A systematic review of syphilis serological treatment outcomes in HIV-infected and HIV-uninfected persons: rethinking the significance of serological non-responsiveness and the serofast state after therapy.
BACKGROUND
Syphilis remains a global public health threat and can lead to severe complications. In addition to resolution of clinical manifestations, a reduction in nontreponemal antibody titers after treatment is regarded as "proof of cure." However, some patients manifest < 4-fold decline ("serological non-response") or persistently positive nontreponemal titers despite an appropriate decline ("serofast") that may represent treatment failure, reinfection, or a benign immune response. To delineate these treatment phenomena, we conducted a systematic review of the literature regarding serological outcomes and associated factors among HIV-infected and -uninfected subjects.


METHODS
Six databases (PubMed, Embase, CINAHL, Web of Science, Scopus, and BIOSIS) were searched with no date restrictions. Relevant articles that evaluated serological treatment responses and correlates of serological cure (≥ four-fold decline in nontreponemal titers) were included.


RESULTS
We identified 1693 reports in the literature, of which 20 studies met selection criteria. The median proportion of patients who had serological non-response was 12.1% overall (interquartile range, 4.9-25.6), but varied depending on the time points after therapy. The serofast proportion could only be estimated from 2 studies, which ranged from 35.2-44.4%. Serological cure was primarily associated with younger age, higher baseline nontreponemal titers, and earlier syphilis stage. The relationship between serological cure and HIV status was inconsistent; among HIV-infected patients, CD4 count and HIV viral load was not associated with serological cure.


CONCLUSIONS
Serological non-response and the serofast state are common syphilis treatment outcomes, highlighting the importance of determining the immunological and clinical significance of persistent nontreponemal antibody titers after therapy.
Department of Medicine, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. idrod@med.unc.edu.
Arlene C
AC
Seña
Sexually Transmitted Diseases Department, Guangdong Provincial Dermatology Hospital, Guangzhou, China. zhangxiaohui360@163.com.
Xiao-Hui
XH
Zhang
School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. trudy_li@med.unc.edu.
Trudy
T
Li
Sexually Transmitted Diseases Department, Guangdong Provincial Dermatology Hospital, Guangzhou, China. zhhpf@hotmail.com.
He-Ping
HP
Zheng
Sexually Transmitted Diseases Department, Guangdong Provincial Dermatology Hospital, Guangzhou, China. yangbin101@hotmail.com.
Bin
B
Yang
Sexually Transmitted Diseases Department, Guangdong Provincial Dermatology Hospital, Guangzhou, China. yanglg3@hotmail.com.
Li-Gang
LG
Yang
Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Connecticut and Connecticut Children's Medical Center, Farmington, Connecticut, USA. jsalazar@uchc.edu.
Juan C
JC
Salazar
Department of Medicine, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. mscohen@med.unc.edu.
Myron S
MS
Cohen
Department of Pediatrics, Division of Pediatric Infectious Diseases, Duke University, Durham, North Carolina, USA. tony.moody@duke.edu.|Duke Human Vaccine Institute, Duke University, Durham, North Carolina, USA. tony.moody@duke.edu.
M Anthony
MA
Moody
Department of Pediatrics, Division of Pediatric Infectious Diseases, University of Connecticut and Connecticut Children's Medical Center, Farmington, Connecticut, USA. jradolf@uchc.edu.|Department of Medicine, UConn Health, Farmington, Connecticut, USA. jradolf@uchc.edu.
Justin D
JD
Radolf
Department of Medicine, Institute for Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jdtucker@med.unc.edu.
Joseph D
JD
Tucker
D000367:Age Factors; D018791:CD4 Lymphocyte Count; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D013587:Syphilis / Q000188:drug therapy* / Q000382:microbiology; D013588:Syphilis Serodiagnosis; D017211:Treatment Failure; D016896:Treatment Outcome; D019562:Viral Load