title: Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer.
abstract: BACKGROUND
  Human papillomavirus (HPV) infection is the main cause of invasive cervical cancer, but cofactors may act in conjunction with HPV. We performed a pooled analysis of seven case-control studies to examine the effect of one possible HPV cofactor, herpes simplex virus-2 (HSV-2) infection, in the etiology of invasive cervical cancer.
  
  
  METHODS
  Blood and exfoliated cervical specimens were obtained from 1263 case patients with invasive cervical cancer (1158 with squamous-cell carcinomas and 105 with adeno- or adenosquamous-cell carcinomas) and 1117 age-matched control subjects. Western blot analysis and/or an enzyme-linked immunosorbent assay were used to detect type-specific serum antibodies to HSV-2 and HSV-1, and Chlamydia trachomatis serum antibodies were detected using a micro-immunofluorescence assay. HPV DNA was detected using a polymerase chain reaction assay. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were computed from unconditional logistic regression models.
  
  
  RESULTS
  Overall, HSV-2 seropositivity was higher among case patients with squamous-cell carcinoma (44.4%, 95% CI = 41.5% to 47.3%) or adeno- or adenosquamous-cell carcinoma (43.8%, 95% CI = 34.2% to 53.5%) than among control subjects (25.6%, 95% CI = 23.0% to 28.2%). Cervical specimens from 1098 (94.8%) squamous-cell carcinoma case patients, 95 (90.5%) adeno- or adenosquamous carcinoma case patients, and 164 (14.7%) control subjects were positive for HPV DNA. Among the HPV DNA-positive women, HSV-2 seropositivity was associated with increased risks of squamous-cell carcinoma (OR = 2.19, 95% CI = 1.41 to 3.40) and adeno- or adenosquamous-cell carcinoma (OR = 3.37, 95% CI = 1.47 to 7.74) after adjustment for potential confounders. A similar association between HSV-2 seropositivity and squamous-cell carcinoma risk was observed after further controlling for markers of sexual behavior (OR = 1.96, 95% CI = 1.24 to 3.09). Among control subjects, HSV-2 seropositivity was associated with markers of sexual behavior, but not with cervical HPV DNA positivity.
  
  
  CONCLUSIONS
  HSV-2 infection may act in conjunction with HPV infection to increase the risk of invasive cervical carcinoma.
authors.affiliation: Unit of Field and Intervention Studies, International Agency for Research on Cancer (IARC), Lyon, France. smith@iarc.fr
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Smith
authors.forename: Rolando
authors.initials: R
authors.lastname: Herrero
authors.forename: Cristina
authors.initials: C
authors.lastname: Bosetti
authors.forename: Nubia
authors.initials: N
authors.lastname: Muñoz
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Bosch
authors.forename: José
authors.initials: J
authors.lastname: Eluf-Neto
authors.forename: Xavier
authors.initials: X
authors.lastname: Castellsagué
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Adriaan J C
authors.initials: AJ
authors.lastname: Van den Brule
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschi
authors.forename: Rhoda
authors.initials: R
authors.lastname: Ashley
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D003075:Coitus; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006558:Herpes Genitalis / Q000150:complications / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000302:isolation & purification / Q000472:pathogenicity*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008393:Marriage; D008875:Middle Aged; D027383:Papillomaviridae / Q000302:isolation & purification / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D012307:Risk Factors; D012725:Sexual Behavior; D012959:Socioeconomic Factors; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000821:virology*
chemical_list: D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G