Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

Unraveling the Mysteries of Acute Flaccid Myelitis: Scientific Opportunities and Priorities for Future Research.

Since 2014, cases of acute flaccid myelitis (AFM) have been reported in the United States in increasing numbers biennially, occurring in the late summer and early fall. Although there is unlikely to be a single causative agent of this syndrome, non-polio enteroviruses, including enterovirus D-68 (EV-D68), have had epidemiological and laboratory associations with AFM. Much remains to be known about AFM and AFM-associated enteroviruses, including disease pathogenesis and the best strategies for development of therapeutics or preventive modalities including vaccines. To catalyze research that addresses these scientific and clinical gaps, the National Institute of Allergy and Infectious Diseases convened a workshop entitled "AFM Preparedness: Addressing EV-D68 and Other AFM-Associated Enteroviruses" on 19-20 February 2020.

Refocusing Research on Sexually Transmitted Infections.

This article highlights biomedical research goals for the development of critical tools, including innovative diagnostics, safe and effective vaccines, and new and improved therapeutics, necessary to achieve an end to the global epidemic of sexually transmitted infections. The incidence of sexually transmitted infections (STIs), including gonorrhea, syphilis, chlamydia, and trichomoniasis, is increasing by over 1 million new cases daily and represents a global public health crisis. There is an alarming increase of gonorrhea and syphilis among men who have sex with men and bisexual men, 2 key populations also at high risk for human immunodeficiency virus. A refocused, dedicated, and intensive biomedical research program is needed targeting development of innovative diagnostics, safe and effective vaccines, and new and improved therapeutics. This article highlights biomedical research goals providing critical tools necessary to achieve an end to the global STIs epidemic.

A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases.

A priority for the National Institute of Allergy and Infectious Diseases is development of a universal influenza vaccine providing durable protection against multiple influenza strains. NIAID will use this strategic plan as a foundation for future investments in influenza research.

Zika Virus and Future Research Directions.

There was a dramatic upsurge in research activity after the recognition of Zika virus (ZIKV) transmission in South America in 2015 and its causal relationship to devastating anomalies in newborn infants. Progress in this area required a community of arbovirologists poised to refocus their research efforts and rapidly characterize the features of ZIKV transmission and infection through diverse multidisciplinary collaborations. Significant gaps remain in our knowledge of the natural history of ZIKV infection, its effects on neurodevelopment, modes and risk of transmission, and its interrelationship with other arbovirus infections. Development of effective countermeasures, such as therapeutics and an effective vaccine, are also research priorities. Lessons learned from our research response to ZIKV may help public health officials plan for the next emerging infectious disease threat.The last 18 months have witnessed one of the most rapid and coordinated research responses against an emerging disease to date. Zika virus, a pathogen that has been known since 1947 but poorly studied until recently because it was believed to only cause a mild infection, has rapidly become the object of intense investigation by the international research community since the link between infection and severe congenital disease was announced by Brazilian authorities in November 2015. According to PubMed, the total number of ZIKV-related publications skyrocketed from 117 in 2015 to 3253 in August of 2017. This supplement summarizes the tremendous progress that has been made since 2015 to elucidate the biology of this virus, its various disease manifestations in humans and animals, the diverse routes by which it is transmitted, and the role of various mosquito vectors in the recent outbreaks. In addition, several efforts have been initiated to develop new diagnostics, therapeutics, vaccines, and vector control strategies to better detect, treat, and prevent this important infection. There are 3 factors that contributed to the rapid progress in ZIKV research: (1) the availability of dedicated funding for ZIKV research; (2) the prior existence of both flavivirologists and maternal-child health researchers who were poised to tackle this new public health challenge; and (3) the high level of coordination and collaboration between different research agencies worldwide.Despite the significant progress, many significant questions remain to be addressed to accelerate the development of effective ZIKV countermeasures and increase our preparedness against this significant public health threat. Some of the most pressing scientific gaps that need to be addressed to advance the field are summarized below.

Alcohol use, anal sex, and other risky sexual behaviors among HIV-infected women and men.

Effective sexual risk reduction strategies for HIV-infected individuals require an understanding of alcohol's influence on specific sexual behaviors. We conducted audio-computer-assisted-self-interviews on 910 patients from two HIV primary care programs. The association between alcohol use and risky sexual behaviors was examined using multivariable logistic regression adjusting for age, education, race/ethnicity and drug use. Frequent/binge drinking was associated with engaging in anal sex and having multiple sex partners among women, engaging in insertive anal sex among gay/bisexual men, and was unrelated to risky sexual behaviors among heterosexual men. Infrequent drinkers did not differ in sexual risk behaviors from abstainers among women or men. Finally, there was no interaction effect between race/ethnicity and alcohol use on the association with sexual risk behaviors. The study has yielded important new findings in several key areas with high relevance to HIV care. Results underscore the importance of routinely screening for alcohol use and risky sexual behaviors in HIV primary care.

Incarceration, high-risk sexual partnerships and sexually transmitted infections in an urban population.

OBJECTIVES: The authors examined the associations between personal and partner incarceration, high-risk sexual partnerships and biologically confirmed sexually transmitted infection (STI) in a US urban population. METHODS: Data from a probability survey of young adults 15-35 years of age in Baltimore, Maryland, USA, were analysed to assess the prevalence of personal and partner incarceration and its association with several measures of high-risk sexual partnerships including multiple partners, partner concurrency and current STI. RESULTS: A history of incarceration was common (24.1% among men and 11.3% among women). Among women with an incarcerated partner in the past year (15.3%), the risk of current STI was significantly increased (adjusted prevalence ratio=2.3, 95% CI 1.5 to 3.5). Multiple partners (5+) in the past year and partner concurrency were disproportionately high among men and women who had been incarcerated or who had sexual partner(s) or who had recently been incarcerated. These associations remained robust independent of personal socio-demographic factors and illicit drug use. CONCLUSIONS: Incarceration may contribute to STI risk by influencing engagement in high-risk behaviours and by influencing contact with partners who engage in risky behaviours and who hence have elevated risk of infection.

Changes in fluoroquinolone use for gonorrhea following publication of revised treatment guidelines.

OBJECTIVES: We evaluated the impact of revised national treatment recommendations on fluoroquinolone use for gonorrhea in selected states. METHODS: We evaluated gonorrhea cases reported through the Sexually Transmitted Disease Surveillance Network as treated between July 1, 2006 and May 31, 2008, using interrupted time series analysis. Outcomes were fluoroquinolone treatment overall, by area, and by practice setting. RESULTS: Of 16,126 cases with treatment dates in this period, 15,669 noted the medication used. After revised recommendations were released, fluoroquinolone use decreased abruptly overall (21.5%; 95% confidence interval [CI] = 15.9%, 27.2%), in most geographic areas evaluated, and in sexually transmitted disease clinics (28.5%; 95% CI = 19.0%, 37.9%). More gradual decreases were seen in primary care (8.6%; 95% CI = 2.6%, 14.6%), and in emergency departments, urgent care, and hospitals (2.7%; 95% CI = 1.7%, 3.7%). CONCLUSIONS: Fluoroquinolone use decreased after the publication of revised national guidelines, particularly in sexually transmitted disease clinics. Additional mechanisms are needed to increase the speed and magnitude of changes in prescribing in primary care, emergency departments, urgent care, and hospitals.

Treatment of syphilis in HIV-infected subjects: a systematic review of the literature.

BACKGROUND: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects remains controversial. OBJECTIVE: To systematically assess the literature for studies evaluating syphilis treatment regimens in this population. METHODS: Two reviewers independently assessed studies published between 1980 and June 2008 in electronic databases, trial registries and bibliographies (with no language restrictions) for content and quality. Studies that included 10 or more people, with documented HIV status, type and duration of syphilis treatment and at least 6 months of follow-up were included. The primary outcome was syphilis serological or clinical failure stratified by syphilis stage. RESULTS: Of 1380 unique citations, 23 studies (22 published papers and 1 conference abstract) were included in the systematic review. Owing to the significant heterogeneity among studies, pooled summary statistics could not be generated. The range of probabilities for serological failure with 2.4 million units (MU) of intramuscular benzathine penicillin G (BPG) was 6.9% (95% CI 2.6% to 14.4%) to 22.4% (11.7% to 36.6%); that of 7.2 MU of BPG in late latent syphilis was 19.4% (11.9% to 28.9%) to 31.1% (22.3% to 40.9%) and failure estimates with 18-24 MU of aqueous penicillin for the treatment of neurosyphilis were 27.3% (6.0% to 61.0%) to 27.8% (14.2% to 45.2%). CONCLUSIONS: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects is unknown; guideline recommendations in this population are based on little objective data.

Screening for acute human immunodeficiency virus infection in Baltimore public testing sites.

BACKGROUND: Human immunodeficiency virus (HIV) RNA testing of pooled HIV antibody-negative specimens can identify acute HIV infection (AHI) and trigger interventions to reduce transmission during this highly infectious period. METHODS: A Baltimore, MD program serving sexually transmitted disease clinics and other high-risk sites combined HIV testing by third-generation enzyme immunoassay (EIA) with RNA testing of pooled antibody-negative specimens. Laboratory and Disease Intervention Specialists' records were reviewed for program evaluation. A cost analysis was performed. RESULTS: In 22 months, we tested 60,695 specimens for HIV. Of these, 1766 (2.9%) tested positive by EIA. Pooled HIV RNA testing of 58,925 EIA-negative specimens detected 7 cases of AHI (0.01%). Reflex HIV RNA testing of EIA-reactive, Western blot-indeterminate specimens confirmed 4 additional AHI cases (total AHI, 0.02%). Contact tracing detected no additional previously unknown cases of HIV infection. CONCLUSIONS: The utility of pooled HIV RNA testing may be limited by advances in HIV testing technology that reduce the seronegative window period and by characteristics of the local HIV epidemic.

Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics.

BACKGROUND: Studies in antenatal care clinics suggest that lower genital tract infections (LGTI) may be associated with adverse pregnancy outcomes (APO). We sought to characterize antenatal care patterns and determine whether LGTI are independently associated with preterm birth and/or low-birth weight among a high-risk public sexually transmitted diseases (STD) clinic population. METHODS: Electronic STD clinic medical records and state birth records were matched for 730 pregnant women age 13 to 49 tested for 5 treatable LGTI (bacterial vaginosis, chlamydia, gonorrhea, early syphilis, and trichomoniasis) in a case-control analysis. Cases were women with preterm and/or low-birth weight newborns; controls were women without APO. The association between LGTI and APO was assessed using logistic regression. RESULTS: Although pregnant women attending STD clinics reported high risk behaviors and were found to have high rates of LGTI (55%), most of these women were engaged in antenatal care (85%). Of the pregnant women, 22% experienced an APO (7% preterm birth, 4% low birth weight, and 12% preterm birth and low birth weight). In multivariate analyses, chlamydia was associated with low-birth weight (adjusted odds ratio [aOR]: 2.07, 95% confidence interval [CI]: 1.01-4.24), and gonorrhea was associated with preterm birth (aOR: 2.01, 95% CI: 1.02-3.97), particularly when diagnosed during the first trimester (aOR: 2.95, 95% CI: 1.30-6.70). CONCLUSIONS: Our findings confirm the association of some LGTI with APO and suggest that timing of LGTI screening may affect outcomes. STD clinic visits represent a critical opportunity to target interventions aimed at improving pregnancy outcomes.

Chlamydia trachomatis infection among 15- to 35-year-olds in Baltimore, MD.

BACKGROUND: Chlamydia trachomatis (Ct) is the most frequently reported infectious disease in the United States. This article reports population and subpopulation prevalence estimates of Ct and correlates of infection among 15- to 35-year-olds in Baltimore, MD. METHODS: The Monitoring STIs Survey Program (MSSP) monitored sexually transmitted infection (STI) prevalence among probability samples of residents of Baltimore, a city with high STI rates. MSSP respondents completed telephone audio computer-assisted self-interviews and provided biospecimens for STI testing. RESULTS: Among 2120 Baltimore residents aged 15 to 35 years, the estimated prevalence of chlamydia was 3.9% (95% confidence interval [CI]: 2.8, 5.0). Prevalence was 5.8% (95% CI: 4.1, 7.6) among black MSSP respondents versus 0.7% (95% CI: 0.0, 1.4) among nonblack respondents; all but 4 infections detected were among black respondents. Sexual behaviors and other factors associated with infection were far more prevalent among black than nonblack Baltimore residents. Racial disparities persisted after adjustment for sociodemographic, behavioral, and health factors. CONCLUSION: The MSSP highlights a higher Ct prevalence among young people in Baltimore than in the United States overall, with notable racial disparities in infection and associated risk behaviors. Public health efforts are needed to improve the diagnosis and treatment of asymptomatic infections in this population.

Safety of COVID-19 vaccines, their components or their platforms for pregnant women: A rapid review.

BACKGROUND: Pregnant women with COVID-19 are at an increased risk of severe COVID-19 illness as well as adverse pregnancy and birth outcomes. Many countries are vaccinating or considering vaccinating pregnant women with limited available data about the safety of this strategy. Early identification of safety concerns of COVID-19 vaccines, including their components, or their technological platforms is therefore urgently needed. METHODS: We conducted a rapid systematic review, as the first phase of an ongoing full systematic review, to evaluate the safety of COVID-19 vaccines in pregnant women, including their components, and their technological platforms (whole virus, protein, viral vector or nucleic acid) used in other vaccines, following the Cochrane methods and the PRISMA statement for reporting (PROSPERO-CRD42021234185).We searched literature databases, COVID-19 and pregnancy registries from inception February 2021 without time or language restriction and explored the reference lists of relevant systematic reviews retrieved. We selected studies of any methodological design that included at least 50 pregnant women or pregnant animals exposed to the vaccines that were selected for review by the COVAX MIWG in August 2020 or their components or platforms included in the COVID-19 vaccines, and evaluated adverse events during pregnancy and the neonatal period.Pairs of reviewers independently selected studies through the COVIDENCE web software and performed the data extraction through a previously piloted online extraction form. Discrepancies were resolved by consensus. RESULTS: We identified 6768 records, 256 potentially eligible studies were assessed by full-text, and 37 clinical and non-clinical studies (38 reports, involving 2,397,715 pregnant women and 56 pregnant animals) and 12 pregnancy registries were included.Most studies (89%) were conducted in high-income countries. The most frequent study design was cohort studies (n=21), followed by surveillance studies, randomized controlled trials, and registry analyses. Most studies (76%) allowed comparisons between vaccinated and unvaccinated pregnant women (n=25) or animals (n=3) and reported exposures during the three trimesters of pregnancy.The most frequent exposure was to AS03 adjuvant in the context of A/H1N1 pandemic influenza vaccines (n=24), followed by aluminum-based adjuvants (n=11). Aluminum phosphate was used in Respiratory Syncytial Virus Fusion candidate vaccines (n=3) and Tdap vaccines (n=3). Different aluminum-based adjuvants were used in hepatitis vaccines. The replication-deficient simian adenovirus ChAdOx1 was used for a Rift Valley fever vaccine. Only one study reported exposure to messenger RNA (mRNA) COVID-19 vaccines that also used lipid nanoparticles. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03) - corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. CONCLUSION: This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines that were selected for review by the COVAX MIWG or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted given their novelty. Our findings support current WHO guidelines recommending that pregnant women may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

Safety of components and platforms of COVID-19 vaccines considered for use in pregnancy: A rapid review.

BACKGROUND: Rapid assessment of COVID-19 vaccine safety during pregnancy is urgently needed. METHODS: We conducted a rapid systematic review, to evaluate the safety of COVID-19 vaccines selected by the COVID-19 Vaccines Global Access-Maternal Immunization Working Group in August 2020, including their components and their technological platforms used in other vaccines for pregnant persons. We searched literature databases, COVID-19 vaccine pregnancy registries, and explored reference lists from the inception date to February 2021 without language restriction. Pairs of reviewers independently selected studies through COVIDENCE, and performed the data extraction and the risk of bias assessment. Discrepancies were resolved by consensus. Registered on PROSPERO (CRD42021234185). RESULTS: We retrieved 6757 records and 12 COVID-19 pregnancy registries from the search strategy; 38 clinical and non-clinical studies (involving 2,398,855 pregnant persons and 56 pregnant animals) were included. Most studies (89%) were conducted in high-income countries and were cohort studies (57%). Most studies (76%) compared vaccine exposures with no exposure during the three trimesters of pregnancy. The most frequent exposure was to AS03 adjuvant, in the context of A/H1N1 pandemic influenza vaccines, (n = 24) and aluminum-based adjuvants (n = 11). Only one study reported exposure to messenger RNA in lipid nanoparticles COVID-19 vaccines. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03), corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. CONCLUSION: This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted, given their novelty. Our findings support current WHO guidelines recommending that pregnant persons may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

Sexually transmitted infection prevalence and behavioral risk factors among Latino and non-Latino patients attending the Baltimore City STD clinics.

BACKGROUND: Many studies have evaluated factors influencing sexually transmitted diseases (STD)/HIV disparities between black and white populations, but fewer have explicitly included Latinos for comparison. METHODS: We analyzed demographic and behavioral data captured in electronic medical records of patients first seen by a clinician in 1 of 2 Baltimore City public STD clinics between 2004 and 2007. Records from white, black, and Latino patients were included in the analysis. RESULTS: There were significant differences between Latinos and other racial/ethnic groups for several behavioral risk factors studied, with Latino patients reporting fewer behavioral risk factors than other patients. Latinos were more likely to have syphilis, but less likely to have gonorrhea than other racial/ethnic groups. English-proficient Latina (female) patients reported higher rates of infection and behavioral risk factors than Spanish-speaking Latina patients. After adjustment for gender and behavioral risk factors, Spanish-speaking Latinas also had significantly less risk of sexually transmitted infections than did English-speaking Latinas. CONCLUSIONS: These results are consistent with other studies showing that acculturation (as measured by language proficiency) is associated with increases in reported sexual risk behaviors among Latinos. Future studies on sexual risk behavior among specific Latino populations, characterized by country of origin, level of acculturation, and years in the United States, may identify further risk factors and protective factors to guide development of culturally appropriate STD/HIV interventions.

Digital divide: variation in internet and cellular phone use among women attending an urban sexually transmitted infections clinic.

We sought to describe: (1) the prevalence of internet, cellular phone, and text message use among women attending an urban sexually transmitted infections (STI) clinic, (2) the acceptability of health advice by each mode of information and communication technology (ICT), and (3) demographic characteristics associated with ICT use. This study is a cross-sectional survey of 200 English-speaking women presenting to a Baltimore City STI clinic with STI complaints. Participants completed a self-administered survey querying ICT use and demographic characteristics. Three separate questions asked about interest in receiving health advice delivered by the three modalities: internet, cellular phone, and text message. We performed logistic regression to examine how demographic factors (age, race, and education) are associated with likelihood of using each modality. The median age of respondents was 27 years; 87% were African American, and 71% had a high school diploma. The rate of any internet use was 80%; 31% reported daily use; 16% reported weekly use; and 32% reported less frequent use. Almost all respondents (93%) reported cellular phone use, and 79% used text messaging. Acceptability of health advice by each of the three modalities was about 60%. In multivariate analysis, higher education and younger age were associated with internet use, text messaging, and cellular phone use. Overall rate of internet use was high, but there was an educational disparity in internet use. Cellular phone use was almost universal in this sample. All three modalities were equally acceptable forms of health communication. Describing baseline ICT access and the acceptability of health advice via ICT, as we have done, is one step toward determining the feasibility of ICT-delivered health interventions in urban populations.

Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms.

BACKGROUND: The decision to perform lumbar puncture in patients with asymptomatic human immunodeficiency virus (HIV) infection and syphilis is controversial. The Centers for Disease Control and Prevention recommend certain criteria that warrant lumbar puncture. Here, we assess the performance of these criteria for detecting asymptomatic neurosyphilis (ANS). METHODS: Eligible subjects consisted of all patients with concurrent HIV infection and syphilis in a prospective clinical cohort who had no neurologic symptoms at the time of lumbar puncture. We retrospectively applied different stratification criteria to calculate the performance of lumbar puncture in detecting ANS: (1) lumbar puncture in patients with late latent syphilis or syphilis of an unknown duration, regardless of the CD4 cell count or rapid plasma reagin titer; (2) lumbar puncture if the CD4 cell count was 350 cells/mL and/or the rapid plasma reagin titer was 1:32, regardless of the syphilis stage; and (3) lumbar puncture in the context of serologic nonresponse to syphilis therapy. RESULTS: Two hundred two of 231 patients with syphilis did not have neurologic symptoms. Immediate lumbar puncture was performed for 46 patients, and 10 cases (22%) of ANS were detected. With use of the first criterion, 2 (14%) of 10 cases of ANS in patients with early-stage syphilis would have been missed (sensitivity, 80% [95% confidence interval [CI], 44%-97%]; specificity, 23% (95% confidence interval [CI], 11.4%-40.2%) [corrected] Criterion 2 would not have missed any cases of ANS (sensitivity, 100% [95% CI, 70%-100%]; specificity, 13.2% (95% CI, 4.4%-29.1%) [corrected] but would have required that a lumbar puncture be performed for 88% of patients. Performance of lumbar puncture performed in 13 cases based on serologic nonresponse to syphilis therapy yielded 4 cases (31%) of ANS. CONCLUSIONS: In patients with concurrent HIV infection and syphilis, the use of criteria based on rapid plasma reagin titer and CD4 cell count, instead of stage-based criteria, improved the ability to identify ANS.

Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients.

BACKGROUND: Syphilis and human immunodeficiency virus (HIV) frequently coexist in patients, but the effects of immunosuppression on the course of syphilis are unknown. Our goal was to determine whether the degree of HIV-mediated immunosuppression and the use of highly active antiretroviral therapy impact syphilis serologic responses. METHODS: We assessed all cases of syphilis with positive serologic test results from 1990 through 2006 in a prospective, observational clinical cohort of HIV-infected patients. We defined seroreversion as the loss of reactivity in a patient who previously had a serologic test result positive for syphilis. We defined serologic failure as the lack of a 4-fold decrease in rapid plasma reagin titers 270-365 days after therapy or a 4-fold increase in titers > or =30 days after therapy. We used Cox proportional hazards models with statistical adjustments for multiple failure instances. RESULTS: One hundred eighty subjects experienced 231 cases of syphilis. The median follow-up time was 5.3 years. A total of 71 episodes of serologic failure were documented. A CD4 cell count of <200 cells/mL at the time of syphilis diagnosis was associated with an increased risk of serologic failure (adjusted hazard ratio, 2.48; 95% confidence interval, 1.26-4.88). The receipt of highly active antiretroviral therapy was associated with a 60% reduction in the rate of serologic failure (adjusted hazard ratio, 0.40; 95% confidence interval, 0.21-0.75), independent of concomitant CD4 cell response. Rapid plasma reagin seroreversion was infrequent (16.1%) and inconsistent, and it was more likely to occur among patients who received macrolides. CONCLUSION: The use of highly active antiretroviral therapy to reverse immunosuppression and the routine use of macrolides for the prevention of opportunistic infections may reduce syphilis serologic failure rates among HIV-infected patients who have syphilis.