Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination.

BACKGROUND: Cellular immunity is involved in spontaneous clearance of anogenital warts caused, most typically, by human papillomavirus (HPV) type 6 or 11, supporting the concept of therapeutic vaccination. A therapeutic vaccine composed of HPV-6 L2E7 fusion protein and AS02A adjuvant was evaluated in conjunction with conventional therapies in subjects with anogenital warts. METHODS: A total of 457 subjects with anogenital warts were screened, of which 320 with HPV-6 and/or HPV-11 infection were enrolled into 2 double-blind, placebo-controlled substudies. Three doses of vaccine or placebo were administered along with either ablative therapy or podophyllotoxin. RESULTS: Although a positive trend toward clearance was seen in patients infected with only HPV-6, in neither substudy did the vaccine significantly increase the efficacy of conventional therapies, despite induction of adequate immune responses. Extensive HPV typing by polymerase chain reaction demonstrated that a majority of screened subjects (73.7%) were infected with HPV-6 and/or HPV-11 and that a large proportion (40.1%) were infected with multiple HPV types. HPV types that put subjects at high risk of development of cervical cancer were detected in 39.8% of subjects. CONCLUSIONS: Infection with multiple HPV types, including high-risk types, is common in anogenital wart disease. Therapeutic vaccination failed to increase the efficacy of conventional therapies.

Rate of human papillomavirus clearance after treatment of cervical intraepithelial neoplasia.

OBJECTIVE: To investigate the rate of clearance of human papillomavirus (HPV) infection after surgical treatment for cervical intraepithelial neoplasia (CIN). METHODS: One hundred nine women with CIN I-III, treated with cryosurgery or conization at a university hospital, were observed with cervical HPV deoxyribonucleic acid (DNA) testing by general primer polymerase chain reaction and HPV typing at 0, 3, 6, 9, 12, and 24 months after treatment. Penile HPV DNA was analyzed from current sexual partners. RESULTS: Eighty-one percent of evaluable women were HPV DNA positive at treatment or enrollment. One year later, seven women (9%) remained positive for the same HPV type. Most women had cleared the HPV infection diagnosed at treatment within 3 months. The cryotherapy group had lower CIN grades, was younger, and had a slower HPV clearance rate (P <.002). Only four couples had HPV DNA of the same type detected. CONCLUSION: Surgical treatment of CIN usually results in clearance of HPV infection within 3 months. Human papillomavirus DNA testing may be useful as a rapid intermediate end point for monitoring the efficacy of treatments.

Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study.

BACKGROUND: Use of oral contraceptives could increase risk of cervical cancer; however the effect of human papillomavirus (HPV), the main cause of cervical cancer, is not usually taken into account. We aimed to assess how use of oral contraceptives affected risk of cervical cancer in women who tested positive for HPV DNA. METHODS: We pooled data from eight case-control studies of patients with histologically confirmed invasive cervical carcinoma (ICC) and from two studies of patients with carcinoma in situ (ISC). Information about use of oral contraceptives was obtained from personal interviews. Effects were estimated as odds ratios, with logistic-regression models adjusted for possible confounders. FINDINGS: 1465 of 1561 (94%) patients with ICC, 211 of 292 (72%) with ISC, and 255 of 1916 (13%) controls were positive for HPV DNA. Compared with never-users, patients who had used oral contraceptives for fewer than 5 years did not have increased risk of cervical cancer (odds ratio 0.73; 95% CI 0.52-1.03). The odds ratio for use of oral contraceptives was 2.82 (95% CI 1.46-5.42) for 5-9 years, and 4.03 (2.09-8.02) for use for 10 years or longer, and these risks did not vary by time since first or last use. INTERPRETATION: Long-term use of oral contraceptives could be a cofactor that increases risk of cervical carcinoma by up to four-fold in women who are positive for cervical HPV DNA. In the absence of worldwide information about HPV status, extra effort should be made to include long-term users of oral contraceptives in cervical screening programmes.

Evidence for Chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines.

Chlamydia trachomatis infection was examined as a cause of invasive cervical cancer (ICC) among women with human papillomavirus (HPV) infection. In total, 499 women with incident ICC (ICC patients) and 539 control patients from São Paulo, Brazil, and Manila, the Philippines, were included. C. trachomatis antibodies were detected by microimmunofluorescence assay. Presence of HPV DNA in cervical specimens was determined by a polymerase chain reaction-based assay. C. trachomatis seropositivity was associated with sexual behavior but not with HPV infection. C. trachomatis increased the risk of squamous cervical cancer among HPV-positive women (odds ratio, 2.1; 95% confidence interval, 1.1-4.0). Results were similar in both countries. There was a suggestion of increasing squamous cancer risk with increasing C. trachomatis antibody titers. This large study examined C. trachomatis and cervical cancer, taking into account the central role of HPV infection. C. trachomatis infection was found to be a possible cofactor of HPV in the etiology of squamous cervical cancer, and its effect may be mediated by chronic inflammation.

Human papillomavirus type 16 E2-specific T-helper lymphocyte responses in patients with cervical intraepithelial neoplasia.

T-cell-mediated immune responses against mucosal oncogenic types of human papillomaviruses (HPV) are thought to play a role in the control of the virus infection and its associated cervical lesions. The in vitro production of interleukin-2 by T-helper (Th) cells in response to the C-terminal and N-terminal domains of the HPV-16 E2 protein was determined in 74 women with cytological evidence of premalignant cervical epithelial neoplasia who participated in a non-intervention follow-up (FU) study. Cross-sectional analysis at the end of FU showed that Th cell responses against the C-terminal domain were associated with evidence of previous or present HPV-16 infection as compared to patients with no evidence of any HPV infection (18.9% versus 0%, P = 0.039). Th cell responses against the N-terminal domain were not associated with evidence of HPV-16 infection. No association with disease outcome was observed with Th cell responses against either of the E2 protein domains. However, longitudinal analysis revealed that Th cell responses against the C-terminal domain frequently occur at the time of virus clearance. Whether these responses are responsible for the clearance of the virus is not known.