Investigation of herpes simplex virus-2 and Chlamydia trachomatis infections as human papillomavirus cofactors in the etiology of invasive cervical cancer in Brazil and the Philippines

Objective. To examine herpes simplex virus type-2 (HSV-2) and Chlamydia trachomatis as risk factors for HPV-induced invasive cervical cancer.; Methods. In Sao Paolo City, Brazil, 199 women with invasive cervical cancer and 225 age-matched hospital-based controls were recruited. In Manila, the Philippines, 356 women with invasive cervical cancer and 387 age-matched controls were identified. Women were interviewed to investigate cervical cancer risk factors. Type-specific HSV-2 IgG serum antibodies were detected. Chlamydia trachomatis serum antibody responses were differentiated from Chlamydia pneumoniae antibody responses using a micro-immunofluorescence assay. HPV was ascertained using PCR-based assays detecting a broad range of HPV DNA types.; Results. Among control participants, the prevalence of HSV-2 was significantly higher in Brazil (42%) than in the Philippines (9%). In Brazil, HSV-2 seropositivity was not significantly associated with invasive cervical cancer in the multivariate model when comparing (i) all invasive cervical cancer cases with controls (OR = 0.5; 95% CI: 0.2--1.1) and (ii) HPV DNA positive cases with HPV DNA positive controls (OR = 0.9; 95% CI: 0.4--2.5). In contrast, in the Philippines, HSV-2 was significantly associated with invasive cervical cancer using similar comparisons: (i) all invasive cervical cancer cases with controls (OR = 2.8; 95% CI: 13--6.0) and (ii) HPV DNA positive cervical cancer cases with HPV DNA positive controls (OR = 14.2; 95% CI: 1.9--107.9). Among control participants, C. trachomatis seropositivity, and not C. pneumonaie seropositivity, was significantly associated with sexual behavior. In the multivariate model, C. trachomatis antibodies were significantly associated with squamous invasive cervical cancer in both Brazil (OR = 2.3; 95% CI: 1.1--5.1) and the Philippines (OR = 2.5; 95% CI: 1.3--5.9). A pattern of increasing squamous cervical cancer risk with increasing C. trachomatis antibody titers was observed. Data indicated that C. trachomatis may increase the risk of cervical cancer among women positive for HPV DNA in the combined country analysis (OR = 1.9; 95% CI: 1.0--3.6). In contrast, C. trachomatis seropositivity was not associated with adenocarcinoma/adenosquamous carcinoma among a smaller number of patients. C. pneumonaie seropositivity was not associated with cervical cancer.; Conclusions. In Brazil, HSV-2 was not associated with an increased invasive cervical cancer risk. In the Philippines, there was some evidence that HSV-2 may be a cofactor of HPV in cervical cancer etiology. Since these results for HSV-2 are based on a small number of HPV DNA positive controls and are inconsistent between these two countries, the role of HSV-2 in the etiology of invasive cervical cancer should be re-examined. This data suggest that C. trachomatis may act in conjunction with HPV in the etiology of squamous cervical cancer in both Brazil and the Philippines.