Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306.

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p < 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p < 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in >20 years. Clinical Trial Registration Number: NCT03734991.

Reduced Antifungal Susceptibility of Vulvovaginal Candida Species at Normal Vaginal pH Levels: Clinical Implications.

OBJECTIVE: The aims of the study were to assess for differences in antifungal in vitro potency at pH 7 and pH 4 and to discuss any potential clinical implications of that difference. MATERIALS AND METHODS: A retrospective analysis of 217 first positive yeast cultures from 217 patients. Yeast isolates underwent antifungal susceptibility testing, with minimum inhibitory concentrations (MICs) (microgram per milliliter) measured at pH 7 and pH 4 for fluconazole, itraconazole, miconazole, clotrimazole, terconazole, and nystatin. Only the first isolates collected from each patient were included in the analysis. RESULTS: Yeast first isolates included 173 Candida albicans, 15 Candida glabrata, and 29 isolates from 8 other species. Geometric mean (GM) MIC values for all antifungals were significantly higher when tested at pH 4 (p < .001 for all comparisons). For C. albicans, the largest GM MIC differences were observed for terconazole (0.17 pH 7 vs 6.17 pH 4) and clotrimazole (0.04 vs 0.24). For terconazole, 97.7% of the isolates had a MIC of 1 or less at pH 7 but 83.2% had a MIC of 4 or higher at pH 4. For C. glabrata, terconazole (GM MIC = 0.26 pH 7 vs >64 pH 4), clotrimazole (0.13 vs 6.96), miconazole (0.06 vs 0.76), and fluconazole (3.17 vs 26.6) were most affected. All C. glabrata isolates had a MIC of 1 or less for terconazole at pH 7 and one had a MIC of 8 at pH 4, whereas all the rest were highly resistant (MIC > 64). CONCLUSIONS: Antifungals have reduced in vitro potency when tested at lower pH. Candida glabrata is more affected than C. albicans. The impact may be greatest for the antifungal terconazole and against C. glabrata isolates.

The Clinical and Economic Benefits of Co-Testing Versus Primary HPV Testing for Cervical Cancer Screening: A Modeling Analysis.

BACKGROUND: Consensus United States cervical cancer screening guidelines recommend use of combination Pap plus human papillomavirus (HPV) testing for women aged 30 to 65 years. An HPV test was approved by the Food and Drug Administration in 2014 for primary cervical cancer screening in women age 25 years and older. Here, we present the results of clinical-economic comparisons of Pap plus HPV mRNA testing including genotyping for HPV 16/18 (co-testing) versus DNA-based primary HPV testing with HPV 16/18 genotyping and reflex cytology (HPV primary) for cervical cancer screening. METHODS: A health state transition (Markov) model with 1-year cycling was developed using epidemiologic, clinical, and economic data from healthcare databases and published literature. A hypothetical cohort of one million women receiving triennial cervical cancer screening was simulated from ages 30 to 70 years. Screening strategies compared HPV primary to co-testing. Outcomes included total and incremental differences in costs, invasive cervical cancer (ICC) cases, ICC deaths, number of colposcopies, and quality-adjusted life years for cost-effectiveness calculations. Comprehensive sensitivity analyses were performed. RESULTS: In a simulation cohort of one million 30-year-old women modeled up to age 70 years, the model predicted that screening with HPV primary testing instead of co-testing could lead to as many as 2,141 more ICC cases and 2,041 more ICC deaths. In the simulation, co-testing demonstrated a greater number of lifetime quality-adjusted life years (22,334) and yielded $39.0 million in savings compared with HPV primary, thereby conferring greater effectiveness at lower cost. CONCLUSIONS: Model results demonstrate that co-testing has the potential to provide improved clinical and economic outcomes when compared with HPV primary. While actual cost and outcome data are evaluated, these findings are relevant to U.S. healthcare payers and women's health policy advocates seeking cost-effective cervical cancer screening technologies.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from six working groups, and a recent symposium co-sponsored by the ACS, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (e.g., management of screen positives and screening interval for screen negatives) of women after screening, age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16/18 infections.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

Screening and management of women and girls with human papillomavirus infection.

In the US, reductions in cervical cancer-related mortality over the past five decades can be attributed to the implementation of screening programs. US-based guidelines recommend that screening should be initiated approximately 3 years after initiation of sexual intercourse, but no later than age 21 years and be continued at least until age 65 or 70. Annual screening is recommended by the American Cancer Society and the American College of Obstetricians and Gynecologists, although in women aged > or =30 years with > or =3 negative Pap tests, screening may be conducted every 2 to 3 years. Human papillomavirus (HPV) testing has been approved by the US Food and Drug Administration and most US guidelines say that it is reasonable to consider HPV testing, in combination with triennial cytology screening. Pharmacoeconomic analyses indicate that combined cytology and HPV testing every three years in women aged > or =30 years is comparable in sensitivity to annual liquid-based cytology for the detection of cervical cancer precursors and is more cost-effective. Both surgical and nonsurgical therapies are commonly employed in patients with HPV lesions although papilloma recurrence is not uncommon. Treatment should be individualized based on the extent of disease and the needs of the patient. Current treatment of cervical cancer reflects the stage of the disease and should take into account patient- and tumor-related factors to ensure optimal patient outcomes.

2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ.

A group of 146 experts representing 29 organizations and professional societies met Sept. 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. The management of low-grade cervical intraepithelial neoplasia (CIN) grade 1 has been modified significantly. Previously, management depended on whether colposcopy was satisfactory and treatment using ablative or excisional was acceptable for all women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option for women with CIN 1 who have low-grade referral cervical cytology, regardless of whether the colposcopic examination is satisfactory. Treatment is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed adenocarcinoma in situ are now included.

2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests.

A group of 146 experts representing 29 organizations and professional societies met September 18-19, 2006, in Bethesda, MD, to develop revised evidence-based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion (LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow-up for 2 years was approved. Recommendations for managing high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC) also underwent only minor modifications. More emphasis is placed on immediate screen-and-treat approaches for HSIL. Human papillomavirus (HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications.

2006 consensus guidelines for the management of women with abnormal cervical screening tests.

OBJECTIVE: To provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening test results. PARTICIPANTS: A group of 146 experts, including representatives from 29 professional organizations, federal agencies, and national and international health organizations, met in Bethesda, MD, September 18-19, 2006, to develop the guidelines. MAJOR CHANGES IN GUIDELINES: The core recommendations for managing women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions were changed minimally. Postcolposcopy management for women with these cytological abnormalities is now identical. Management recommendations for these conditions did change for "special populations," such as adolescents for whom a more conservative approach incorporating cytological follow-up for 2 years was approved. Core recommendations for managing women with high-grade squamous intraepithelial lesions and atypical glandular cells also underwent only minor modifications. More emphasis is placed on immediate "screen-and-treat" approaches when managing women with high-grade squamous intraepithelial lesion. Testing for high-risk human papillomavirus DNA is incorporated into the management of women with atypical glandular cells after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening in women 30 years and older was formally adopted with only very minor modifications. CONCLUSIONS: The 2006 Consensus Guidelines reflect recent data from large clinical trials and advances in technology and are designed to assist clinicians of all subspecialties.

2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ.

OBJECTIVE: To provide updated consensus guidelines for the management of women with cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ (AIS). PARTICIPANTS: A group of 146 experts including representatives from 29 professional organizations, federal agencies, and national and international health organizations met on September 18-19, 2006, in Bethesda, MD, to develop the guidelines. MAJOR CHANGES IN THE GUIDELINES: The management of women with CIN grade 1 (CIN 1) has been modified significantly. In the earlier guidelines, management depended on whether the colposcopic examination was satisfactory and treatment using ablative or excisional methods was acceptable for women with CIN 1. In the new guidelines, cytological follow-up is the only recommended management option, regardless of whether the colposcopic examination is satisfactory, for women with CIN 1 who have a low-grade referral cervical cytology. Treatment of CIN 1 is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy-confirmed AIS are now included. CONCLUSION: Updated evidenced-based guidelines have been developed for the management of women with CIN or AIS. These guidelines reflect recent changes in our understanding of human papillomavirus-associated diseases of the cervix and the potential impact of treatment on future pregnancies.

Home Study Course: summer 2006.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management, or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The American Society for Colposcopy and Cervical Pathology designates this educational activity for a maximum of 1 AMA PRA Categorys I Creditt. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCCP also designates their educational activity for 1 Category 1 credit hour of the ASCCP's Program for Continuing Professional Development. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements. DISCLOSURES: The clinical history and images in the Home Study Course may represent an actual case, but not always. To improve educational quality, some gross, cytological, or histological images may come from photographic libraries. Good teaching cases are often difficult to obtain, and we encourage our readers to submit cases with high-quality images to the Home Study Course editor or executive editor to consider for publication. Lastly, faculty must disclose any significant financial interest or relationship with proprietary entities that may have a direct relationship to the subject matter. For this course, the authors had no such relationship to report.

Home Study Course: Spring 2006.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or hercolposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or to present colposcopic cases that demonstrate new and important knowledge in the area of colposcopyor pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ASCCP designates this continuing medicaleducation activity for 1 hour category 1 credit of the ASCCP's Program for Continuing Professional Development and the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements. DISCLOSURE: Faculty must disclose any significant financial interest or relationship with proprietary entities that may have a directrelationship to the subject matter. For this course, the author had no such relationship to report.

Management of histologic abnormalities of the cervix.

The American Society for Colposcopy and Cervical Pathology sponsored a consensus conference in 2001 to develop evidence-based guidelines for women with histologic abnormalities of the cervix. The options for management of cervical intraepithelial neoplasia 1, 2, and 3 are ranked according to the strength of the recommendation and the quality of the evidence. Follow-up with repeat cytology at six and 12 months or DNA testing for high-risk types of human papillomavirus at 12 months is the preferred management approach for women with cervical intraepithelial neoplasia 1 and satisfactory initial colposcopy. If results from repeat cytology are reported as atypical squamous cells of undetermined significance or greater, or if DNA human papillomavirus testing is positive for oncogenic types of the virus, repeat colposcopy is preferred. When the initial colposcopy is unsatisfactory, a diagnostic excisional procedure is preferred. Follow-up without treatment is acceptable only in women who are pregnant and adolescents with cervical intraepithelial neoplasia 1 who had unsatisfactory colposcopy. Biopsy-confirmed cervical intraepithelial neoplasia 2 and 3 requires treatment except during pregnancy and in compliant adolescents with cervical intraepithelial neoplasia 2 and negative endocervical curettage. When colposcopy is satisfactory, treatment includes ablative or excisional procedures. A diagnostic excisional procedure is recommended in women with biopsy-confirmed cervical intraepithelial neoplasia 2 or 3 and unsatisfactory colposcopy.

Preparing digitized cervigrams for colposcopy research and education: determination of optimal resolution and compression parameters.

OBJECTIVE: Visual assessment of digitized cervigrams through the Internet needs to be optimized. The National Cancer Institute and National Library of Medicine are involved in a large effort to improve colposcopic assessment and, in preparation, are conducting methodologic research. MATERIALS AND METHODS: We selected 50 cervigrams with diagnoses ranging from normal to cervical intraepithelial neoplasia 3 or invasive cancer. Those pictures were scanned at 5 resolution levels from 1,550 to 4,000 dots per inch (dpi) and were presented to 4 expert colposcopists to assess image quality. After the ideal resolution level was determined, pictures were compressed at 7 compression ratios from 20:1 to 80:1 to determine the optimal level of compression that permitted full assessment of key visual details. RESULTS: There were no statistically significant differences between the 3,000 and 4,000 dpi pictures. At 2,000 dpi resolution, only one colposcopist found a slightly statistically significant difference (p = 0.02) compared with the gold standard. There was a clear loss of quality of the pictures at 1,660 dpi. At compression ratio 60:1, 3 of 4 evaluators found statistically significant differences when comparing against the gold standard. CONCLUSIONS: Our results suggest that 2,000 dpi is the optimal level for digitizing cervigrams, and the optimal compression ratio is 50:1 using a novel wavelet-based technology. At these parameters, pictures have no significant differences with the gold standard.