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With more than 100 known types, the human papillomavirus (HPV) is the most common sexually transmitted infection with approximately 75% of sexually active adults acquiring one or more genital HPV types at some point in their lifetimes.1 HPV is spread from skin to skin because HPV lives only in keratinocytes. The progression of HPV-related cervical disease is well characterized and proceeds through distinct phases. LSIL corresponds to the histologic diagnoses of flat condylomas and CIN 1, whereas HSIL corresponds to the histologic diagnoses of CIN 2 and 3. However, a small proportion of women have persistent detectable HPV infection.7 Women who continue to have detectable levels of HPV at the age of 30 years and older are considered to have persistent HPV infection, which is one of the strongest predictors of eventual development of cervical cancer.
In the United States, 8 to 10 per 100,000 women develop cervical cancer, with 14,000 new cases per year.9 Cervical cancer occurs disproportionately in lower socio-economic subgroups due to lack of adequate access to healthcare and routine cervical cytology screening. There is biological similarity between the cervix and the anus with respect to the preferred location of HPV infection; this is an additional area of interest in the pathogenesis of HPV. In contrast to the data regarding women and cervical HPV, anal HPV in the HIV-negative men who have sex with men (MSM) population seems to follow a different course.
This may be attributed to differences between the biology of the anal canal and the cervix, but more likely it is a result of the acquisition of other HPV types from new sexual partners over time.
The pattern of HPV prevalence is also consistent in anal cytology, with 25% to 30% of MSM having either AIN 1 or AIN 2-3 after the age of 20. HIV-negative men who have sex with men (MSM), by age group and by cancer-associated risk type.
ASIL includes both low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). In women, the prevalence of anal HPV is actually higher than the prevalence of cervical HPV, independent of HIV status and level of immunosuppression (Figure 8) and the incidence of anal cancer is 7-fold higher in HIV-positive women compared with HIV-negative women at high risk for HIV.16,29,31 The relationship between anal HPV infection and cervical HPV infection is poorly understood, as is the effect of anal HPV infection on the biology of cervical disease. Pathogenesis of HPV-associated neoplasia and effect of highly active antiretroviral therapy (HAART).
If this model of pathogenesis is correct, then highly active antiretroviral therapy (HAART) would be expected to be maximally beneficial to reduce the incidence of high-grade anogenital neoplasia if an individual has no disease or low-grade disease when beginning HAART, as restoration of the immune response might still be of value to control the development of high-grade disease.
While the efficacy of therapeutic vaccines to treat AIN is still under investigation, much attention has been given to the recently approved preventive HPV vaccines. The incidence of AIN and anal cancer is much higher in HIV-positive women and MSM than in the general population, and HAART has had little or no impact on this trend. To help us protect you from SPAM, please do not include your e-mail address or other personal contact information in the body of your comment. If you wish to respond to another reader's comment, please post a response on this website rather than contact the writer directly. In their excellent review on screening for HPV disease in patients with HIV, Jason Bratcher and Joel Palefsky point out that the New York State Department of Health (NYSDOH) recommended in September 2007 the use of anal cytology for the prevention of anal cancer, the first state or federal agency to do this.
The decision on the part of the NYSDOH AIDS Institute to recommend annual anal Pap smear screening for certain members of our HIV infected citizenry was based on public health obligation. As a general screening method, Pap smears although they have a limited specificity, have the advantage of over 75 years of clinical familiarity and are part of routine laboratory pathology department protocols. If you are interested in learning high-resolution anoscopy (HRA), the UCSF Anal Neoplasia Group recommends that prospective trainees take a basic colposcopy course to understand the fundamentals of colposcopy and lesion recognition, a didactic course in HRA, and then a preceptorship observing the performance of HRA in an established anal neoplasia clinic. Immunoreacivity for Rac1, RhoA, Tiam1 and beta-Pix was stronger in L-SIL and H-SIL, compared to samples without SIL, and it was significantly associated with the histological diagnosis.
Rac1 is expressed in the nucleus of epithelial cells in SILs and cervical cancer cell lines, and chemical inhibition of Rac1 reduces cellular proliferation. 102 paraffin-embedded cervical tissue specimens were obtained from the Department of Pathology at the "Vicente Guerrero" General Regional Hospital (IMSS), in Acapulco, Mexico.
Approval to conduct this study was obtained from the Institutional Ethics Comitee at the "Universidad Autonoma de Guerrero". The presence of HR-HPV was determined by in situ hybridization using the GenPoint tyramide amplification signal kit (DAKO, Carpinteria, CA). For immunohistochemistry, 3-micron paraffin sections were deparaffinized and rehydrated, followed by 20 min incubation in sodium citrate buffer (pH 6.0) at 110°C for antigen retrieval, using a pressure cooker (T-FAL Clipso). Cells were seeded on petri dishes and incubated for 24 h in the presence or absence of the Rac1 inhibitor NSC23766.
8 ? 103 cells were plated on 24-well plates (Sarstedt AG & CO, Germany) and cultured in DMEM medium supplemented with 10% FBS for 24 h. Association between variables was evaluated by Chi squared test or Fisher's exact test, as appropriate. Expression of Rho-GTPases and Rho-GEFs in cervical epithelium without squamous intraepithelial lesions, low-grade squamous intraepithelial lesions (L-SIL), and high-grade squamous intraepithelial lesions (H-SIL). We observed a strong nuclear reactivity for Rac1 in a subset of L-SIL and H-SIL samples, whereas no nuclear reactivity was observed in samples without SIL (Figure 2A).
Nuclear expression of Rac1 in squamous intraepithelial lesions and cervical cancer cell lines.
Effect of the Rac1 chemical inhibitor NSC23677 on the subcellular localization of Rac1, and on cell proliferation. Overexpression of Rho-GTPases and Rho-GEFs has been described in various types of human tumors [18], and in some cases overexpression is associated with tumor progression or poor prognosis [22, 23]. Rac1 has a nuclear localization signal (NLS) [24], and it has been recently shown that the importin Karyopherin alpha 2 (KPNA2) mediates Rac1 nuclear import trough the interaction with its NLS, and that KPNA2-mediated nuclear import of Rac1 requires Rac1 activation [25].
In our study, we observed overexpression of Rac1, RhoA and Tiam1 in L-SIL and H-SIL, and beta-Pix in H-SIL, when compared with epithelia without SIL. We found that the increased immunoreactivity of Rac1, RhoA and beta-Pix correlates with the histological diagnosis but not with HR-HPV infection. One of the limitations in our study is that expression of the analyzed proteins in cervical biopsies was studied only by immunochemistry. In conclusion, Rac1 and Tiam1 are overexpressed in L-SIL and H-SIL, RhoA and beta-Pix are overexpressed in H-SIL. Introduction: Cervical infection with high-risk human papillomavirus (HRHPV) induces cervical cancer and is present in 14% of women in Europe. Methods: Prospective observational program of screening and follow up of HRHPV cervical infection performed by Hybrid Capture in 825 HIV-positive women between 2002 and 2011. Conclusion: We found a high HRHPV prevalence of 43% and an incidence rate of 13 per 100 women-years in this cohort of HIV-positive women living in Europe and on cART. Human papillomavirus (HPV) may induce various diseases in women depending on the genotype: high-risk (HR) genotypes are associated with cervical, vulvar and anal cancer and low risk (LR) with benign condyloma [1]. Several large studies have demonstrated the clinical efficacy of two prophylactic vaccines against HPV that protect against persistent HR HPV, HSIL and CC in HIV-negative adolescent girls and women [5,6]. A better understanding of the natural history of HR HPV cervical infection and its epidemiology in HIV-positive women is essential before designing studies evaluating vaccination of these women against HPV. Most studies performed in HIV-positive women have reported cervical HPV prevalence mixing both LR and HR HPV and few have generated incidence rates; most of them were performed in the United States or in Africa in women not receiving combined antiretroviral therapy (cART) and very few have reported data coming from European countries.
Since 2002 an ongoing prospective observational programme of screening and follow-up of HR HPV infection is systematically offered to all women followed for HIV-1 infection in our AIDS reference centre.
The screening programme and the data collection were both approved by the Ethics Committee of Saint-Pierre University Hospital in Brussels.
Chi-square or Fisher's exact and Kruskal–Wallis tests were performed for univariate analysis for categorical data and continuous data, respectively. To calculate the incidence of new HR HPV detection, we considered all women with a first negative HR HPV test followed by at least one second sample. The cohort consisted mainly of sub-Saharan African women (n=528, 81%) with heterosexual HIV acquisition (n=613, 94%) and non-smoking habits (n=476, 73%).
Among the 528 women with African ethnical origin, 422 (79%) had immigrated to Belgium and we could retrieve the exact date of arrival for 385 women (91%). The influence of both age and CD4 cell count level on HR HPV prevalence are shown in Figure 1. Smoking status, previous pregnancies or risk factor for HIV acquisition did not influence HR HPV prevalence.
There were 165 patients with a first negative HPV screening followed with at least one subsequent test allowing for the calculation of HR HPV incidence rate. In this prospective observational cohort of HIV-positive women, the prevalence of cervical HR HPV infection is 43%.
The prevalence of 43% found in our cohort is higher than those reported in other HIV populations from Western European countries or North-America over the last decade.
In a recent study performed in the United States, the prevalence of HR HPV screened by PCR before initiating cART was 23% among HIV-positive women free of cervical lesions, with a median age similar to our cohort [14]. Our HIV cohort is characterised by a large proportion of patients born in central Africa (Congo, Rwanda and Cameroun) with heterosexual acquisition of HIV and who came to Belgium as adults [17]. Incidence could have been underestimated in our cohort because the median interval between HR HPV screens is 16 months and we could have missed transient new infection or reactivation of HR HPV. Our findings, as well as other studies, show that HR HPV prevalence and incidence is even higher in HIV-positive women originating from Africa. Increased susceptibility to HPV infection could also be due to immune-genetic differences: some major histocompatibility complex haplotypes have been associated with increased risk of CC according to ethnic origin [31]. In conclusion, we found a very high prevalence of HR HPV of 43% and a very high incidence rate of 13 per 100 women-years in a HIV cohort of women living in Europe and treated with antiretroviral therapy.
Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. Cervical human papillomavirus infection and cervical intraepithelial neoplasia and cancer in the era of highly active antiretroviral therapy. Safety and immunogenicity of a quadrivalent human papillomavirus (Type 6, 11, 16 and 18) vaccine in HIV-infected children 7 to 12 years old. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-positive women.
Prevaccination distribution of human papillomavirus types in women attending at cervical cancer screening in Belgium.
Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women. Epidemiological data of different human papillomavirus genotypes in cervical specimens of HIV-1-infected women without history of cervical pathology.
Human papillomavirus infection and cervical cytology in HIV-infected and HIV-uninfected Rwandan women. Sexual risk behaviors among youth heads of household in Gikongoro, south province of Rwanda.
Incidence, duration, and determinants of cervical human pappillomavirus Infection in a cohort of Colombian women with normal cytological results. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. Determinants of incidence and clearance of high-risk human papillomavirus infections in rural Rakai, Uganda.
Restricted cross-reactivity of hybrid capture 2 with nononcogenic human papillomavirus types. Human immunodeficiency virus infection in vitro activates naturally integrated human papillomavirus type 18 and induces synthesis of the L1 capsid protein. High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: risk factors for cervical viral shedding. Genital human papillomavirus prevalence and human papillomavirus concordance in heterosexual couples are positively associated with human immunodeficiency virus coinfection.
Variants of human papillomaviruses 16 and 18 and their natural history in human immunodeficiency virus-positive women. Association between HLA-DQB1 alleles and risk for cervical cancer in African-American women.
The association between cervical human papillomavirus infection and HIV acquisition among women in Zimbabwe.
Human papillomavirus distribution in invasive cervical carcinoma in sub-Saharan Africa: could HIV explain the differences?
High-risk (HR) types include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73; low-risk types include 6, 11, 53-56, 66, Pap 155, and Pap 291. Most individuals are assumed to acquire HPV infection early after the initiation of sexual activity, and may acquire HIV infection sometime thereafter. This assumes that HAART is capable of restoring HPV-specific immunity, but this has not yet been shown. The vaccines work by expressing a major capsid protein encoded by the L1 gene of HPV in eukaryotic cells.49 The L1 proteins, or virus-like particles (VLP) auto-assemble into a three-dimensional structure that closely resembles that of the native HPV viral capsid. There is a growing need for definitive guidelines to assess for AIN, and with better treatment options available, it is even more crucial to identify these patients at an earlier stage. Palefsky and Bratcher for this excellent review of the relationship of HPV infection to anogenital cancers in HIV-infected men and women. The same HPV genotypes, mostly 16 and 18, are found in both cervical and anal cancers, and the oncogenic potential of these viruses has been well established over the past 30 years both experimentally and, especially in the case of cervical cancer, epidemiologically. For example, both anatomic sites have a squamo-columnar junction, but only the cervix has a transformation zone defined by the area covered by the squamo-columnar junction as it recedes towards the os during lifetime.
So far these studies, which are uncontrolled, focus on the treatment of anal high grade squamous intraepithelial lesions (HSIL). Cytologic abnormalities should prompt an evaluation by high-resolution anoscopy, which requires training and practice.
However, this approach was never submitted to a double-blind study showing its efficacy in reducing the morbidity and mortality of cervical cancer in women [14]. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies.
Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high risk HIV-negative women.
Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome.
Anal human papillomavirus infection among human immunodeficiency virus-seropositive and -seronegative men.
Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus.
AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Infrared coagulator treatment of high-grade anal dysplasia in HIV-infected individuals: an AIDS malignancy consortium pilot study. High-Resolution Anoscopy Targeted Surgical Destruction of Anal High-Grade Squamous Intraepithelial Lesions: A Ten-Year Experience. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. Overview of important cervical cancer screening process values in European Union (EU) countries, and tentative predictions of the corresponding effectiveness and cost-effectiveness.
These screening tests allow, if nothing else, an alert to the medical provider that a potential malignant lesion may be present and monitoring (and if necessary treatment) is appropriate. Anal screening and treatment programs should be guided by the best data possible and by years of experience with screening for cervical disease; 3.
As an example, colposcopy training programs require 25-50 proctored examinations including at least 3 high-grade cervical cases and at UCSF it is 100. Further studies are needed to better understand the role of Rho-GTPases in cervical cancer progression.

Infection with High-Risk Human Papillomavirus (HR-HPV) is considered the main risk factor for developing cervical cancer and its precursor lesions [1–3]. Eighty-two samples corresponded to cervical biopsies or cones with confirmed histological diagnosis of L-SIL (n = 51) or H-SIL (n = 31), and 20 corresponded to cervical tissue specimens without SIL, selected from patients undergoing hysterectomy for benign conditions, without a history of SIL or abnormal Pap results.
Briefly, 3- micron paraffin sections were placed on silanized slides, deparaffinized, and incubated for 5 min at 37°C with proteinase K.
Samples were incubated for 10 min with immunodetector peroxidase block solution (Bio-SB Inc. Cells were treated with the Rac1 inhibitor NSC23766 (Santa Cruz Biotechnology Inc, CA) at 25 ?M or 50 ?M or with vehicle. Representative images of immunohistochemical analysis of Rac1, RhoA, Cdc42, Tiam, and beta-Pix expression.
Imnunocytochemical analyses of NSC23766-treated cells showed an apparent reduction in the nuclear Rac1 immunoreactivity in both cell lines, as well as a reduction of the perinuclear immunoreactivity in SiHa cells (Figure 3A).
Here we show that the nuclear localization of Rac1 in C33A and SiHa cells is not affected by treatment with the Rac1 inhibitor NSC23766. In vitro experiments in HeLa cells demonstrate that Rac1 [34] and Rho [35] activation is required for cell growth and migration.
In contrast, Tiam1 immunoreactivity was associated with both histological diagnosis and HR-HPV infection. Further studies using Western blotting, as well as analysis of a larger number of samples are required. Rac1 is expressed in the nucleus of cervical premalignant-lesions and cervical cancer derived cells lines.
76689 from the National Council of Science and Technology (CONACYT) to ECS and BIA, and a grant from the Public Education Secretariat (SEP-Promep) to ECS.
We assessed the prevalence and incidence of cervical HRHPV in a cohort of HIV-positive women living in Belgium. It is estimated that 12% of women with normal cervical cytology are infected with HR HPV worldwide [2]. A similar immunogenicity (level of antibody response) and safety profiles of the quadrivalent HPV vaccine have been recently confirmed in HIV-positive girls and women [7–9].
To analyze the epidemiology and the natural history of cervical HR HPV in HIV-positive women treated with cART, we initiated a prospective longitudinal cohort in 2002. Women are seen by a dedicated gynaecologist within the centre and are then followed every year or more often if they have complaints or abnormal smear results.
Women with previous HSIL or CC confirmed by biopsy (n=141) or non-cancerous hysterectomy (NCHST) (n=32) were excluded, leaving 652 patients for final analysis. HR HPV screening had been performed once in 304 women, twice in 155 women and three or more times in 193 women.
This is more than three times the prevalence of 12% found in the general population in Belgium and in Europe [11,12]. HR HPV carriage significantly declines as immune level increases which is also consistent with the literature [3,4]. In a large meta-analysis in HIV-positive women with normal cervical cytology, the HPV prevalence was 31% in North America, 32% in Europe and 57% in Africa [13]. In a UK study, the prevalence among women with a median age of 33 years and normal cervical cytology was 23% [15]. The high prevalence of HR HPV that we found is in agreement with other studies performed in Africa.
HC has been reported to slightly overestimate HR HPV detection when compared to PCR techniques likely due to cross-reaction with LR HPV [25]. A recent study in South Africa among heterosexual couples showed that the prevalence of HR HPV infection is 43% in men when both partners are HIV-negative and 70% when they are both HIV-positive [29].
DK contributed to conceptualization of the study, acquisition of the data, interpretation of the data, drafting, revising and final approval of the manuscript. Epidemiologic classification of human papillomavirus types associated with cervical cancer.
Disclaimer: The Journal of the International AIDS Society is an official journal of and is published by the International AIDS Society. HPV types 16 and 18 are found in a high proportion of advanced cervical intraepithelial neoplasia (CIN) and are considered to be precursors to invasive cancer in about 50% and 20% of all cervical cancer cases in the United States, respectively.
This area, as well as the distal squamous epithelium, is susceptible to HPV infection and is the area of interest when performing anal cancer screening (Figure 4).The histopathologic classification of AIN 1, 2, and 3 corresponds to CIN 1, 2, and 3. Infection with multiple HPV types may occur, but as long as HIV-associated immunosuppression remains minimal, there is good control of HPV replication and little anogenital disease.
At the other end of the pre-cancerous spectrum, following initiation of HAART, restoration of immune competence in general and of HPV-specific immunity in particular should have limited or no benefit for regression of high-grade AIN or CIN. Performing the DRE to feel for subcutaneous masses is particularly important to fully assess for presence of anal cancer, because these tumors may be entirely below the epithelial surface and can occasionally be missed on visual inspection of the surface using HRA. When injected into humans, these VLPs stimulate immunity against the real HPV virus.There are two different vaccines, one of which is currently FDA-approved in the United States.
New York is the first state to institute guidelines for anal cytology screening in HIV-positive patients. Indeed, HPV vaccination is now recommended without conclusive proof that it prevents cervical cancer, or any other HPV-related cancer.
This lack of proper evidence no doubt contributed to disparate screening policies throughout the world [15], and explains why as of early 2000, there was still a need to prove the effectiveness of cervical cytology [16]. Bratcher and Palesky does not decrease with effective immune reconstitution with ARV therapy. It will take some time to amass the data that we all want, and there is controversy as to how best to proceed until we have those data; 4.
Experienced colposcopists find that learning HRA can be challenging; visualizing anal lesions is more difficult that performing cervical colposcopy. In this study we analyzed the expression of the GTPases Rac1, RhoA, Cdc42, and the Rho-GEFs, Tiam1 and beta-Pix, in cervical pre-malignant lesions and cervical cancer cell lines. Development of cervical Low-grade Squamous Intraepithelial Lesions (L- SIL) and High-grade Squamous Intraepithelial Lesions (H-SIL), and progression to invasive carcinoma, are associated with alterations in the regulation of several cellular processes such as cell cycle progression, apoptosis, and DNA repair [2, 4, 5]. Samples were dehydrated, and a mixture containing a pool of biotinilated DNA probes (directed against HPV 16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59 and 68 types) was added to each section. Santa Barbara, CA.) to inactivate endogenous peroxidase, blocked with PBS + 1% BSA during 30 min, and incubated with primary antibodies for 1 h at room temperature.
Representative images showing nuclear Rac1 expression in low-grade squamous intraepithelial lesions (L-SIL) and high-grade squamous intraepithelial lesions (H-SIL) but not in epithelium without squamous SIL.
However, cellular fractionation and Western blot analysis demonstrated that treatment with the Rac1 inhibitor does not affect the nuclear localizacion of Rac1 in these cell lines (Figure 3B). Representative images of immunocytochemical analysis for Rac1 in C33A and SiHa cells, treated or not with the Rac1 inhibitor NSC23677.
Here, using immunohistochemistry, we show that the immunoreactivity of the GTPases Rac1 and RhoA, and the Rho GEFs Tiam1 and beta-Pix, is increased in SILs, compared to cervical epithelium without SIL. These data indicate that in these cells, the presence of Rac1 in the nucleus is not dependent on its activation. Similarly, experiments in CaSki cells showed that inhibition of migration and invasion by the anticancer agent JOTO1007, is associated with a reduction in the expression of RhoA and the Rho downstream effector ROCK-1 [36]. These observations suggest that altered expression of Tiam1, but not that of Rac1, RhoA and beta-Pix may be dependent of HR-HPV infection. MAMC and HNVF received a postgraduate master fellowship from the National Council of Science and Technology (CONACYT).
Representative images of (a) L-SIL sample in which HPV-probe set was excluded (negative control); (b-d) HR-HPV positive H-SIL showing strong nuclear staining. To analyze the differences in the intensity in immunoreactivity of the five proteins, we defined four categories based on signal intensity: a) negative, b) low, c) moderate and d) strong. BIA and MAMC participated in interpretation and analysis of data and manuscript preparation. The magnitude of HRHPV epidemiology should prompt to evaluate the clinical efficacy of vaccines against HPV in HIV-infected women. However, data of the clinical efficacy against HPV-induced lesions have not yet been reported despite the higher magnitude of the HPV morbidity is this population. We report here on the prevalence and incidence of HR HPV infection in this cohort of HIV-positive women living in Belgium.
To estimate the relative risk (RR) and confidence intervals (CI) of HR HPV carriage according to age and CD4 cell count level, we used a modified Poisson regression model by using robust error variances [10]. Women who developed HSIL or CC (n=29) or had NCHST (n=5) after being included in the screening programme were censored at the time of the event.
The influence of age and CD4 count level were independently statistically significant (p=0.06 for interaction, by logistic regression).
However our cohort provides new information on the different prevalence in subgroups of patients according to both age and immunity level underlining the very high prevalence of HR HPV infection in women less than 40 years of age both in the very low CD4 cell count strata as expected but also in the higher CD4 strata. These figures might be overestimating HR HPV prevalence as they reported both LR and HR HPV prevalence together and information on the median age and level of immunity, which are important associated factors, were not available. In Zimbabwe, the prevalence of HR HPV was 64% among HIV-positive women with a median age of 25 years, in accordance with our rates of 65% in younger women, although the Zimbabwean cohort included women with abnormal cervical cytology [18]. However, a Spanish study showed that HC was less sensitive than PCR for screening HR HPV in HIV-positive patients [16]. These results suggests that the risk for a woman to be HR HPV infected by a new partner is high in sub-Saharan Africa. Recently, HPV infection has been found to be a significant risk factor for HIV acquisition [32]; conversely, as mentioned above, HIV enhances HPV acquisition and persistence.
The magnitude of HR HPV epidemiology should be a prompt to evaluate the clinical efficacy of vaccination against HPV in HIV-positive women.
YM, CG and PB contributed to take the HPV cervical samples during gynaecological examinations of the patients and to critical revision of the manuscript.
The costs of the Journal of the International AIDS Society are secured by the International AIDS Society.
The percentages of cervical cancers associated with HPV types 31, 33, and 35 are lower and vary from country to country.3 This review will discuss the pathogenesis of HPV in HIV-positive patients, provide an update regarding anal intraepithelial neoplasia (AIN), and outline screening guidelines for patients at risk for HPV-related disease. As HIV associated immunosuppression progresses, there is increased HPV replication and the development of AIN 1 or AIN 2-3.
It should also have limited impact on reduction in anal or cervical cancer, given the limited role of the immune response at these stages of disease (Figure 9).Data have now been accumulating regarding the effect of HAART on the natural history of HPV disease, and the evidence to date suggests that there is limited or no benefit for reduction of high-grade disease and cancer.
DRE should be performed at least annually on all patients at risk for anal cancer, and is an especially important tool in clinical settings where anal cytology or HRA are not available. If anal cytology and HRA are not available, all high-risk patients should be screened with a DRE as there are many benefits to early detection of anal cancer. Future efforts around this issue should address the disparity between the demand for screening and the resources. Reduced to these simple arguments, the rationale for anal cytology screening is straightforward and powerful. The use of oral contraceptive is a well-identified risk factor for the development of cervical cancer [1], but has not been reported to play any role in anal cancer.
However, in addition to the absence of controls other than historical, other considerations mitigate the impact of these results. However, the expectation that it will be effective for these goals is firmly grounded on basic science and epidemiologic evidence. The effects on morbidity could be difficult to measure accurately, and those on mortality will take time to document. It would be regrettable if in the well-intended push to disseminate anal cytology without sufficient evidence and monitoring tools, one would ultimately delay the proper assessment of its indications, efficacy, mode of implementation, and cost-effectiveness.
The population of the HIV infected individuals in New York not only continues to grow but is aging as well. This may take a number of years based on the volume of patients that a provider sees and whether the patients have a high likelihood of disease. For the AIDS Malignancy Consortium HPV Working Group, the following standards for proficiency were determined.
All SIL cases were additionally reviewed by a second pathologist (JFC) to establish a consensus diagnosis (discrepancies relative to the original diagnoses were resolved by the interpretation of a third pathologist).
Sections were covered with a glass coverslip, denatured for 10 min at 95°C, and hybridization was performed for 20 h at 37°C in a humidified atmosphere in a Dako hybridizer (Dako, Carpinteria, CA). Next, we determined the expression of Rac1, RhoA, Cdc42, Tiam1 and beta -Pix in cervical samples. We next tested whether the chemical inhibition of Rac1 has an effect on the proliferation of Hacat, C33A and SiHa cells. Interestingly, we found that Rac1 is present in the nucleus of a subset of L-SIL and H-SIL, but not in samples without SIL. Moreover, experimental evidences indicate that Rho GTPases play a role in cellular transformation. However, further studies are needed in order to determine if increase levels of Rho proteins and their GEFs is induced directly by HPV oncoproteins or is the result of a secondary event related to the progression of the malignancy. To our knowledge, this is the first report showing abnormal expression of Rho-GTPases in cervical cancer, Further studies are needed to better understand the role of the overexpression of Rho-GTPases, as well as the nuclear Rac1 expression in cancer progression. ECS conceived the project, designed experiments, analyzed the data, supervised the whole project and wrote the manuscript. Age is one of the main factors influencing these figures: prevalence peaks before 25 years, then decreases progressively until a second peak after 45 years. HR HPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) are detected by Hybrid Capture (hc2 High-Risk HPV DNA Test, Digene®, USA). Kaplan-Meier curves for the risk of acquiring new HR HPV infection stratified by age and CD4 cell count level were performed and were not statistically significant (data not shown).
In a study performed in Rwanda, 42% of HIV-positive women between 35 and 44 years had HR HPV, which is again consistent with our findings [19]. In addition, non-European variants of HPV 16 have been found more frequently in African and African American than in Caucasian women [30]. As sub-Saharan Africa holds the highest rates of both HIV and HPV infection worldwide, this might contribute to fuel both HPV and HIV epidemics [33]. JdM contributed to perfom hybrid captur analysis and to critical revision of the manuscript. This support does not in any way affect the editorial independency of the Journal of the International AIDS Society.
Progression from AIN 2-3 to invasive cancer may take many years or decades, in which the key progression events are driven by host genetic change. In studies examining CIN, HAART seems to have little or no effect on regression of CIN 2-3. At present there are no data on the effect of AIN screening on the incidence of anal cancer.
There is some confusion about the reported efficacy of the vaccines since the efficacy will depend on the proportion of women in the study population (or general population) that has not previously been exposed to the HPV types in the vaccine.
HPV vaccines have the potential to reduce the incidence of anal cancer, but more studies are needed to evaluate the efficacy in patients infected with HIV. Training more providers to do the screening and prevention is essential, but further research may also address this issue. In HIV positive and negative women the prevalence of HPV DNA is higher in the anal canal than in the cervix [2], yet HPV-related anal diseases are not as prevalent as cervical diseases [3]. As with the cervix, anal cytology and histology have modest intra- and inter-observer reliability [12], this causes patient misclassification that reduces the accuracy of the measurement of the true treatment effect.

As discussed earlier, the best literature available so far is largely limited to the treatment of HSIL with the infrared coagulator.
Moreover, their significance might be difficult to analyze due to confounding variables such as sexual behavior and treatments. The Medical Care Criteria Committee, composed of some of New York State’s most eminent HIV treating physicians, used the following rationale in recommending to the AIDS Institute that screening for HPV associated anal malignancy be instituted.
Examiners are asked to submit logs of 50 consecutive exams performed in HIV-positive patients listing cytology and histology.
Rho-GTPases are small signaling proteins involved in the regulation of crucial cellular functions such as cell shape, cell-cell adhesion, cell proliferation, cell division, migration and invasion [13–15].
The slides were incubated with a streptavidin peroxidase-conjugated primary antibody, followed by incubation with biotil-tyramide, and with streptavidin.
Cells were maintained on DMEM medium (Invitrogen, Carlsbad, CA,) supplemented with 10% FBS (Byproductos, Mexico) at 37°C in a 5% CO2 atmosphere. The relative number of cells was determined by measuring the optical density of each well at 600 nm in a biophotometer (Eppendorf RS-2312 DH 8.5 mm). Expression of the five proteins was observed in all cervical samples and the intensity of the signal for Rac1, RhoA, Tiam1, and beta-Pix was stronger in L-SIL and H-SIL, when compared to samples without SIL (Figure 1). These observations were further confirmed using cellular fractionation and Western blot analyses.
Representative images of immunocytochemical analysis showing nuclear Rac1 expression in cervical cancer cells C33A and SiHa, but not in non-tumorigenic Hacat cells.
We found that tNSC23766 treatment resulted in a significant decrease in the proliferation of the three cell lines (Figure 3C). It has been shown that Rac1 and its activator Tiam1 are required for Src-induced transformation [37]. Our data indicate that nuclear expression of Rac1 in cervical lesions may be independent of HR-HPV infection as not all HR-HPV positive samples have nuclear staining for Rac1.
HIV infection is also an important associated condition: progressive immunodeficiency significantly increases the prevalence and the persistence of HR HPV infection and worsens its evolution leading more commonly to cervical high-grade squamous intraepithelial lesions (HSIL) and cervical cancer (CC) [3,4]. A large proportion of women from our cohort came from countries where age of first sexual intercourses is less than 15 years [20,21].
This could reflect sexual mixing behaviours suggesting that people born in Africa are more likely to have an African-born partner even if they are living outside Africa. FF and DL contributed to analysis the cytology and histology of the cervical samples and to critical revision of the manuscript. Material published in the journal is entirely independent of the opinion of external sponsors and the society.
Less-advanced immunosuppression and early stages of AIN may therefore respond to the initiation of HAART, due to the restoration of HPV-specific immune responses.
Another source of reduced vaccine efficacy is disease due to HPV types other than 16, 18, 6 or 11. In this commentary, I wish to point out that in several ways the rationale for anal cancer screening with anal cytology and its implementation are not as firmly grounded as it may seem, and that overlooking these weaknesses may lead to unfortunate consequences and waste of resources to combat a real problem. This does not mean that every proctologic operator will have this instrument available, or will accept for HSIL or any other HPV-related condition a uniform management approach.
It will also be very difficult in the absence of controls to assess the magnitude of the unnecessary and harmful interventions, a critical information to capture not only to improve the guidelines, but also to measure the true costs of screening.
At least 30% of subjects should have high-grade neoplasia as the most severe histology per patient.
Experiments using cell culture and animal models have demonstrated an important role for these proteins in carcinogenesis [16, 17].
The reaction was developed by adding DAB, followed by staining with Mayer's hematoxylin (Merck, Germany), and mounted with Entellan mounting medium (Merck, Germany). Where indicated, cells were treated with the Rac1 chemical inhibitor NSC23766 (Santa Cruz Biotechnology Inc, CA) at 25 ?M or 50 ?M. Whole cell, cytoplasmic and nuclear proteins were separated by SDS- PAGE in 10% acrylamide gels, transferred to PVDF membranes and detected by Western blot using antibodies against alpha-tubulin, lamin B, Rac1 (all from Millipore) and Tiam1 (Santa Cruz Biotechnology).
Similarly, it has been demonstrated that Rac1 and Cdc42 are necessary for H-Ras-induced transformation, although overexpression of constitutively active forms of Rac1 or Cdc42 is not sufficient for cellular transformation [38]. Moreover, both HPV-negative and HPV-positive cervical cancer derived cells have nuclear staining for Rac1.
Women with previous hysterectomy or conization or HSIL or CC both confirmed by biopsy were not included in the cohort as their cervix could not be considered as intact anymore and the natural history of HR HPV infection could be altered.
As these women came to Europe as adults and were diagnosed HIV-positive shortly after arrival, we may assume that most of them had acquired both HR HPV and HIV before coming to Belgium. Having an African-born partner who is himself at higher risk of carrying HR HPV might explain the very high incidence of new HR HPV infection found among our patients.
MD contributed to build the database, to perform the statistical analysis and to critical revision of the manuscript.
The beneficial effect of HAART may be less pronounced by the time an individual is diagnosed with AIN 2-3, either because HIV-associated immune response has been damaged so severely that immune restoration due to HAART fails to restore HPV-specific immunity, or because a proportion of AIN 2-3 has accumulated sufficient genetic changes by the time of HAART initiation that HAART-associated restoration of HPV-specific immunity is insufficient by itself to lead to lesion regression. Nonetheless, the prevalence of HPV DNA in the oral cavity is higher in HIV seropositive than in seronegative subjects [7]. Because the interventions and treatments are not free from financial, psychologic, and physical adverse effects [12], it is essential to know what happens to all patients subjected to anal cytology testing, not just those who qualify for a particular diagnosis and are treated.
To date proctologic practices vary widely, and are largely informed by case-series, expert opinions, and personal experience, not an ideal basis for public policies. The level of 30% was chosen to represent what is felt to be a low estimate of the actual prevalence of HSIL in HIV-positive patients. Moreover, it has been shown that expression of some Rho-GTPases and their regulatory proteins is altered in human cancers such as prostate, colon, lung, and breast cancer [18]. The positive reaction was seen as a maroon or brown nuclear signal (Additional file 1: Figure S1).
24 h or 48 h after plating, cells were fixed with methanol-acetone (1:1) for 30 min, washed with PBS and antigen retrieval, blocking and primary antibody incubation were performed as described for immunohistochemistry.
In HaCat cells, in which Rac1 is localized to the cytoplasm, chemical inhibition of Rac1 may reduce its nuclear translocation during the G2 phase of the cell cycle, resulting in a reduction in cell proliferation. It has also been shown that RhoA overexpression can induce pre-neoplastic transformation of primary mammary epithelial cells [39]. However, as mentioned above, it is possible that infection with other HPV types not detected by ISH technique we used in this work may affect the subcellular localization of Rac1. Women who developed HSIL or CC or who had a hysterectomy after being included in the screening programme were censored at the time of the event. However, among women without HR HPV at baseline, the incidence rate of HR HPV new infection was also very high (13.4 per 100 women-year). SDW and NC contributed to conceptualization of the study, interpretation of the data, to critical revision and final approval of the manuscript. Studies of both heterosexual men and MSM are in progress, and if the vaccines are shown to be effective in this setting, discussions will be initiated to determine the merits of vaccinating both men and women.
Or is it safe to wait until say… age 30 because of the biological differences between anal cancer and cervical cancer?
These observations suggest that if the general principles of cervical and anal cytology are similar, there are quantitative nuances whose magnitude and variability need to be well measured to accurately define the place of anal cytology in anal cancer screening. This variability of treatment mixed with the variability of diagnosis ensures that unnecessary and inappropriate treatments will occur. Providers are certified after a final visit in which an expert in HRA directly observes 10 HRA exams.
Cell culture experiments showed that RhoC regulates invasion and motility of cervical cancer cells [19, 20]. These data suggest that overexpression of Rho GTPases in SILs may cooperate with other signaling pathways to promote tumor progression. Moreover, ISH does not allow us to identify which HR-HPV type is present in the samples, and it is possible that infection with some HR-HPVs such as HVP16 and HPV18 will have a more dramatic effect on the expression of these proteins. In contrast, HIV-negative women with similar age and cytology have a much lower incidence of five per 100 women-year [22,23].
Additional risk factors for anal cancer in MSM include having an increased number of unprotected anal receptive sexual partners, being 50 years of age or older, having an HIV-positive status, using tobacco consistently, and having a low nadir CD4+ T-cell count.38,40 Other HPV-related carcinomas, such as vulvovaginal, penile and oral cancers, are also higher in HIV-positive patients.
Since AIN can be challenging to treat, and since a high proportion of anal cancers are associated with HPV 16, vaccines may be an excellent prevention strategy for anal cancer in the long-term, provided that at-risk individuals receive the vaccine before they have been exposed to HPV. More clearly defining the at-risk population would help us focus our resources on those most at need.
These are costs that have not been incorporated in otherwise favorable cost-effectiveness analyses of anal cytology screening [13]. Santa Barbara, CA.), following manufacturer's instructions, samples were counterstained with Harris's hematoxylin and mounted using Entellan mounting medium (Merck, North America Inc).
Data shown are average optical density values plus standard deviation of experiments performed in triplicate. This could be of particular relevance for our study population, as in a recent study performed on women from Guerrero state in the south of Mexico, Illades-Aguiar et al., (2010) reported that whereas HPV16 is the most frequent HPV type present in women with cervical cancer, the most frequent type in women with L-SIL was HPV33 [40]. In HIV-positive women, very few studies have generated crude incidence rates for HR HPV and our results are in accordance with a survey performed among younger women (median age 28 years) from Uganda with an incidence of 17 per 100 women-year [24].
In the case of MSM and the psychosocial dynamics of coming out and seeking health care, this may be especially challenging if boys in the general population are not routinely vaccinated prior to sexual debut.HPV vaccination presents another challenge in the HIV-positive population.
However, expression of other Rho-GTPases has not been investigated in cervical cancer or its precursor lesions. Antibodies used were: Rac1 (C-14), RhoA (C-15), Cdc42 (B-8), Tiam1 (C-16), and beta- Pix (C-19) (Santa Cruz Biotechnology Inc, CA). We also found moderate-strong reactivity for the five proteins in samples without SIL (Table 1). HIV-positive men and women are clearly at high risk of disease due to HPV types in the vaccines, and may benefit from vaccination.52 However, it is not known how effective vaccination will be in the HIV-positive population since immunosuppression may attenuate development of protective titers of HPV antibodies. The aim of this study was to investigate the alterations on the expression of the GTPases Rac1, RhoA, and Cdc42, and the Rho GEFs Tiam1 and beta-Pix in cervical premalignant lesions.
The intensity of cytoplasmic staining was scored as weak, moderate or strong at 40? magnification (Additional file 2: Figure S2).
Activation of the Wnt signaling pathway plays an important role during cervical cancer progression [28, 29]; therefore nuclear Rac1 may cooperate with this pathway to stimulate proliferation of cervical cancer cells. The safety of the vaccine has not yet been studied in HIV-positive adults and this population may already have been exposed to some or all of the types in the vaccine. No significant association was found between the reactivity of Cdc42 and L-SIL or H-SIL, or between the reactivity of RhoA or beta-Pix and L-SIL. We found that chemical inhibition Rac1 in C33A and SiHa cells, in which Rac1 localizes both to the cytoplasm and the nucleus, impairs proliferation without affecting Rac1 nuclear localization. It is possible that some of the samples without SIL that showed moderate-strong reactivity are positive to HR-HPV. Overall, HIV positive patients most likely will have a reduced efficacy of vaccination, and as with MSM in general, the optimal strategy to prevent HPV infection in this population would be to vaccinate all boys and girls before sexual debut. We found that the intensity of Tiam1 immunoreactivity was associated with HR-HPV infection (p = 0.014), whereas no significant association was found between the immunoreactivity of Rac1, Cdc42, RhoA or beta-Pix, and HR-HPV infection (data not shown). In these cells, inactivation of the nuclear pool of Rac1 may impair the interaction of Rac1 with nuclear proteins such as TCF4 and beta-catenin, resulting in a reduction in the expression of proliferation-related genes and therefore the reduction in cell proliferation.
Given the current debate about vaccinating girls prior to sexual debut, such a recommendation would undoubtedly stimulate even more vigorous debate.
Therefore, it is possible that inhibition of the cytoplasmic pool of Rac1 in both cervical cancer-derived and non-tumorigenic cells may result in a reduction of cell proliferation, independently of Rac1 nuclear functions.
Further studies using more sensitive techniques such as PCR-RFLP or sequencing for the detection and typing of HPV infection will be required to answer to this concern. Altogether, these data suggest that nuclear Rac1 may play an important role in regulating cell proliferation and gene expression in cervical cells, and that the presence of Rac1 in the nucleus of cervical epithelial cells from pre-malignant lesions may contribute to cancer progression. Further investigation is required to determine the possible association between the overexpression of Rho-GTPases and HR-HPV infection. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia.
2006 consensus guidelines for the management of women with abnormal cervical screening tests. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women.
Natural history of grade 1 cervical intraepithelial neoplasia in women with human immunodeficiency virus. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and HPV-related diseases. Age-Specific prevalence of anal human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: prevalence and risk factors. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men.
Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women.
Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. Detection of genetic changes in anal intraepithelial neoplasia (AIN) of HIV-positive and HIV-negative men. High rate of recurrence of cervical intraepithelial neoplasia after surgery in HIV-positive women. A population-based analysis of temporal trends in the incidence of squamous anal canal cancer in relation to the HIV epidemic.
The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy.
Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Infrared coagulator ablation of high-grade anal squamous intraepithelial lesions in HIV-negative males who have sex with males. High-resolution anoscopy targeted surgical destruction of anal high-grade squamous intraepithelial lesions: a ten-year experience. Invasive anal squamous-cell carcinoma in the HIV-positive patient: outcome in the era of highly active antiretroviral therapy.

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