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Association of Herpes Simplex Virus Type 2 Infection and Syphilis with Human Immunodeficiency Virus Infection among Men Who Have Sex with Men in Peru

  1. Javier R. Lama1,
  2. Aldo Lucchetti1,
  3. Luis Suarez2,
  4. Victor A. Laguna-Torres3,
  5. Juan V. Guanira2,
  6. Monica Pun2,
  7. Silvia M. Montano3,
  8. Connie L. Celum4,
  9. Jean K. Carr5,
  10. Jorge Sanchez1,
  11. Christian T. Bautista3,a and
  12. Peruvian HIV Sentinel Surveillance Working Group3,6,b
  1. 1Asociación Civil Impacta Salud y Educación,
  2. 2Direction of General Epidemiology, Ministry of Health of Peru, and
  3. 3US Naval Medical Research Center Detachment, Lima, Peru;
  4. 4Departments of Medicine and Epidemiology, University of Washington, Seattle;
  5. 5Division of Epidemiology and Prevention, Institute of Human Virology, Baltimore, and
  6. 6Department of Defense Global Emerging Infections Surveillance and Response System, Walter Reed Army Institute of Research, Silver Spring, Maryland
  1. Reprints or correspondence: Dr. Jose L. Sanchez, Dept. of Defense Global Emerging Infections Surveillance and Response System, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910-7500 (sanchezjl{at}amedd.army.mil)
 
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Abstract

BackgroundWe evaluated associations between human immunodeficiency virus (HIV) infection, herpes simplex virus type 2 (HSV-2) infection, and syphilis among men who have sex with men (MSM) in Peru

MethodsA surveillance survey of 3280 MSM was conducted; sexual behavior was assessed with a structured computer-assisted self-interview, and serum antibody testing was performed for HIV, HSV-2, and Treponema pallidum

ResultsHIV, HSV-2, and syphilis seroprevalences of 13.9%, 46.3%, and 13.4% were detected, respectively. HSV-2 seroprevalence was twice as high in HIV-infected subjects (80.5%) than it was in HIV-uninfected subjects (40.8%) (P<.01), and HSV-2 seropositivity (adjusted odds ratio [AOR], 5.66) was found to be strongly associated with HIV infection. In addition, homosexual self-definition (AOR, 3.12), exchange of sex for money (AOR, 1.61), unprotected sex (no condom) (AOR, 2.81), history of sex work (AOR, 1.89), oral receptive sex (AOR, 1.43), and cocaine use before/during sex (AOR, 2.53) within the preceding 6 months, as well as such sexually transmitted infections (STIs) and STI syndromes as proctitis (AOR, 2.80), genital ulcer disease (GUD) (AOR, 2.06), prior syphilis (AOR, 2.64), genital warts (AOR, 1.70), and self-reported STIs within the preceding 6 months (AOR, 1.61), were also found to be significant predictors of HIV infection

ConclusionsWe found a strong association between HSV-2 seropositivity and HIV infection. Intervention measures against GUD due to HSV-2 infection and syphilis, such as routine testing, early detection, HSV-2 suppressive treatment, and condom distribution, need to be enhanced as part of STI prevention strategies at a national level to effectively reduce HIV infection among MSM in Peru

After sub-Saharan Africa and Asia, the region most impacted by HIV infection is Latin America, where the epidemic reflects diverse transmission patterns [1]. In all countries of the Andean region (Venezuela, Colombia, Ecuador, Peru, and Bolivia), men who have sex with men (MSM) account for a substantial proportion of HIV infections [2] and compose a “bridging group” for transmission to heterosexuals because of the high frequency of reported bisexuality among MSM [3]

Since 1996, the Peruvian Ministry of Health (MoH) has implemented HIV prevention activities targeted at vulnerable populations. Specifically among MSM, these activities have included the promotion and distribution of condoms at venues and a public information campaign aimed at reduction of high-risk sexual behaviors, as well as the establishment of voluntary counseling and testing sites. Targeted interventions among MSM communities have also included the provision of free medical exams and diagnosis of HIV infection and other sexually transmitted infections (STIs). However, herpes simplex virus type 2 (HSV-2) infection has not been a focus of these prevention efforts

High HSV-2 seroprevalences have been well documented among MSM groups in developed countries [4], with rates as high as 26%–66% in several US cities [5, 6], 33%–58% in Amsterdam [7, 8], 15% in Rotterdam [9], 51%–86% in Rome [10], and 11%–61% in London [11]. HSV-2 seroprevalence data from developing countries have been generated primarily from African and Asian countries [12] and have focused on non-MSM risk groups, such as female sex workers, bar workers, and STI clinic attendees [13]. Specifically, data are limited regarding the seroprevalence of HSV-2 and syphilis among MSM communities in large urban centers in Latin America, which have HIV-infection rates comparable to those in urban US cities

HSV-2 and HIV interactions have been examined by many investigators over the past 2 decades [4, 6–8, 12,13, 14–16]. In a number of observational studies, STIs, particularly HSV-2 infection, increase the probability of acquisition and transmission of HIV by increasing susceptibility to and infectiousness of HIV, respectively [14]. Thus, it would be anticipated that such high levels of infection would greatly contribute to a high proportion of the HIV infections that are attributable to HSV-2, as suggested by Wald and Link [15] and Freeman et al. [16] in 2 recent meta-analyses of HSV-2 and HIV infection. To date, there appear to be no published reports of the relationship between HIV and HSV-2 infection among MSM risk groups in Latin America

To study associations of HSV-2 infection and syphilis with HIV infection in Peru, we assessed their seroprevalences among MSM enrolled as part of a large, second-generation HIV surveillance survey conducted by the National AIDS and Sexually Transmitted Disease (STD) Control Program of the Peruvian MoH during 2002–2003. Results of the first MSM HIV surveillance survey conducted in 1996 have been published elsewhere [3] but did not include an evaluation of HSV-2 infection

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Subjects, Materials, and Methods

Study population and study designDuring November 2002 and February 2003, a second-generation HIV surveillance study of MSM was conducted at 12 sites involving 6 major urban cities in Peru (Sullana, Piura, Lima/Callao, Iquitos, Pucallpa, and Arequipa). A convenience sample of men who were at least 18 years of age and who reported previous sexual intercourse with 1 or more men during the preceding year were invited to participate, regardless of history of HIV testing, serostatus, or treatment. There was no effort to oversample HIV-infected persons during this process

Outreach work and “snowball” techniques were used to recruit potential participants. Recruiters and peer educators, representing the diverse MSM subcultures in these cities, visited different and previously mapped venues (including saunas, pornographic movie theaters, pornographic video arcades, prostitution areas, discotheques, bars, beauty parlors, transvestite houses, MSM sport events, and others) to contact potential participants and to refer them to the study clinics. To refer participants, recruiters and peer educators used diverse methods, including posters, flyers, and informational meetings, depending on where recruitment activities were conducted

To sample a diverse population of MSM, 5 geographically dispersed STI clinics served as sentinel sites in Lima/Callao (corresponding to major parts of the capital’s metropolitan area), as well as 1–2 STI clinics in each of the other cities. Participants were recruited after referral from MSM gathering points as well as from those subjects attending these STI clinics for care. At each sentinel site, a counselor explained the study objectives to potential participants and obtained written, informed consent for their participation as well as for providing blood samples for nonanonymous HIV, HSV-2, and syphilis testing, including consent for storage of samples for further testing and/or for contact for future studies. Those participants who agreed and provided voluntary informed consent underwent a computer-assisted self-interview, which included a total of 114 questions dealing with demographics, sexual risk behavior, and previous HIV testing and diagnosis, as well as self-reported sexual identity and self-reported past evidence of STIs and illegal drug use in the recent past (6–12 months). Counselors assisted participants in case of illiteracy or unfamiliarity with computers. Physicians obtained a brief medical history, and a targeted physical examination was performed, including examination of the genitals, anus, lymph nodes, skin, and oropharynx. No other specific genitourinary or STI-related diagnostic testing or sampling was performed as part of this surveillance study

All participants received pre- and posttest counseling and sexual risk behavior reduction education. Participants who were diagnosed with an STI received syndromic (or, in the case of syphilis, etiologic) treatment, in accordance with Peruvian STD treatment guidelines [17], which essentially follow Centers for Disease Control and Prevention guidelines [18]. Participants who received a diagnosis of HIV infection received standard health care, in accordance with Peruvian HIV and AIDS health care management guidelines [19], which did not include antiretroviral therapy at the time this survey was conducted

Laboratory proceduresA peripheral venous blood sample was obtained for detection of antibodies to HIV-1, as determined by ELISA (Vironostika; Organon Tecnica) and confirmed by Western blot assay (Biorad Laboratories). Antibodies to Treponema pallidum were qualitatively detected and then quantified by rapid plasma reagin (RPR) (Organon Tecnica), with confirmation by microhemagglutination assay (MHA-TP; Organon Tecnica). Syphilis seroreactivity was defined by an RPR titer ⩾1:1 and a reactive MHA-TP; a presumptive diagnosis of early syphilis was made for participants having an RPR titer ⩾1:16 and a reactive MHA-TP. HSV-2 antibody testing was determined by type-specific ELISA (Focus Technology). HSV-2 seropositivity was defined by a reactive ELISA with an index ratio ⩾3.5, compared with the cutoff value, to improve the specificity of the assay [20, 21]

Ethics approvalsThe study protocol (NMRCD.2003.0003, DoD No. 32513, “Second Generation Surveillance of STD/HIV/AIDS in Men Who Have Sex with Other Men, Peru—2002”), informed consent, and recruitment materials used in this HIV sentinel surveillance study were approved by the institutional review boards and scientific ethics committees at the Asociación Civil Impacta Salud y Education, Lima, Peru; at the University of Washington, Seattle; and at the US Navy Medical Research Center, Silver Spring, Maryland

Statistical analysisExploratory evaluation of possible associations between HIV infection and other variables was done by use of odds ratios (ORs) and associated 95% confidence intervals (CIs), which were estimated by use of random effects multiple logistic regression, for which the city was defined as the group variable. All ORs were adjusted (AOR) by age, educational level, unprotected sex at last sexual encounter (without condom), and number of male sex partners in a random effects multiple logistic regression analysis. A ρ statistic was estimated to analyze whether there was a clustering of HSV-2 infections. All statistical analyses were 2-tailed and were performed using STATA (version 8.0; StataCorp). P<.05 was considered to be statistically significant

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Results

Characteristics of study populationA total of 3280 MSM met the entry criteria and accepted participation in the 2002–2003 HIV surveillance survey. Demographic, educational, and sexual behavior characteristics of this population are shown in table 1. The median age of participants was 24 years (range, 18–71 years). Only 351 (10.9%) reported having a primary-level education or less. Notably, 336 (10.4%) participants self-identified as being heterosexual even though eligibility criteria included having had sex with a man in the preceding year. Thirty-one percent stated that they had received money or gifts in exchange for sex, and approximately one-tenth self-identified as being sex workers

Seroprevalence for HIV infection and other STIsHIV infection was documented in 456 (13.9% [95% CI, 12.7%–15.1%]) of 3280 subjects (table 1). HIV seroprevalence was found to be at least twice as high in the large urban center of the capital region of Lima/Callao (22.3%) than in any of the other cities (range, 5.7%–11.6%) (P<.05). A pattern of increasing HIV seroprevalence with age was noted, with a low of 4.4% in those 20 years of age or less and a high of 21.9% in those 31–40 years of age (P<.001, χ2 test for trend) (figure 1). HIV-positive subjects were also significantly older than HIV-negative ones (29.3 vs. 26.1 years; P<.001)

Figure 1
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Figure 1

Seroprevalences of HIV infection, syphilis, and herpes simplex virus type 2 (HSV-2) infection by age group among 3280 subjects (men who have sex with men) in Peru, 2002–2003. Increasing seroprevalence by age group was found for HIV infection, syphilis, and HSV-2 infection (P<.001, χ2 test for trend)

Serologic evidence of past genital ulcer disease (GUD) was common. Syphilis seropositivity was documented in 440 participants (13.4% [95% CI, 12.3%–14.6%]) (table 1), with evidence of early syphilis in 112 (3.4%) overall, representing approximately one-fourth of all RPR/MHA-TP seroreactive participants. HSV-2 seroprevalence (46.3% [95% CI, 44.6%–48.0%]) was 3.5-fold higher than that of syphilis. Both syphilis and HSV-2 seroprevalences were found to be substantially higher in the lowland, Amazon River basin cities of Iquitos and Pucallpa than in other cities. As with HIV seroprevalence, syphilis and HSV-2 seroprevalences increased with age (P<.001, χ2 test for trend) (figure 1). HSV-2 seroprevalence was also noted to be twice as high among those who were HIV positive (367 [80.5%] of 456) than among HIV-negative subjects (1151 [40.8%] of 2824) (P<.01)

Table 1
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Table 1

Characteristics of HIV sentinel surveillance survey population by city in Peru, 2002–2003

Factors associated with HIV infection (univariate analysis)Significant demographic and behavioral risk factors associated with HIV infection included lower educational level (OR, 1.62), self-identifying as homosexual (as opposed to bisexual, transvestite, or heterosexual) (OR, 3.04), 4 or more male sex partners in the preceding 6 months (OR, 1.55), unprotected sex at last sexual encounter (without a condom) (OR, 2.83), history of sex work (OR, 1.91), and cocaine use before or during sex (OR, 2.11). Oral insertive sex (OR, 0.69) and anal insertive sex with the last partner (OR, 0.59), illegal drug use (including injection drug use) (OR, 0.72), and alcohol use before or during sex (OR, 0.75) in the preceding 6 months were inversely associated with HIV infection (table 2)

Table 2
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Table 2

Univariate and multiple analysis of risk factors for HIV infection among 3280 subjects (men who have sex with men) in Peru, 2002–2003

A self-reported history of an STI (OR, 1.74) was associated with HIV infection, including, specifically, a history of GUD (OR, 2.50), a history of proctitis (OR, 3.36), and genital warts (OR, 2.05). More important, serologic markers of past T. pallidum infection (OR, 2.14), as well as past HSV-2 infection (OR, 6.23), were also found to be strongly associated with HIV infection

Factors associated with HIV infection (multiple analyses)The results of the random effects multiple logistic regression analysis are also shown in table 2. Significant behavioral risk factors associated with HIV infection after adjustment for age, educational level, condom use, number of male sex partners, and city were as follows: (1) identifying as homosexual (AOR, 3.12), (2) exchange of sex for money (AOR, 1.61), (3) unprotected sex (without condom) at last sexual encounter (AOR, 2.81), (4) a history of sex work (AOR, 1.89), (5) oral receptive sex with last partner (AOR, 1.43), and (6) use of cocaine before or during sex (AOR, 2.53). Interestingly, bisexual self-definition (AOR, 0.38) was inversely associated with HIV infection

Among STI-associated variables, we found that a self-reported history of any STI (AOR, 1.61), including, specifically, a previous GUD (AOR, 2.06), a history of proctitis (AOR, 2.80), and genital warts (AOR, 2.06), in the preceding year was also associated with HIV infection. More important, we found a strong association between HIV infection and evidence of past syphilis (AOR, 2.64) as well as between HIV infection and HSV-2 infection (AOR, 5.66). In addition, a significant degree of clustering of HSV-2 infection by city was documented (ρ statistic, 15% [95% CI, 7%–30%]; P<.001)

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Discussion

To our knowledge, this is the first large study among Latin American MSM that examines the association between HIV infection and GUD to include HSV-2 infection and syphilis, in 6 major cities in Peru. This HIV surveillance survey adds to previous reports that indicate the high prevalence of HIV infection in Latin American cities and the risk factors for this infection among MSM communities [2, 3, 22, 23]. Previous studies have characterized HSV-2 prevalence among general antenatal populations and STI clinic attendees in this region and have reported evidence of an increasing HSV-2 prevalence with age, especially among females [12, 13], but did not include MSM populations

In this study, HSV-2 seroprevalence was ∼2-fold higher (80.5% vs 40.8%) among HIV-infected than among HIV-uninfected MSM. More important, HSV-2 infection was associated with a >5-fold higher HIV infection rate in the adjusted analyses (table 2). The most compelling evidence for an association between HSV-2 and HIV infection among MSM is provided by the findings among 4295 high-risk HIV-negative individuals who participated in an intensive behavioral intervention study (the EXPLORE cohort) in 6 major urban centers in the United States between 1999 and 2003 and who were followed up for a period of >3 years [24, 25]. In the EXPLORE cohort study, a significant increase in the risk of HIV infection was associated with recently acquired and prevalent HSV-2 infection—by 3.6-fold and 1.5-fold, respectively [26]. Notably, we observed a 2-fold higher HSV-2 seroprevalence among the HIV-negative MSM in our study than in the EXPLORE cohort, indicating that HSV-2 may account for a substantially greater proportion of new infections in this MSM population [26]

In previous studies of MSM in Peru, high HIV incidences have also been noted [27–30]. Such studies have included cross-sectional studies in which HIV incidence was measured using single, simple, sensitive/less sensitive ELISA testing methodology [27], as well as longitudinal studies in which the observed HIV incidences were 3.3 and 6.2 infections/100 person-years between 1998 and 2000 [28, 29] and between 2001 and 2003 [30], respectively. These cohort studies have shown that incident HIV infection is closely related to newly acquired STIs, especially those associated with genital or anorectal ulcers, as well as to unprotected receptive anal sex with casual male partners [28, 29]

We were also able to detect an association between HIV and T. pallidum infection, another prevalent cause of GUD among MSM in Peru. Serologic evidence of syphilis was associated with a 2.6-fold increase in HIV infection. Interestingly, the prevalence of syphilis was also significantly higher in those cities where the HIV prevalences were lower (table 1). This seemingly counterintuitive finding may be partly explained by the ongoing decreasing trend in syphilis prevalence among MSM in Peru, as documented in a recent study by our group in Lima [31], where we have estimated an annual decrease of 10%–20% in syphilis seroreactivity rates during the period 1996–2002. This finding is also in stark contrast with recent evidence of increases in primary and secondary syphilis in the United States, especially among MSM and African American men, which have been found to be associated with high rates of HIV coinfection, high-risk sexual behavior, and use of drugs such as methamphetamines [32, 33]

The associations found with other STIs, as reflected by a self-reported history of proctitis and/or genital warts (table 2), remained significant in multiple logistic regression analysis. It is difficult for us to try to “tease out” these relationships any further, given the known limitations in terms of the reliability and validity of self-reported STI data, as described below. Future prospective cohort studies of HIV infection and other STIs among MSM communities need thorough clinical and laboratory STI evaluations to be conducted to more reliably assess these associations

Our study suffered from a number of limitations. First and most importantly, as in most sentinel surveillance surveys, convenience-based sampling was conducted. Individuals were recruited by experienced outreach workers, whose composition was not necessarily uniform across time. Although all surveys followed standard guidelines promulgated by authorities in the field of HIV surveillance systems [34] and recruited large samples of diverse participants representing the diverse MSM subcultures in Peru, sampling may have been biased by the recruiters’ knowledge of, and access to, different subgroups of MSM. This is reflected in the diverse study population composition based on self-reported sexual identity (table 1). To ensure better representation of this MSM study population, future sampling should consider the implementation of stratified cluster sampling techniques, as described elsewhere [35]

Second, given that 12 different clinic sites and hundreds of field personnel participated in the surveys in all 6 cities, it is possible that differences in volunteer recruitment and study interview administration may have existed. There is no way for us to be able to assess intra- or intercity variability in terms of volunteer recruitment and quality of data collection across sites. No significant changes occurred in the structure of study clinics and in the procedures followed by study personnel, however

Third, we could not objectively assess the role that other STI-causing pathogens may have played in explaining the difference in risk between HIV-infected and HIV-uninfected participants. Laboratory evaluation for bacterial (chlamydia, gonorrhea, and chancroid) and viral (hepatitis B and hepatitis C) infections was not done during this survey, because of the limitations in study funding and the need for additional laboratory diagnostic support that was not available at the time. Therefore, objective, laboratory-based evaluation of such important coinfections was not performed and could not be controlled for in the analyses

Fourth, evidence of previous herpes and/or syphilis was found to be considerably common in our study population. Given that previous herpes (as reflected by HSV-2 seropositivity) was at least 3 times as common as T. pallidum infections in our sample, the potential cofactor effect that prior syphilis may have had on HIV infection may have been “diluted out” by the high prevalence of, and strong association with, HSV-2 infection. Thus, the extent to which these 2 variables could represent confounding (or interactive) factors in their association with HIV infection could not be determined

Fifth, because both HIV and HSV-2 infections are STIs, concerns about the confounding of the effect that HSV-2 infection has on HIV acquisition by other unmeasured risky sexual behaviors remain, as pointed out elsewhere by Wald and Link [15]. To address this problem, we forced the inclusion of proxy measures of risky sexual behavior in the adjusted analyses in table 2 (such as unprotected sex [without condom] and number of male sexual partners). No significant changes in AORs were noted when compared with a model not including such variables

Last, the temporal sequence of HSV-2 and HIV infection cannot be determined from this cross-sectional surveillance study, a drawback inherent to all such studies, in which all association estimates (i.e., ORs) given are less accurate than those measured in prospective, controlled cohort studies

HSV-2 suppression has been demonstrated to reduce systemic and mucosal HIV-1 levels among HIV/HSV-2–coinfected subjects [36]. The question of whether there are public health benefits of HSV-2 suppressive treatment is pending the results of ongoing randomized trials of acyclovir suppression to prevent HIV acquisition and transmission [14], as well as of ongoing evaluations of preexposure antiretroviral prophylaxis, which will provide guidance about their role as additional HIV prevention strategies to reduce HIV susceptibility and infectiousness among MSM in Peru

In summary, high HIV, HSV-2, and syphilis seroprevalences were noted among MSM groups from 6 cities in Peru. Our findings extend the observations about HSV-2 infection and HIV infection among MSM in North America [15, 16] to MSM in Latin America. An association with symptomatic evidence of STIs and STI syndromes in the near or remote past, such as GUD, proctitis, and genital warts, as well as a strong association with HSV-2 seropositivity and syphilis, was noted. Intervention measures against HSV-2 infection and syphilis, such as community education about herpes and genital ulcer syndromes, routine serologic screening for HSV-2 and syphilis, improved clinical diagnostic strategies, and condom distribution, could be incorporated as part of current STI prevention strategies

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Peruvian HIV Sentinel Surveillance Working Group

Members of the Peruvian HIV Sentinel Surveillance Working Group include Luis Suarez and Mónica Pun, Direction of General Epidemiology, Ministry of Health, Lima, Perú; César Cabezas and Patricia Caballero, National Institute of Health, Ministry of Health, Lima, Perú; Jorge Sánchez, Javier Lama, Juan Guanira, Aldo Lucchetti, Pedro Goicochea, Jorge Vergara, and Rosa Galván, Asociación Civil Impacta Salud y Educación, Lima, Perú; Martín Casapía and Juan Carlos Hinojosa, Asociación Civil Selva Amazonica, Iquitos, Perú; Victoria Zamalloa, Instituto Sur Peruano de Infectologia, Arequipa, Perú; Abner Ortiz, Centro Médico Cayetano Heredia, Pucallpa, Perú; Nora Ojeda, Asociación de Servicios Generales de Salud y Educación, Sullana, Perú; Anabeli Tataje, Policlínico Daniel Alcides Carrión, Ica, Perú; Pablo Campos, Patricia García, and César Cárcamo, Universidad Peruana Cayetano Heredia, Lima, Perú; Connie L. Celum, King K. Holmes, Joseph Zunt, and William Whittington, University of Washington, Seattle; and José L. Sánchez (past member), Silvia Montano, Victor A. Laguna-Torres, and Tadeusz Kochel, US Naval Medical Research Center Detachment, Lima, Perú

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Acknowledgments

We acknowledge the contributions made by the staff of the participating health centers in each of the 6 cities and by all the participants who so graciously provided their time to participate in this study. We also give special thanks to Jorge Vergara for his contributions as central coordinator of surveillance efforts and to Rosa Galvan for all laboratory study coordination and testing support, as well as to all the study recruiters and peer educators who provided us with invaluable field support

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Footnotes

  • ↵Potential conflicts of interest: none reported

    Financial support: Ministry of Health of Peru; Asociación Civil Impacta Salud y Educación; US National Institutes of Health; Fogarty International Center, University of Washington AIDS International Training and Research (grant D43-TW00007); US Naval Medical Research Center (work unit 62787A.873.H.B0002); US Military HIV Research Program, Walter Reed Army Institute of Research (work unit 62787A.S17.H.B0002)

    The opinions and assertions made by the authors do not reflect the official position or opinion of the government of the Republic of Peru, the Ministry of Health of Peru, the US Departments of the Army or Navy, or of any of the other organizations listed

  • ↵Present affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Rockville, Maryland

  • ↵Study group members are listed after the text

  • Received June 9, 2006.
  • Accepted July 22, 2006.
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  1. J Infect Dis. (2006) 194 (10): 1459-1466. doi: 10.1086/508548
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