meta-analysis of high-risk sexual behavior in persons aware and unaware that they are HIV infected with HIV in the United States. J Acquir Immun Defic Syndr. In press.
51. Centers for Disease Control and Prevention. Increases in HIV diagnoses: 29 States, 1999–2002. MMWR Morb Mortal Wkly Rep 2003; 52:1145–1148.
52. Goldbaum G, Reidy WJ, Buskin S. Trends in HIV incidence in King County, Washington. 2004 American Public Health Association conference; November 6–10, 2004; Washington, DC.
53. Murphy G, Charlett A, Brown AE, Gill ON, Parry JV. Is HIV incidence increasing in homo/bisexual men attending GUM clinics in England, Wales and Northern Ireland? Commun Dis Public Health 2004; 7:11–14.
54. Kahn RH, Moseley KE, Johnson G, Farley TA. Potential for community-based screening, treatment, and antibiotic prophylaxis for syphilis prevention. Sex Transm Dis 2000; 27:188–192.
55. van der Bij AK, Stolte IG, Coutinho RA, Dukers NH. Increase of sexually transmitted infections, but not HIV, among young homosexual men in Amsterdam: are STIs still reliable markers for HIV transmission? Sex Transm Infect 2005; 81:34–37.
56. Dukers NH, Spaargaren J, Geskus RB, et al. HIV incidence on the increase among homosexual men attending an Amsterdam sexually transmitted disease clinic: using a novel approach for detecting recent infections. AIDS 2002; 16:F19–F24.
57. Porco TC, Martin JN, Page-Shafer KA, et al. Decline in HIV infectivity following the introduction of highly active antiretroviral therapy. AIDS 2004; 18:81–88.
58. Guzman R, Colfax GN, Wheeler S, et al. Negotiated safety relationships and sexual behavior among a diverse sample of HIV-negative men who have sex with men. J Acquir Immun Defic Syndr 2005; 38:82–86.
59. Vittinghoff E, Douglas J, Judson F, et al. Per-contact risk of human immunodeficiency virus transmission between male sexual partners. Am J Epidemiol 1999; 150:306–311.
60. Varghese B, Maher JE, Peterman TA, Branson BM, Steketee RW. Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use. Sex Transm Dis 2002; 29:38–43.
61. Edwards S, Carne C. Oral sex and transmission of non-viral STIs. Sex Transm Infect 1998; 74:95–100.
62. Centers for Disease Control and Prevention. HIV transmission among black college student and non-student men who have sex with men: North Carolina, 2003. MMWR Morb Mortal Wkly Rep 2004; 53:731–734.
63. Webster RD, Darrow WW, Paul JP, et al. HIV infection and associated risks among young men who have sex with men in a Florida resort community. J Acquir Immun Defic Syndr 2003; 33:223–231.
64. Centers for Disease Control and Prevention. HIV incidence among young men who have sex with men: seven U.S. cities, 1994–2000. MMWR Morb Mortal Wkly Rep 2001; 50:440–444.
65. Porter CA, Thompson D, Erbelding EJ. Differences in demographics and risk factors among men attending public versus non-public STD clinics in Baltimore, Maryland. Sex Transm Infect 2004; 80:488–491.
66. Centers for Disease Control and Prevention. Number of persons tested for HIV: United States, 2002. MMWR Morb Mortal Wkly Rep 2004; 53:1110–1113.
67. Kellogg TA, Loeb L, Dilley J, et al. Comparison of three methods to measure HIV incidence among persons seeking voluntary, anonymous counseling and testing. J Acquir Immun Defic Syndr 2005; 39:112–120.
68. Centers for Disease Control and Prevention. HIV prevention through early detection and treatment of other sexually transmitted diseases: United States: recommendations of the Advisory Committee for HIV and STD Prevention. MMWR Recomm Rep 1998; 47:1–24.
69. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002: Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51:1–78.
70. Centers for Disease Control and Prevention. Incorporating HIV prevention into the medical care of persons living with HIV: recom-mendations of CDC, the Health Resources and Services Administration, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2003; 52:1–24.
71. Centers for Disease Control and Prevention. Advancing HIV prevention: new strategies for a changing epidemic: United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:329–332.
72. Janssen RS, Valdiserri RO. HIV Prevention in the United States: increasing emphasis on working with those living with HIV. J Acquir Immun Defic Syndr 2004; 37(suppl 2):S119–S121.
73. Valdiserri RO, Ogden LL, McCray E. Accomplishments in HIV prevention science: implications for stemming the epidemic. Nat Med 2003; 9:881–886.
74. Centers for Disease Control and Prevention. HIV prevention in the third decade: activities of CDC’s Divisions of HIV/AIDS Prevention. Available at: http://www.cdc.gov/hiv/HIV_3rdDecade
. Accessed May 26, 2005.
75. Pilcher CD, McPherson JT, Leone PA, et al. Real-time, universal screening for acute HIV infection in a routine HIV counseling and testing population. JAMA 2002; 288:216–221.