Elizabeth A. Stier

Safety and Immunogenicity of the Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Men

BACKGROUNDnHuman immunodeficiency virus type 1 (HIV-1)-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types.nnnMETHODSnAIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multicenter clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, and 18) vaccine in HIV-1-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and week 24. The primary end points were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination.nnnRESULTSnThere were no grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least 1 vaccine dose. Seroconversion was observed for all 4 types: type 6 (59 [98%] of 60), type 11 (67 [99%] of 68), type 16 (62 [100%] of 62), and type 18 (74 [95%] of 78). No adverse effects on CD4 counts and plasma HIV-1 RNA levels were observed.nnnCONCLUSIONSnThe quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-1-infected men. Efficacy studies in HIV-1-infected men are warranted. Clinical trials registration. NCT 00513526.

Prevalence of anal human papillomavirus infection and anal HPV-related disorders in women: a systematic review

The aim of this study was to systematically review the findings of publications addressing the epidemiology of anal human papillomavirus (HPV) infection, anal intraepithelial neoplasia, and anal cancer in women. We conducted a systematic review among publications published from Jan. 1, 1997, to Sept. 30, 2013, to limit to publications from the combined antiretroviral therapy era. Three searches were performed of the National Library of Medicine PubMed database using the following search terms: women and anal HPV, women anal intraepithelial neoplasia, and women and anal cancer. Publications were included in the review if they addressed any of the following outcomes: (1) prevalence, incidence, or clearance of anal HPV infection, (2) prevalence of anal cytological or histological neoplastic abnormalities, or (3) incidence or risk of anal cancer. Thirty-seven publications addressing anal HPV infection and anal cytology remained after applying selection criteria, and 23 anal cancer publications met the selection criteria. Among HIV-positive women, the prevalence of high-risk (HR)-HPV in the anus was 16-85%. Among HIV-negative women, the prevalence of anal HR-HPV infection ranged from 4% to 86%. The prevalence of anal HR-HPV in HIV-negative women with HPV-related pathology of the vulva, vagina, and cervix compared with women with no known HPV-related pathology, varied from 23% to 86% and from 5% to 22%, respectively. Histological anal high-grade squamous intraepithelial lesions (anal intraepithelial neoplasia 2 or greater) was found in 3-26% of the women living with HIV, 0-9% among women with lower genital tract pathology, and 0-3% for women who are HIV negative without known lower genital tract pathology. The incidence of anal cancer among HIV-infected women ranged from 3.9 to 30 per 100,000. Among women with a history of cervical cancer or cervical intraepithelial neoplasia 3, the incidence rates of anal cancer ranged from 0.8 to 63.8 per 100,000 person-years, and in the general population, the incidence rates ranged from 0.55 to 2.4 per 100,000 person-years. This review provides evidence that anal HPV infection and dysplasia are common in women, especially in those who are HIV positive or have a history of HPV-related lower genital tract pathology. The incidence of anal cancer continues to grow in all women, especially those living with HIV, despite the widespread use of combined antiretroviral therapy.

Quantitative spectroscopic imaging for non-invasive early cancer detection.

We report a fully quantitative spectroscopy imaging instrument for wide area detection of early cancer (dysplasia). This instrument provides quantitative maps of tissue biochemistry and morphology, making it a potentially powerful surveillance tool for objective early cancer detection. We describe the design, construction, calibration, and first clinical application of this new system. We demonstrate its accuracy using physical tissue models. We validate its diagnostic ability on a resected colon adenoma, and demonstrate feasibility of in vivo imaging in the oral cavity.

Safety and efficacy of topical Cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women

Objective:To evaluate the safety and efficacy of topical cidofovir for treatment of high-grade squamous perianal intraepithelial neoplasia (PAIN) and vulvar intraepithelial neoplasia (VIN) lesions in HIV-positive individuals. Design:Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium. Methods:HIV-positive patients with biopsy-proven high-grade PAIN that was at least 3u200acm2 were enrolled. PAIN biopsy specimens were assessed for human papillomavirus (HPV) using PCR and type-specific HPV probing. Participants applied 1% topical cidofovir to PAIN and VIN (if present) for six 2-week cycles. Results were designated as complete response (CR), partial response (PR) (>50% reduction in size), stable disease, or progressive disease (PD). Results:Twenty-four men and nine women (eight with high-grade VIN as well) were enrolled. Mean age was 44 years and mean CD4+ cell count was 412u200acells/&mgr;l. HPV DNA (most commonly HPV16) was detected in all pretreatment study specimens. Twenty six (79%) participants completed treatment per protocol: CR, five (15%); PR, 12 (36%), stable disease, seven (21%); PD, two (6%) (one with a superficially invasive cancer and one with new area of high-grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/burning/irritation (25 patients) and ulceration (13 patients). Conclusion:Topical cidofovir had 51% efficacy in the short-term treatment of high-grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed.

Abnormal anal cytology in HIV-infected women

OBJECTIVEnThe purpose of this study was to assess the prevalence of and risk factors for abnormal anal cytology and human papillomavirus (HPV) infections in women who are human immunodeficiency virus (HIV) positive.nnnSTUDY DESIGNnWe conducted an observational single center study of 100 HIV-infected women with cervical and anal specimens that were obtained for cytologic and high-risk HPV testing with Hybrid Capture 2.nnnRESULTSnSeventeen women had abnormal anal cytology; 16 women had anal HPV; 21 women had abnormal cervical cytology, and 24 women had cervical HPV. Abnormal anal cytology was associated with cervical HPV infection, abnormal cervical cytology, and anal HPV infection in univariate analysis. In multivariate analysis, abnormal anal cytology was associated with a CD4 count <200 cells/mm(3), a history of sexually transmitted disease, and concurrent cervical cytologic abnormality.nnnCONCLUSIONnHIV-infected women are at high risk for abnormal cytology and HPV infections of both the anus and cervix. Risk factors for abnormal anal cytology include abnormal cervical cytology, cervical and anal HPV infections, and low CD4 count.

Effect of anatomy on spectroscopic detection of cervical dysplasia

It has long been speculated that underlying variations in tissue anatomy affect in vivo spectroscopic measurements. We investigate the effects of cervical anatomy on reflectance and fluorescence spectroscopy to guide the development of a diagnostic algorithm for identifying high-grade squamous intraepithelial lesions (HSILs) free of the confounding effects of anatomy. We use spectroscopy in both contact probe and imaging modes to study patients undergoing either colposcopy or treatment for HSIL. Physical models of light propagation in tissue are used to extract parameters related to tissue morphology and biochemistry. Our results show that the transformation zone, the area in which the vast majority of HSILs are found, is spectroscopically distinct from the adjacent squamous mucosa, and that these anatomical differences can directly influence spectroscopic diagnostic parameters. Specifically, we demonstrate that performance of diagnostic algorithms for identifying HSILs is artificially enhanced when clinically normal squamous sites are included in the statistical analysis of the spectroscopic data. We conclude that underlying differences in tissue anatomy can have a confounding effect on diagnostic spectroscopic parameters and that the common practice of including clinically normal squamous sites in cervical spectroscopy results in artificially improved performance in distinguishing HSILs from clinically suspicious non-HSILs.

Detecting high-grade squamous intraepithelial lesions in the cervix with quantitative spectroscopy and per-patient normalization

This study develops a spectroscopic algorithm for detection of cervical high grade squamous intraepithelial lesions (HSILs). We collected reflectance and fluorescence spectra with the quantitative spectroscopy probe to measure nine spectroscopic parameters from 43 patients undergoing standard colposcopy with directed biopsy. We found that there is improved accuracy for distinguishing HSIL from non-HSIL (low grade SIL and normal tissue) when we “normalized” spectroscopy parameters by dividing the values extracted from each clinically determined suspicious site by the corresponding value extracted from a clinically normal squamous site from the same patient. The “normalized” scattering parameter (A) at 700nm, best distinguished HSIL from non-HSIL with sensitivity and specificity of 89% and 79% suggesting that a simple, monochromatic instrument measuring only A may accurately detect HSIL.

Phase IIA trial of 1% topical cidofovir for treatment of high-grade perianal squamous intraepithelial neoplasia in HIV-infected men and women (AMC046)

Phase IIA trial of 1% topical cidofovir for treatment of high-grade perianal squamous intraepithelial neoplasia in HIV-infected men and women (AMC046) Elizabeth A Stier, Stephen E Goldstone, Mark H Einstein, Naomi Jay, J Michael Berry, Timothy Wilkin, Jeannette Lee, Lori Panther, David Aboulafia, Joel Palefsky From 12 International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI) Bethesda, MD, USA. 26-27 April, 2010

If a Man Needs a Gynecologist, Will He Be Able to Find One?

In September 2013, the American Board of Obstetrics and Gynecology (ABOG) revised its definition of obstetrician-gynecologist. With few exceptions, gynecologists risked losing their board certification if they treated men. Anoscopy (on men) and vasectomy were explicitly prohibited (1). Pressure from the public and media (1), National Institutes of Health (NIH), and private letter-writing campaigns (2) resulted in the ABOGs reversing its stance step by step until it fully reversed itself in January 2014 (24). Although it may seem that restricting specialists in womens medicine to treating only women should create neither hardship nor protest, it is in fact a problem. Gynecologists often provide essential treatment that men cannot easily obtain from other practitionersfor example, high-resolution anoscopy (HRA). The incidence of anal cancer is increasing in both women and men and is especially high in HIV-infected men who have sex with men (5). High-resolution anoscopydirected biopsy is an important part of the diagnostic evaluation for anal cancer and its precursors. A relatively new procedure, HRA utilizes advanced colposcopic skills and requires significant training and experience. Gynecologists, with their expertise in colposcopy, have been the quickest to master HRA and thus make up a large percentage of the limited number of clinicians qualified to perform the procedure in this country (1). Gynecologists also play an important role in performing vasectomies. Although it is one of the safest and most cost-effective methods of contraception, vasectomy accounts for only 1 in 3 sterilizations in this country and is utilized preferentially by high-income white men (6). In rural and low-income areas, insufficient access to providers is one of the primary barriers to vasectomy. Gynecologists trained in the procedure during a family planning fellowship may be the only qualified, accessible providers in these areas (7). There are other situations as well in which gynecologists are the most appropriate physicians for men. For example, debilitating pelvic pain can affect men (albeit less prevalently than women). With their wider exposure to this problem, gynecologists are often the only practitioners able to properly diagnose and treat pelvic pain in men (8). Although, as noted, the ABOG has reversed all of these restrictions, we are troubled by the fact that a specialty board would attempt to limit the otherwise lawful and ethical practice of its diplomates. These restrictions raise ethical problems that go well beyond a simple public relations failure. Indeed, it is only in the context of an ethical failure that the ABOGs attempted policy initiative can be fully understood. First, the restrictions relied on an untenable distinction between men and women. A division of humans into 2 sexes or genders is perforce arbitrary. Any such classification must account for at least 4 factors: chromosomal sex, genitalia present at birth, genitalia currently present, and lived identity (which may or may not be made to conform to expected appearances with hormones or other means). It is not necessary to list all of the possible combinations of these factors to see that only 2 unequivocally fit the malefemale dichotomy the ABOGs edict createdintersexuality and transsexuality are completely unaccounted for. Although this may seem to be only an intellectual or practical problem, it is also an ethical one. By ignoring intersexual and transsexual persons when limiting the practice of gynecology, the ABOG ensured that such patients would be treated, or not treated, arbitrarilyin other words, unfairly. That the ABOGs policy had an exception for the treatment of transgender conditions (Web page no longer active) did not solve the problem. This exception was sufficiently vague that it was unclear who could be treated for what. Moreover, it did not seem to cover intersexual or transgender persons who may feel more comfortable with a gynecologist treating matters not related to their transgender conditions. By failing to account for these groups, the ABOG betrayed the trust of a vulnerable group of patients, who often receive their care from gynecologic endocrinologists. Second, the ABOGs restrictions compelled individual practitioners to abandon active patients who may not have had adequate alternatives for care (1, 8). This violates the heart of the physicianpatient relationship and harms identifiable patients. In addition to being unethical (9), it could be considered malpractice (10). Third, the restrictions discriminated against specific disadvantaged groups. As noted, gynecologists are especially important providers of vasectomy in underserved areas. In the case of HRA, those at greatest risk for anal cancer, and thus most in need of skilled HRA providers, are HIV-infected men who have sex with men. A fourth issue is that the ABOGs action could have interfered with important NIH-sponsored research. Although HRA has been increasingly accepted as an important part of screening for anal cancer, the optimal management of precursors to anal cancer is unknown. A major NIH-funded study of HRA in anal cancer prevention is about to start, and restricting investigators to enrolling only women threatened the integrity of the study. The ABOGs reversal has resolved this problem, but its willingness to scuttle a valuable study of public interest raises serious concern. Nor did the ABOGs stated reasons for its action support the restriction it imposed. The ABOG said it wanted to address the problem of gynecologists branching out into practices for which they are not trained and that are not covered by their board certification, such as administering testosterone injections to men and practicing cosmetic medicine (1, 3). Many physicians performing these procedures are apparently claiming that they are board-certified without indicating that their certification is in gynecology, which is irrelevant to those practices (3). In addition to protecting the public, the ABOG wanted to protect its specialtys reputation from gynecologists who perform procedures for which they are unqualified (1). The ABOG also wanted to ensure an adequate supply of physicians to treat women and that womens health is not short-changed in research (3). However, none of these concerns justified a ban on treating men. If the goal was restricting gynecologists from performing procedures in which they are untrained or not board-certified, then that should have been the prohibition. A ban on treating men still allowed the problematic behavior to occur with female patients. Those few gynecologists treating male patients would not have materially reduced the number of physicians treating women, nor would it have affected research agendas or funding. For all of these reasons, we believe that the ABOGs initial decision to impose restrictions on its diplomates practice was deeply flawed, and we are pleased it has made a full reversal. The ABOG should not have prohibited gynecologists from treating patients who need their help or performing skilled procedures for which these physicians are uniquely qualified. Medicine is constantly evolving, and arbitrary limitations on practice inhibit this development. The primary function of a medical board is to evaluate candidates in its primary specialty and to certify those qualified as diplomates of that board. In this way, patients can be assured that board-certified physicians are up-to-date in their specialties. Medical boards should not attempt to interfere with qualified physicians rendering appropriate care to their patients.

Early detection of high-grade squamous intraepithelial lesions in the cervix with quantitative spectroscopic imaging

Abstract. Quantitative spectroscopy has recently been extended from a contact-probe to wide-area spectroscopic imaging to enable mapping of optical properties across a wide area of tissue. We train quantitative spectroscopic imaging (QSI) to identify cervical high-grade squamous intraepithelial lesions (HSILs) in 34 subjects undergoing the loop electrosurgical excision procedure (LEEP subjects). QSI’s performance is then prospectively evaluated on the clinically suspicious biopsy sites from 47 subjects undergoing colposcopic-directed biopsy. The results show the per-subject normalized reduced scattering coefficient at 700 nm (An) and the total hemoglobin concentration are significantly different (p<0.05) between HSIL and non-HSIL sites in LEEP subjects. An alone retrospectively distinguishes HSIL from non-HSIL with 89% sensitivity and 83% specificity. It alone applied prospectively on the biopsy sites distinguishes HSIL from non-HSIL with 81% sensitivity and 78% specificity. The findings of this study agree with those of an earlier contact-probe study, validating the robustness of QSI, and specifically An, for identifying HSIL. The performance of An suggests an easy to use and an inexpensive to manufacture monochromatic instrument is capable of early cervical cancer detection, which could be used as a screening and diagnostic tool for detecting cervical cancer in low resource countries.