Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

A comparison of urinary incontinence among African American, Asian, Hispanic, and white women.

OBJECTIVE: This study was undertaken to compare urodynamic findings and the rate of incontinence diagnoses among various ethnic groups. STUDY DESIGN: Data were collected for all new patients referred to the urogynecology clinic during a 10-year period. One hundred ninety-five Hispanic, 95 white, 66 Asian, and 59 African American women had urodynamic testing and were included in the study. All women had a complete history, physical examination, and multichannel urodynamic studies. Demographic data, urodynamic data, and final diagnoses differences were analyzed. RESULTS: African American women had higher maximum urethral closure pressures than Hispanic, white, or Asian women (58 cm H2O vs 47, 47, and 48 cm H2O; P =.001, P =.005, and P =.02). African American women were less likely to be diagnosed with genuine stress incontinence than were Hispanic or white women (42% vs 67% and 59%; P <.001 and P =.046). Detrusor instability was diagnosed more often in African American women than in Hispanic, white, or Asian women (29% vs 8%, 15%, and 14%; P <.001, P =.04, and P =.04). CONCLUSIONS: African American women with urinary incontinence have different urodynamic diagnoses than Hispanic, white, or Asian women. Hispanic, white, and Asian women have similar rates of genuine stress incontinence. Although African American women have lower rates of genuine stress incontinence than Hispanic and white women, they have higher rates of detrusor instability than all 3 groups.

Ovarian steroid and cytokine modulation of human endometrial angiogenesis.

A key mechanism underlying the cyclical growth of the endometrium is its ability to regenerate a vascular capillary network. In normal cycling human endometrium, angiogenesis is influenced by both endocrine and paracrine factors. Hormonal manipulation of the endometrium, such as that occurring during the use of steroidal contraception, appears to result in capillary proliferation and fragility. As a consequence of these vascular changes, contraceptive users may be predisposed to unpredictable uterine bleeding, which is responsible for the high frequency of contraceptive discontinuation. In this paper we address mechanisms responsible for vascular endothelial cell proliferation in normal and contraceptive steroid-exposed endometria. We propose that regulation of endometrial angiogenesis is mediated indirectly, via steroid and cytokine actions on vascular endothelial growth factor (VEGF), and we present data indicating that VEGF expression in normal endometrial stromal cells is increased by oestrogens and progestins. Three proinflammatory cytokines with angiogenic effects in other systems (i.e. interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma) do not appear to up-regulate VEGF expression in normal endometrial stromal cells. Well-characterized in-vitro models in conjunction with immunohistochemistry provide useful experimental systems to study endometrial neovascularization under physiological conditions and in those potentially perturbed via the use of contraceptive steroids.

Importance of atypical glandular cells of uncertain significance in cervical cytologic smears.

OBJECTIVE: To determine the clinical implications of atypical glandular cells of uncertain significance (AGCUS) in cervical cytologic smears. STUDY DESIGN: Retrospective analysis. RESULTS: Eighty-eight of 32,181 (0.27%) cervical smears obtained during the study period contained AGCUS. Of the 47 women with AGCUS, 16 had intraepithelial or invasive neoplasms (34%; 95% confidence interval, 21-49%), including 9 low or high grade squamous intraepithelial lesions, 1 adenocarcinoma in situ of the cervix, 3 adenocarcinomas of the cervix, 2 adenocarcinomas of the endometrium and 1 adenoid basal cell carcinoma of the cervix. CONCLUSION: The high prevalence of cervical and endometrial neoplasia among women with the isolated finding of AGCUS on cervical cytologic smears warrants a thorough diagnostic evaluation.

Risk factors for plasma cell endometritis among women with cervical Neisseria gonorrhoeae, cervical Chlamydia trachomatis, or bacterial vaginosis.

OBJECTIVE: We sought to determine potential risk factors for upper genital tract inflammation in women with cervical Neisseria gonorrhoeae, Chlamydia trachomatis, or bacterial vaginosis. STUDY DESIGN: In a case-controlled study we compared 111 women with cervical Neisseria gonorrhoeae, Chlamydia trachomatis, or bacterial vaginosis (the study group) with 24 women who had negative tests for each of these infections (the control group). We evaluated potential risk factors for upper genital tract inflammation by use of bivariate and then logistic regression analysis. RESULTS: We found plasma cell endometritis in 53 of 111 women in the study group and 3 of 24 controls (odds ratio = 6.4, 95% confidence interval 1.7 to 35.0). On logistic regression, the study group women who were in the proliferative phase had increased likelihood of plasma cell endometritis (odds ratio = 4.5, 95% confidence interval 1.6 to 12.4). CONCLUSION: The proliferative phase of the menstrual cycle seems to be the primary risk factor for ascending infection by organisms associated with pelvic inflammatory disease. This may be due to a hormonal effect or to the loss of the cervical barrier during menstruation.

Vulvar intraepithelial neoplasia in women with HIV.

The increasing incidence of lower genital tract neoplasia in HIV-infected women and the inherent difficulties in diagnosis and treatment have undermined effective management and contributed significantly to the morbidity of this population. The Centers for Disease Control and Prevention has included high-grade squamous intraepithelial lesions, as well as cervical carcinoma in situ, as part of the classification of HIV, with invasive cervical cancer as an AIDS-defining condition. The incidence of vulvar intraepithelial neoplasia (VIN) nearly doubled between 1973 and 1987. In one study, VIN has been reported to occur 29 times more frequently in HIV-infected women than in a control group of self-identified non-HIV-infected women. Because women with HIV are now living longer, they face an increased possibility of the development of these infections along with the long-term sequelae and the risk of transformation to cancer. Treatment of VIN is guided by the size and location of the lesion, the grade of the dysplasia, and identification of coexisting disease in other sites. The case study presented exemplifies many of the management and education issues encountered following women with HIV disease and lower genital tract neoplasia, one of the most difficult issues being that the best mode of treatment for VIN has yet to be determined. Screening of the entire lower genital tract, including the vulva for dysplasia, is recommended for early detection and timely initiation of management.

Pelvic inflammatory disease in women infected with HIV.

Pelvic inflammatory disease (PID) and HIV infection are frequently coincident. The diagnosis of PID can be more difficult to make in HIV-infected than in uninfected women. In general, HIV-infected women with PID have a good response to standard intravenous antibiotic therapy. However, surgical therapy is more frequently required for HIV-infected women with PID, especially those with more severe degrees of immunosuppression, than for uninfected women.

Lower genital tract neoplasia in women with HIV infection.

Women who are infected with human immunodeficiency virus (HIV) are at greater risk for the development of lower genital tract neoplasia than are HIV-negative women. Among HIV-positive women, those who are more severely immunosuppressed appear to be at higher risk for cervical intraepithelial neoplasia (CIN), also known as squamous intraepithelial lesions (SILs). Women who are HIV-positive also are more likely than HIV-negative women to have multifocal lower genital tract neoplasia. Cervical cancer is one of the most important acquired immune deficiency syndrome (AIDS)--related malignancies in women. Cancer and intraepithelial neoplasia of the lower genital tract can be persistent, progressive, recurrent, and difficult to treat in HIV-positive women. The most effective method for treating SILs has not been determined. Regular performance of Pap smears in HIV-positive women is of critical importance, as is careful examination of the entire lower genital tract. Also, women with high-grade intraepithelial or cervical cancer should be tested for HIV.

Does vaginal cuff closure decrease the infectious morbidity associated with abdominal hysterectomy?

BACKGROUND: Infectious morbidity after total abdominal hysterectomy includes fever (31%) and antibiotic administration (45%). Whether vaginal cuff closure reduces postoperative infectious morbidity remains unresolved. STUDY DESIGN: We reviewed the records of 172 consecutive abdominal hysterectomies for nonmalignant disease performed at an inner-city hospital. We identified potential risk factors for infectious morbidity by univariate analysis and determined adjusted odds ratios by multiple logistic regression analysis. RESULTS: The open vaginal cuff technique was associated with an increased risk of wound infection. Use of prophylactic antibiotics was associated with a decreased risk of febrile morbidity and a decreased risk of prolonged hospitalization. Body weight in the heaviest quartile was associated with increased risk of wound infection, increased risk of prolonged hospitalization, and decreased risk of postoperative vaginal cuff granulation tissue. Older age was associated with an increased risk of prolonged hospitalization. CONCLUSIONS: Closure of the vaginal cuff and use of prophylactic antibiotics at total abdominal hysterectomy were associated with decreased infectious morbidity in a high-risk population.

Gynecology and family planning care for the woman infected with HIV.

This article reviews the interactions between HIV infection and a variety of gynecologic conditions, including lower genital tract neoplasia, pelvic inflammatory disease, menstrual disorders, sexually transmitted diseases, and vaginitis. Important considerations in choosing a family planning method for women infected with HIV-infected women will respond to standard therapy, but require multiple courses of treatment or use of innovative treatment methods. All HIV-infected women deserve careful evaluation for and treatment of gynecologic diseases.

PIP: The US Centers for Disease Control's revised (1993) case definition for HIV infection now includes several gynecologic diseases. Clinical category B illnesses (attributable to or complicated by HIV) include persistent, frequent, or poorly responsive vaginal candidiasis; moderate or severe cervical intraepithelial neoplasia; and pelvic inflammatory disease. Clinical category C illnesses (AIDS-defining) include chronic herpes simplex virus ulcers and invasive cervical cancer. This article reviews current knowledge on the interrelationship of each of these gynecologic diseases and HIV infection. Also discussed are contraceptive options for women with HIV. Until data on the impact of contraceptives on the clinical course of HIV are available, a combination of barrier and hormonal methods or tubal ligation is recommended. All HIV-infected women deserve careful, nonjudgmental evaluation for gynecologic disease and contraception.

Bacillary angiomatosis of the cervix and vulva in a patient with AIDS.

BACKGROUND: Bacillary angiomatosis is a clinicopathologic entity that most often is identified in the skin of patients with AIDS. This report presents an example of bacillary angiomatosis of the female genital tract. CASE: Bacillary angiomatosis presented as red-purple nodules of the vulva and cervix in a 32-year-old woman with AIDS. Histologic examination revealed the lobular epithelioid vascular proliferation and hazy clumps of bacteria that characterize bacillary angiomatosis. The diagnosis was confirmed on Warthin-Starry-stained issue and by blood cultures, which were positive for Bartonella (Rochalimaea) henselae. CONCLUSION: Accurate diagnosis of this infection is important because 1) bacillary angiomatosis is commonly mistaken for Kaposi sarcoma, 2) it is effectively treated with inexpensive antibiotics, and 3) undiagnosed and/or untreated bacillary angiomatosis may lead to overwhelming disseminated infection and death.

Operations for stress urinary incontinence in the United States, 1988-1992.

OBJECTIVES: To determine the frequency and cost of operations for stress urinary incontinence in the United States. METHODS: We reviewed data from the 1988-1992 National Hospital Discharge Surveys and the 1991 California Office of Statewide Health Planning Survey. We determined the frequency and type of surgical procedures performed for stress urinary incontinence and estimated the total direct costs of these operations in the United States. RESULTS: From 1988 to 1992, the total number of operations for stress incontinence increased from 78,000 to over 100,000. The rate of operations increased most in women older than 65 years of age. The total direct cost for treatment of stress urinary incontinence in the United States in 1991 was about $0.5 billion. CONCLUSIONS: Operations for treatment of stress urinary incontinence are increasing in frequency in the United States. They are both more commonly performed and more costly than have been previously reported.

Vulvar intraepithelial neoplasia in women infected with human immunodeficiency virus-1.

The purpose of this study was to determine the response of vulvar intraepithelial neoplasia (VIN) lesions to standard treatment methods in women infected with human immunodeficiency virus (HIV). We reviewed all cases of VIN over a 4-year period at an inner-city hospital. We reviewed the clinical records of these women to abstract demographic information as well as information about tobacco use, injection drug use, results of HIV testing, T cell count, stage of HIV infection, colposcopic and cytologic findings, treatment of lesions, and follow-up. Eight of the 28 women (29%) with VIN were infected with HIV. The relative risk for recurrence or persistence of VIN after treatment was 3.3 (95% confidence interval, 1.4-7.4; P = 0.01) in the HIV+ compared with the HIV- group. The high rate of HIV infection among women with VIN supports recommendation of HIV testing for women with VIN. Women known to have HIV infection should be carefully examined for vulvar lesions. Further study is needed to determine the optimum treatment for VIN in women infected with HIV.

Commonly used diagnostic criteria for pelvic inflammatory disease have poor sensitivity for plasma cell endometritis.

BACKGROUND: The majority of women with tubal damage do not have a history of acute pelvic inflammatory disease. The prevalence of upper genital tract inflammation was evaluated in women deemed not to have pelvic inflammatory disease by common diagnostic criteria. GOAL OF THIS STUDY: To compare clinical signs and laboratory tests used to diagnose pelvic inflammatory disease with endometrial biopsy histopathology. STUDY DESIGN: Endometrial biopsy and commonly used physical and laboratory tests were performed on 52 women with pelvic tenderness, 51 with vaginosis or cervicitis, and 22 control subjects who had no evidence of infection with Neisseria gonorrhoeae or Chlamydia trachomatis and who tested negative for bacterial vaginosis using vaginal swab Gram's stain. RESULTS: Thirty-six of 52 patients (69%) with pelvic tenderness, compared with 22 of 51 patients (43%) with vaginosis or cervicitis and two of 22 control subjects (9%), had plasma cell endometritis. The Centers for Disease Control and Prevention minimal diagnostic criteria for pelvic inflammatory disease had a sensitivity of 33% for plasma cell endometritis. CONCLUSIONS: The clinical diagnosis of pelvic inflammatory disease using published criteria correlates poorly with plasma cell endometritis.

Gynecologic disease in women infected with human immunodeficiency virus type 1.

Gynecologic disease is commonly encountered in women infected with the human immunodeficiency virus (HIV). The clinical course of cervical intraepithelial neoplasia, invasive cervical cancer, pelvic inflammatory disease, syphilis, and vaginal candidiasis may be altered by HIV infection and may be refractory to standard treatment, especially with increasing degrees of immune suppression. Careful screening for gynecologic disease and vigilant surveillance for treatment failure are important in the care of women infected with HIV.

Multifocal lower genital tract neoplasia in women with HIV disease.

Lower genital tract neoplasia appears to occur often and in multiple sites in women infected with the human immunodeficiency virus (HIV). To describe the prevalence of lower genital tract neoplasia in HIV-infected women in our clinic we performed a retrospective chart review of 38 HIV-infected women who had received screening colposcopy. Fourteen percent of the women had VIN on biopsy. In addition, 50% of the women had abnormal Pap smears and 24% had CIN on biopsy. In this study, lower genital tract neoplasia was multifocal in nature and included a relatively high prevalence of VIN not previously reported in the literature.

Plasma cell endometritis in women with symptomatic bacterial vaginosis.

OBJECTIVE: To evaluate the endometrial microbiology and histopathology in women with symptomatic bacterial vaginosis but no signs or symptoms of upper genital tract disease or other vaginal or cervical infections. METHODS: Endometrial biopsies were performed on 41 women complaining of vaginal discharge or pelvic pain at a sexually transmitted disease clinic. These women had neither culture nor serologic evidence of Neisseria gonorrhoeae or Chlamydia trachomatis infection. Twenty-two women with bacterial vaginosis diagnosed by Gram stain examination of vaginal fluid, but with neither signs nor symptoms of upper genital tract infection, were compared with 19 women who had no evidence of bacterial vaginosis on vaginal fluid Gram stain. Endometrial biopsies were evaluated for histopathologic evidence of plasma cell endometritis and were cultured for N gonorrhoeae, C trachomatis, aerobic and anaerobic bacteria, Mycoplasma species, and Ureaplasma urealyticum. RESULTS: Ten of 22 women with bacterial vaginosis had plasma cell endometritis, compared with one of 19 controls (odds ratio [OR] 15, 95% confidence interval [CI] 2-686; P < .01). Bacterial vaginosis-associated organisms were cultured from the endometria of nine of 11 women with and eight of 30 women without plasma cell endometritis (OR 12.4, 95% CI 2-132; P = .002). CONCLUSION: Plasma cell endometritis was frequently present in women with bacterial vaginosis and without other vaginal or cervical infections. This suggests the possibility of an association between bacterial vaginosis and nonchlamydial, nongonococcal, upper genital tract infection.