Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer.
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.
Smith
Jennifer S
JS
Unit of Field and Intervention Studies, International Agency for Research on Cancer (IARC), Lyon, France. smith@iarc.fr
Herrero
Rolando
R
Bosetti
Cristina
C
Muñoz
Nubia
N
Bosch
F Xavier
FX
Eluf-Neto
José
J
Castellsagué
Xavier
X
Meijer
Chris J L M
CJ
Van den Brule
Adriaan J C
AJ
Franceschi
Silvia
S
Ashley
Rhoda
R
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*
D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G