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Natural History and Clinical Management of Anal Human Papillomavirus Disease in Men and Women Infected with Human Immunodeficiency Virus
Abstract
Before the introduction of highly active antiretroviral therapy (HAART), several studies demonstrated a high prevalence of
human papillomavirus (HPV) infection and associated anal intraepithelial neoplasia (AIN) in men who have sex with men, particularly
in human immunodeficiency virus (HIV)–infected men with low CD4+ cell counts. Similarly high levels of anal HPV infection and AIN have been found in HIV-positive women. HIV-positive men
and women are at an increased risk of developing anal cancer compared with the general population. Data suggest that there
has been no reduction in the incidence of AIN after the introduction of HAART. Screening efforts have the potential to decrease
the incidence of invasive anal cancer, and cost-effectiveness analyses have demonstrated the utility of anal cancer screening
in select populations. Treatment for AIN remains challenging, but AIN is easier to treat when the lesions are small, and it
is likely that a screening program would identify affected individuals at an earlier stage of disease.
... Patients with the HSIL on the initial screening anal cytology are more likely to have HSIL on HRA [4,5]. HIV positive patients with HSIL but subsequent HRA rendering no anal lesion, need follow-up in one year [4]. ...
... Patients with the HSIL on the initial screening anal cytology are more likely to have HSIL on HRA [4,5]. HIV positive patients with HSIL but subsequent HRA rendering no anal lesion, need follow-up in one year [4]. ...
... HRA examination was considered to be negative if there was no high-grade anal lesion identified. In HIV positive patients with HSIL on cytology but subsequent HRA rendering no anal lesion needs follow-up in one year [4]. However, a six-month follow-up HRA was performed at our institution. ...
Background: There is an increase in the rates of the Human Papilloma virus (HPV) related anal cancer in human immunodeficiency virus (HIV) positive individuals. The anal dysplasia screening is offered to the individuals at risk and anal cytology is one of the screening modalities. High resolution anoscopy (HRA) is performed for the further evaluation of the abnormal anal cytology. HRA plays a key role in the identification and management of high-grade squamous intraepithelial lesion (HSIL). Yield of HRA to detect HSIL in patients with HSIL on anal cytology can be affected with factors like difficult anal anatomy and use of microscope respectively. Acquiring HRA skills and using a microscope to increase the yield has a steep learning curve, and hence leaving most gastroenterologists untrained in this examination.
... HGAIN has been highlighted as a cause of anal canal cancer and plays a key role in its development. 6,7 Treatment Infrared coagulation (IRC) under HRA is common treatment for HGAIN, including intraepithelial carcinoma, in Europe and the United States. This method is more curative than cryotherapy or topical agents, less invasive than electrocautery, and can provide larger area ablation. ...
... Based on the protocol recommended by Chin-Hong and Palefsky, 6 APS was performed using a treatment algorithm. ...
... 12,13 The Committee on Immunization Practices (CIP) recommends that the vaccine should be administered routinely to females and males aged between 11 and 12; however, a study in this age group is limited. 14,15 This study aimed to determine the prevalence of HPV infected cases in developing various cancers in Libya in the past decade. Furthermore, knowledge of HPV vaccines in the community was explored, hoping to educate various ethnicities in Libya about different types of HPV infection in women and men, and awareness of vaccinations against HPV. ...
... In high-risk HPVs, viruses that have a high possibility to develop cancer, include genotype HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59; of which two genotypes are the most prevalent, which are genotype HPV 16 and 18, causing the majority of HPV-linked cancers. 14,15 There are vaccines for HPV available, which cover high-risk HPV genotype 16 and 18 (2-valent), and another one also covers lowrisk HPV genotype 6 and 11 (4-valent). Genital warts, predominantly caused by low-risk HPV genotype 6 and 11, are not carcinogenic. ...
Background: Human papillomavirus (HPV) plays a role in increasing the risk of cervical cancer and other cancers. This study aimed to explore the incidence of HPV infection among various ethnicities in Libya. Furthermore, awareness and knowledge of HPV vaccines in the community were explored.
Methods: A descriptive study was conducted to present HPV infection among cancer cases using the National Cancer Registry of Libya year 2011-2020, including gender, skin color, and ethnicity. Furthermore, awareness and knowledge of the HPV vaccines were assessed using questionnaires distributed through social media. Data were presented in percentage.
Results: In total, there were 33,526 (58.1%) infected HPV-related cancers out of 57,620 cancer cases, of whom 25,296 (75.4%) were women and 8,230 (24.6%) were men. Based on cancer sites, the incidence of HPV-related cancers among whites was higher (>63% and more) than blacks except for anal cancer, of which blacks had a slightly higher incidence (54%) in females and 57% in males). Based on ethnicity, native Libyans such as Tabu, Touareg, and Berbers had different cancer sites. Moreover, the knowledge and awareness about HPV and related cancers were very poor among the population in Libya.
Conclusions: Although HPV cancers represent a high percentage of cancer burdens among Libyans, awareness and knowledge on HPV and related cancer are lacking. Better education and provision of the HPV vaccines for future generations may eliminate and reduce HPV-related cancers.
... 1,2 Screening and surveillance intervals, however, are not well defined and are burdensome, with the most aggressive protocols surveying patients every 3 months. 3,4 Data are lacking on objective markers of increased risk of high-grade anal dysplasia and anal cancer that could help tailor screening and surveillance intervals for high-and low-risk individuals. 1 When patients are first infected with HIV, CD8 cells become more prevalent in the blood, and then there is a decline in CD4 T cells until therapy is started. ...
... Our institution follows expert opinion recommendations to screen HIV+ patients for anal dysplasia with annual anal Pap testing. [1][2][3][4] When examining baseline patient characteristics of those patients who were diagnosed with advanced disease (high-grade anal dysplasia or invasive anal cancer) versus those who were negative for disease, the cohorts were similar aside from their history of anal condyloma. Anal condyloma history remained a risk predictor for advanced disease on multivariate analysis as well. ...
Background:
People living with HIV are at risk for anal dysplasia/cancer. Screening/surveillance is costly and burdensome, and the frequency is not evidence based. Objective markers of increased risk of anal carcinogenesis are needed to tailor screening/surveillance. Low CD4/CD8 ratio is associated with increased overall cancer risk in people living with HIV but has yet to be examined for quantifying anal cancer risk.
Objective:
We hypothesized that low CD4/CD8 ratios correlate with increased risk for high-grade anal dysplasia and cancer.
Design:
This is a single-institution, retrospective review of people living with HIV from 2002 to 2018.
Setting:
This study was conducted at the University of Wisconsin School of Medicine and Public Health.
Patients:
Patients with advanced disease (high-grade anal dysplasia and/or anal cancer) were compared with patients with negative anal cytology.
Main outcome measures:
The independent variables were lowest (nadir) CD4/CD8 and CD4/CD8 nearest to screening/diagnosis. Logistic regression modeling was used to estimate the adjusted odds of advanced disease.
Results:
A total of 377 people living with HIV were examined: 266 with negative cytology and 111 with advanced disease (16 cancer, 95 high-grade anal dysplasia). Mean nadir ratio and mean nearest ratio were lower in patients with advanced disease than in those with negative screening (0.26 vs 0.47 (p < 0.001) and 0.61 vs 0.87 (p < 0.001)). In adjusted analyses, increase in nadir ratio or nearest ratio of 1 unit conferred decreased risk of advanced disease (OR, 0.10; 95% CI, 0.02-0.45; p = 0.002) and (OR, 0.31; 95% CI, 0.12-0.83; p = 0.02). The optimal threshold for using CD4/CD8 ratio as a risk factor for advanced disease was 0.47 for nadir ratio (sensitivity 0.59 and specificity 0.91) and 0.95 for nearest ratio (sensitivity 0.56 and specificity 0.92).
Limitations:
This is a retrospective, single-institution study.
Conclusions:
Low CD4/CD8 ratio confers additional risk of high-grade anal dysplasia and anal cancer beyond the diagnosis of HIV, even when adjusting for known risks factors of anal cancer. Our data suggest that the CD4/CD8 ratio may be able to help identify people living with HIV who are at higher risk of anal cancer development. See Video Abstract at http://links.lww.com/DCR/B336. LA RELACIÓN CD4 / CD8 COMO UN MARCADOR NOVEDOSO PARA EL AUMENTO DEL RIESGO DE DISPLASIA ANAL DE ALTO GRADO Y CÁNCER ANAL EN PACIENTES VIH+: UN ESTUDIO DE COHORTE RETROSPECTIVO: Las personas que viven con el virus de la inmunodeficiencia humana están en riesgo de displasia / cáncer anal. La detección / vigilancia es costosa, laboriosa y la frecuencia no se basa en evidencias. Se necesitan marcadores objetivos de mayor riesgo de carcinogénesis anal para adaptar la detección / vigilancia. La relación baja de CD4 / CD8 se asocia con un mayor riesgo general de cáncer en personas que viven con el virus de inmunodeficiencia humana, pero aún no se ha examinado para cuantificar el riesgo de cáncer anal.Hicimos la hipotesis de que la relación baja de CD4 / CD8 se correlacionan con un mayor riesgo de displasia anal de alto grado y cáncer.Revisión retrospectiva de una sola institución de personas que viven con el virus de la inmunodeficiencia humana desde 2002 hasta 2018.Facultad de Medicina y Salud Pública de la Universidad de Wisconsin.Los pacientes con enfermedad avanzada (displasia anal de alto grado y / o cáncer anal) se compararon con pacientes con citología anal negativa.Las variables independientes más bajas fueron (nadir) CD4 / CD8 y la relación CD4 / CD8 más cercanas a la detección / diagnóstico. Se utilizó el modelo de regresión logística para estimar las probabilidades ajustadas de enfermedad avanzada.Se examinaron un total de 377 personas que viven con el virus de inmunodeficiencia humana, 266 con citología negativa y 111 con enfermedad avanzada (16 cáncer, 95 displasia anal de alto grado). La tasa nadir y la tasa media más cercana fueron más bajas en pacientes con enfermedad avanzada vs. aquellos con cribado negativo (0.26 v. 0.47 (p <0.001) y 0.61 v. 0.87 (p <0.001), respectivamente. En los análisis ajustados, el aumento en la tasa nadir o la tasa más cercana a una unidad confirió una disminución del riesgo de enfermedad avanzada (OR de 0,10 (IC del 95%: 0,02, 0,45, p = 0,002)) y (OR 0,31 (IC del 95%: 0,12, 0,83, p = 0.02)), respectivamente. El umbral óptimo para usar la relacion CD4 / CD8 como factor de riesgo de enfermedad avanzada fue 0,47 para la tasa nadir (sensibilidad 0,59 y especificidad 0,91) y 0,95 para la tasa más cercana (sensibilidad 0,56 y especificidad 0,92).Este es un estudio retrospectivo de una sola institución.La baja relación CD4 / CD8 confiere un riesgo adicional de displasia anal de alto grado y cáncer anal más allá del diagnóstico del virus de inmunodeficiencia humana, incluso cuando se ajustan los factores de riesgo conocidos de cáncer anal. Nuestros datos sugieren que la relación CD4/CD8 puede ayudar a identificar a las personas que viven con el virus de inmunodeficiencia humana que tienen un mayor riesgo de desarrollar cáncer anal. Consulte Video Resumen en http://links.lww.com/DCR/B336.
... [2] Persistence of these high-risk infections is a critical step in the progression to invasive cancer. [3] Men living with HIV (MLHIV) have a high prevalence of HPV infection and are more likely to be infected with multiple high-risk types compared to HIV-negative men. [4] HIV coinfection increases the prevalence, persistence and progression to pre-neoplastic squamous intraepithelial lesions (SILs). ...
... [28,29] This high proportion is a cause for concern as persistent anal HPV infection is necessary for progression to anal SIL. [3] A third of participants in this cohort had persistent anal dysplasia, and a further quarter (27%) of MLHIV who had normal cytology at enrolment also developed dysplasia during follow-up. Despite this, there were no high-grade SIL cases at baseline or follow-up. ...
Background:
Men living with HIV (MLHIV) have a high burden of human papillomavirus (HPV)-related cancer. Understanding serological dynamics of HPV in men can guide decisions on introducing HPV vaccination and monitoring impact. We determined HPV seroprevalence and evaluated factors associated with HPV seroconversion among MLHIV in Johannesburg, South Africa.
Methods:
We enrolled 304 sexually active MLHIV ≥18 years and collected socio-behavioral data, blood samples (CD4+ counts, HIV-1 plasma viral load [PVL] and HPV serology), genital and anal swabs (HPV DNA and HPV Viral Load [VL]) at enrolment and 6-monthly for up to 18 months. Antibodies to 15 HPV types were measured using HPV pseudovirions. Generalised estimating equations were used to evaluate correlates of HPV seroconversion.
Results:
Median age at enrolment was 38 years (IQR:22-59), 25% reported >1 sexual partner in the past 3 months and 5% reported ever having sex with other men. Most participants (65%) were on antiretroviral therapy (ART), with median CD4+ count of 445 cells/µL (IQR:328-567). Seroprevalence for any-HPV type was 66% (199/303). Baseline seropositivity for any bivalent (16/18), quadrivalent (6/11/16/18) and nonavalent (6/11/16/18/31/33/45/52/58) vaccine-types were 19%, 37% and 60% respectively. At 18 months, type-specific seroconversion among 59 men whose genital samples were HPV-DNA positive but seronegative for the same type at enrolment was 22% (13/59). Type-specific seroconversion was higher among men with detectable HIV-PVL (adjusted odds-ratio [aOR]=2.78, 95%CI:1.12-6.77) and high HPV-VL (aOR=3.32, 95%CI:1.42-7.74).
Conclusion:
Seropositivity and exposure to nonavalent HPV types were high among MLHIV. HPV vaccination of boys before they become sexually active could reduce the burden of HPV infection among this at-risk population.
... [2] Persistence of these high-risk infections is a critical step in the progression to invasive cancer. [3] Men living with HIV (MLHIV) have a high prevalence of HPV infection and are more likely to be infected with multiple high-risk types compared to HIV-negative men. [4] HIV coinfection increases the prevalence, persistence and progression to pre-neoplastic squamous intraepithelial lesions (SILs). ...
... [28,29] This high proportion is a cause for concern as persistent anal HPV infection is necessary for progression to anal SIL. [3] A third of participants in this cohort had persistent anal dysplasia, and a further quarter (27%) of MLHIV who had normal cytology at enrolment also developed dysplasia during follow-up. Despite this, there were no high-grade SIL cases at baseline or follow-up. ...
Objective
To estimate the prevalence, incidence and persistence of anal HPV infection and squamous intra-epithelial lesions (SILs) among men living with HIV (MLHIV), and determine their risk factors.
Methods
We enrolled MLHIV ≥18 years, who attended 6-monthly visits for 18 months. Socio-behavioural data were collected by questionnaire. Clinicians collected blood sample (CD4+ count and HIV plasma viral load), anal swabs (HPV DNA testing) and anal smears (Bethesda classification) at each visit. HPV DNA testing and classification of smears were done at enrolment and last follow-up visit (two time points). Factors associated with persistent anal HPV infection and SILs were evaluated with generalized estimating equations logistic regression and standard logistic regression respectively.
Results
Mean age of 304 participants was 38 (Standard Deviation, 8) years; 25% reported >1 sexual partner in the past 3 months. Only 5% reported ever having sex with other men. Most (65%) participants were taking antiretroviral treatment (ART), with a median CD4+ count of 445 cells/μL (IQR, 328–567). Prevalence of any-HPV infection at enrolment was 39% (88/227). In total, 226 men had anal HPV DNA results at both enrolment and final visits. Persistence of any-anal HPV infection among 80 men who had infection at enrolment was 26% (21/80). Any persistent anal HPV infection was more frequent among MLHIV with low CD4+ count (<200 vs. >500 cells/μL; aOR = 6.58; 95%CI: 2.41–17.94). Prevalence of anal SILs at enrolment was 49% (118/242) while incidence of SILs among MLHIV who had no anal dysplasia at enrolment was 27% (34/124). Of the 118 men who had anal dysplasia at enrolment, 15% had regressed and 38% persisted by month 18. Persistent anal HPV infection was associated with persistent SILs (aOR = 2.95; 95%CI: 1.08–10.89). ART status or duration at enrolment were not associated with persistent anal HPV infection or persistent SILs during follow-up.
Conclusion
In spite of a high prevalence of anal HPV, HIV-positive heterosexual men have a low burden of anal HPV related disease. HPV vaccine and effective ART with immunological reconstitution could reduce this burden of infection.
... 3 Persistence of genital HPV infection is important for progression to disease. 4 HIV infection is associated with an increased risk of persistence and progression to disease. 5 6 People living with HIV (PLHIV) have a higher prevalence of genital HPV infection and are more likely to be infected with multiple HPV types compared to HIV negative individuals. ...
... 21 These data show that about a third of genital HPV infections persist after 12 months and thus could potentially progress to HPV-related diseases. 4 This also suggests that a significant proportion of men infected with HPV will harbour the virus and transmit it to their sexual partners. ...
Objective:
To estimate the incidence; persistence and correlates of HPV infection and anogenital warts (AGW) among men living with HIV (MLHIV).
Methods:
Overall, 304 MLHIV ≥18 years were enrolled and attended follow-up visits at 6, 12 and 18 months. Clinicians examined for AGW, collected blood, and penile swabs for HPV testing (Roche Linear Array) at each visit. Time to AGW incidence or clearance was estimated by Kaplan-Meier method. Factors associated with persistent HPV infection and AGW clearance were evaluated with generalized estimating equations and Cox regression respectively.
Results:
Mean age of participants was 38 (Standard Deviation, 8) years; 25% reported >1 sexual partner in the past 3 months. Most (65%) participants were on antiretroviral treatment (ART) with a median CD4+ count of 445 cells/μL (IQR, 328-567). Prevalence of HPV infection and AGW at enrolment were 79% (224/283) and 12% (36/304) respectively. 259 men were followed for a median (IQR) 1.4 years (0.5-1.7). Incidence of any-genital HPV infection was 2.9 (95% CI: 1.5-5.5) per 100 person-years. Persistence of any-genital HPV infection was 35% (68/192) and was higher among MLHIV with low CD4+ count (adjusted Odds Ratio=3.54; 95%CI: 2.07-6.05). Incidence of AGW was 1.4 per 100 person-years. MLHIV with high CD4+ count were more likely to clear AGW than those with low CD4 count (adjusted Hazard Ratio=3.69; 95%CI: 1.44-9.47). No associations were observed between persistent genital HPV infection, AGW clearance with enrolment ART status or duration.
Conclusion:
HIV-positive men have a high burden of genital HPV infection and AGW. ART and HPV vaccine could reduce this burden.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
... Furthermore, blood transfusions may be indicated in severe cases of anemia to rapidly restore hemoglobin levels and alleviate symptoms. [51][52][53][54][55][56][57][58][59][60] In addition to hematological interventions, strategies aimed at enhancing immune function and splenic clearance may help mitigate the adverse effects of HJBs in HIV patients. Immunomodulatory therapies, such as cytokine therapy or immune checkpoint inhibitors, may be explored to augment immune responses and reduce viral replication in affected individuals. ...
Howell-Jolly bodies (HJBs), typically associated with functional asplenia or splenic dysfunction, have gained recognition as potential indicators of hematological abnormalities in HIV patients. The morphological features of HJBs, characterized by small, round, basophilic inclusions within erythrocytes, signify underlying abnormalities in erythropoiesis and splenic function. While traditionally regarded as benign inclusions, the presence of HJBs in HIV patients reflects the complex interplay between viral pathogenesis, hematological abnormalities, and immune dysregulation. Beyond their prognostic significance, HJBs may contribute to clinical manifestations and complications in HIV patients, including anemia, fatigue, and decreased physical functioning. The presence of HJBs may exacerbate existing hematological abnormalities and impair QoL, highlighting the need for targeted therapeutic interventions to mitigate their impact. Optimizing QoL in HIV patients requires a multifaceted approach that addresses underlying hematological abnormalities, viral suppression, and immune reconstitution. Further research is warranted to elucidate the impact of HJBs on QoL outcomes and explore novel therapeutic strategies to mitigate their adverse effects, ultimately optimizing personalized approaches to care for individuals living with HIV.
... By integrating multiple diagnostic modalities and biomarkers, clinicians can improve diagnostic accuracy and tailor therapeutic interventions to address splenic dysfunction in HIV-infected individuals. [51][52][53][54][55][56][57][58][59][60] Therapeutic interventions for HIV-infected individuals with splenic dysfunction aim to mitigate the adverse effects of compromised splenic function and enhance overall clinical outcomes. This may include optimizing antiretroviral therapy (ART) to suppress viral replication, restore immune function, and mitigate hematological complications. ...
Howell-Jolly bodies (HJBs), observed as cytoplasmic remnants within erythrocytes, have emerged as potential indicators of splenic dysfunction in HIV-infected individuals. This review evaluates the diagnostic accuracy of HJBs in identifying HIV-associated splenic dysfunction, examining their morphological features, clinical significance, and implications for disease management. HJBs exhibit characteristic morphological features, including small, round, basophilic inclusions within erythrocytes, typically visualized on peripheral blood smears. While traditionally associated with functional asplenia or splenic dysfunction, the presence of HJBs in HIV patients suggests underlying abnormalities in erythropoiesis and compromised splenic function. Quantitative assessment of HJB abundance may offer valuable diagnostic insights, guiding risk stratification and prognostication for HIV-infected individuals with splenic dysfunction, thereby informing disease management strategies. Despite their potential as biomarkers of splenic dysfunction, the diagnostic accuracy of HJBs in identifying HIV-associated splenic dysfunction remains uncertain. While the presence of HJBs on peripheral blood smears is suggestive of splenic dysfunction, it lacks specificity to HIV and may be observed in other conditions.
... In cases of diagnostic uncertainty or progressive renal impairment, renal biopsy may be performed to confirm the diagnosis and guide therapeutic decision-making. [51][52][53][54][55][56][57][58][59][60] Therapeutic Interventions ...
Howell-Jolly bodies (HJBs) have garnered attention in the context of HIV infection due to their
potential association with kidney disease. The pathophysiology of HJBs in HIV-associated kidney
disease involves a complex interplay between viral replication, immune dysregulation, and renal
inflammation. HIV-associated nephropathy (HIVAN), characterized by collapsing focal segmental
glomerulosclerosis and tubular injury, represents one of the most severe renal manifestations of
HIV infection. The detection of HJBs holds diagnostic and prognostic implications for HIV- associated kidney disease, offering insights into disease severity, progression, and clinical outcomes. Higher levels of HJBs have been associated with more advanced stages of kidney disease and increased risk of progression to end-stage renal disease in HIV-infected individuals. Therefore, the presence of HJBs may serve as a valuable biomarker for renal dysfunction, guiding
risk stratification and therapeutic interventions in affected individuals.
... Prompt initiation of ART in pediatric patients with detectable HJBs can help mitigate disease progression, reduce viral burden, and improve overall clinical outcomes. [56][57][58][59][60] In addition to ART, adjunctive therapies targeting hematological abnormalities and immune dysfunction may be considered in pediatric HIV patients with detectable HJBs. These may include erythropoiesis-stimulating agents or iron supplementation for children with anemia or underlying nutritional deficiencies. ...
Howell-Jolly bodies (HJBs), once regarded as mere remnants of erythropoiesis, have emerged as
intriguing markers of hematological abnormalities in pediatric patients with HIV. This review
delves into the clinical considerations and management strategies associated with the presence of
HJBs in pediatric HIV, shedding light on their significance as indicators of disease progression
and guiding therapeutic interventions. The morphological features of HJBs, characterized by
small, round, basophilic inclusions within erythrocytes, signify underlying abnormalities in
erythropoiesis and splenic function. In the context of pediatric HIV, the presence of HJBs on
peripheral blood smears offers valuable diagnostic clues for assessing disease severity and
monitoring disease progression. Furthermore, numerous studies have reported a positive
correlation between the presence of HJBs and advanced HIV disease stages in pediatric patients,
highlighting their potential as prognostic markers for disease progression in this population. HIV- induced immunosuppression and chronic inflammation contribute to splenic dysfunction, impairing the spleen's ability to clear abnormal erythrocytes from circulation and leading to the accumulation of HJBs. Early recognition of HJBs allows clinicians to initiate timely interventions, including antiretroviral therapy (ART) and adjunctive therapies targeting hematological abnormalities and immune dysfunction, ultimately improving patient outcomes in pediatric HIV.
... By identifying individuals at higher risk of disease progression and adverse clinical outcomes, the presence of HJBs can inform clinical decision-making and guide therapeutic interventions aimed at improving patient outcomes and quality of life. Therefore, understanding the association between HJBs and disease progression in HIV-infected individuals is crucial for optimizing patient care and enhancing clinical outcomes in this population.[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] ...
Howell-Jolly bodies (HJBs) have emerged as intriguing morphological features in HIV-infected individuals, offering insights into bone marrow pathology and hematopoiesis. This review delves into the presence, significance, and implications of HJBs in HIV infection, synthesizing existing literature to elucidate their role as surrogate markers of bone marrow dysfunction and hematological abnormalities. By examining the association between HJBs and disease progression, as well as their utility in diagnosis and prognosis, this article aims to provide a comprehensive understanding of the clinical implications of HJBs in HIV-infected individuals. The presence of HJBs in peripheral blood smears serves as a morphological indicator of altered erythropoiesis and compromised splenic function in HIV-infected individuals. Beyond their traditional association with functional asplenia, the presence of HJBs suggests underlying abnormalities in bone marrow pathology and hematopoietic processes. Quantitative assessment of HJB abundance may offer valuable diagnostic insights, guiding risk stratification and prognostication for HIV-infected individuals with hematological abnormalities, thus facilitating targeted therapeutic interventions and improving clinical outcomes. Insights into bone marrow pathology provided by HJBs shed light on the dysregulation of erythropoiesis, impaired splenic function, and chronic inflammation in HIV-infected individuals. Their abundance correlates with disease progression, including increased viral loads, decreased CD4+ T-cell counts, and heightened susceptibility to opportunistic infections, underscoring their potential as prognostic markers.
... As morphological biomarkers of splenic dysfunction and altered erythropoiesis, HJBs provide clinicians with valuable diagnostic clues for identifying individuals at higher risk of developing HIV-related complications and guiding therapeutic interventions. 59 One of the primary clinical implications of detecting HJBs in HIV patients is their utility as prognostic markers for assessing disease severity and predicting clinical outcomes. The presence and abundance of HJBs have been correlated with advanced HIV disease stages, opportunistic infections, and mortality, highlighting their potential as indicators of disease progression and poor prognosis. ...
Howell-Jolly bodies (HJBs), cytoplasmic remnants of DNA in erythrocytes, have garnered attention as potential indicators of disease progression in HIV patients. This review explores the intricate relationship between the presence of HJBs and the progression of HIV, elucidating morphological features and underlying mechanisms linking their occurrence to disease severity. The morphological features of HJBs, observed as small, round, basophilic inclusions within erythrocytes, signify abnormalities in erythropoiesis and splenic function, providing valuable insights into HIV-related complications. Moreover, elevated viral loads and decreased CD4+ T-cell counts are often concomitant with an abundance of HJBs, suggesting their potential as prognostic markers and therapeutic targets. Mechanistically, dysregulated erythropoiesis, increased red cell turnover, and impaired splenic function in HIV-infected individuals contribute to the formation of HJBs, highlighting the intricate interplay between HIV pathogenesis and hematological abnormalities. Detection of HJBs in HIV patients holds clinical significance, offering a non-invasive means of assessing disease progression and identifying individuals at higher risk of developing complications. Integrating HJB assessment into routine hematological evaluations may facilitate early intervention and tailored therapeutic approaches, ultimately improving patient outcomes.
... Screening has been recommended for early detection of AIN and prevention of anal SCC. An anal Pap smear should be performed for patients identified to be at high-risk for AIN such as immunocompromised individuals or men having sex with men (MSM) [22][23][24]. If atypical cells are detected in the Pap smear, high-resolution anoscopy (HRA) with magnifying observation of the anal canal and tissue biopsy are recommended. ...
Anal squamous cell carcinoma (SCC) is rare, but it has been commonly detected as an invasive cancer. The standard treatment for anal SCC was surgical resection. However, recent medical advances have enabled the standard treatment to be chemoradiotherapy. Anal intraepithelial neoplasia (AIN) is a premalignant lesion of SCC. The screening test for AIN and human papilloma virus vaccine are important for the following high-risk patients: patients positive for human immunodeficiency virus and men who have sexual intercourse with men. Although cytology can be easily applied for a screening test, the false-negative rate for AIN is high. Instead, high-resolution anoscopy (HRA) has been gaining attention as a promising screening method for high-risk patients. Investigations comparing characteristic findings of HRA with the histology of AIN have demonstrated that HRA is a highly specific test for AIN.
Magnifying or image-enhanced endoscopies are also routinely used for colonoscopy, as they allow detailed observations at higher magnifications than those of HRA. Hence, these endoscopic modalities can be applied for assessing AIN. Ablation therapies or topical medications are available as the local treatment for AIN. Although endoscopic submucosal dissection is considered to be feasible to remove AIN, it has a technical difficulty to approach endoscopically invisible areas. Hence, this technique may be useful to resect AIN localized in the endoscopically visible areas, when the localization is confirmed via targeted biopsy.
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... The fact of the matter is that, recent development in the field of anal cancer screening research has highlighted the potential role for anal Pap testing in providing long-term risk stratification for anal precursors in HIV positive MSM [70] . The sensitivity of anal cytology may also be improved by targeted repeated testing every 12 months among MSM who are HIV-positive but do not yet have signs of anal squamous intraepithelial lesions, or every 2-3 years for HIV-negative MSM [34,[71][72][73]. ...
Background
Anal squamous intraepithelial lesions (ASIL), strongly related to human papilloma virus (HPV) infection, is more prevalent among men who have sex with men (MSM). However, no such data are available for Pakistan yet, and neither HPV vaccination nor anal-cytology screening is implemented in Pakistan. The purpose of this first ever study was to assess the prevalence of HPV-related anal cytological abnormalities among MSM and transgender women living with and without HIV infection in Pakistan.
Methods
We conducted a cross-sectional study from March 2016 to November 2017 at sexual health centers run by the Perwaaz Trust and the National AIDS Control Program in Karachi. The study enrolled MSM and transgender women aged greater-than-and-equal-to-18-years who reported anal sex in the preceding 6 months. We collected two anal samples for liquid-based cytology and HPV type testing by PCR, and socio-demographic and behavioral data were collected through face-to face interviews. ASIL and its associations with biological and behavioral risk factors were analyzed through Cox regression for prevalence ratios (PR) and corresponding 95% confidence intervals (CIs).
Results
Out of 271 qualifying participants, 79% were MSM and 21% transgender women. The mean age was 28.8 (± 8) years. Almost 35% (93/271) of the study population had ASIL detected, ASIL was significantly more common among participants living with HIV than in HIV negative ((50/118) 42.4%; vs. (43/153) 28.1%) (p ≤ 0.001). Among ASIL, 66% (61/93) had low-grade squamous intraepithelial lesions (LSIL), and 3.6% (3/93) had high-grade squamous intraepithelial lesions (HSIL). The overall, HPV16 positivity was 35.5% (33/93) among all abnormal anal lesions and all 3 HSIL were HPV16 positive, however, HPV16 positivity could show its association with ASIL detection in univariate model only (PRcrude: 2.11(1.39–3.18)). Moreover, any HR-HPV type (PR 3.04; 95% CI 1.75–5.26), concurrent sexually transmitted infection (STI) (2.13; (1.28–3.55)) and HIV + /HPV + coinfection (1.75; (1.07–2.88)) remained independently associated with ASIL in the multivariate model.
Conclusions
Abnormal anal cytology among MSM and transgender is prevalent enough to consider optimal screening regimens. Further studies are required to see if periodic anal cytology can be made part of HIV care and treatment programs among MSM in Pakistan.
... The difference between the proportion of interventions targeting female and male populations is enormous despite the gender-neutral vaccination policy active in the US [44]. Likewise, there is a huge difference between the proportion of interventions targeting heterosexual and minorities such as MSM (men that have sex with men) even though the latter populations are well known to be at a higher risk [45][46][47]. Our findings are aligned with previous studies, which also reported a few interventions addressing boys [16]. ...
Purpose
Theoretical frameworks are useful tools to explain the dynamics of behavioral change, develop, and implement intervention studies. The purpose of this systematic review and meta-analysis is to evaluate the application of theoretical frameworks and models to HPV vaccination intervention studies in the United States (US) from January 2006 to December 2019.
Methods
A comprehensive search across databases, including PubMed, EMBASE, ERIC, CINAHL, Academic Search Complete, Scopus, Web of Science, and PsycINFO, was conducted. Articles were included in the systematic analysis if at least one theory was used to develop the intervention phase. All intervention studies targeting populations in the US without restrictions of age, income, sex, and ethnicity were included. Articles were included in the meta-analysis if vaccine uptake and/or vaccine completion was addressed.
Results
The Health Belief Model, Motivational Interviewing, Theory of Planned Behavior, and Information–Motivation–Behavioral Skills were the most used theories. Based on theory integrity, theory rationale, and theory operationalization, most of the studies (60%) were rated high for the application of the theoretical frameworks. Our results suggest a preference for theoretical frameworks targeting individual change rather than community change and the existence of gender disparities in the application of theoretical frameworks. The association between theory and increase of likelihood in vaccine uptake and completion was not supported.
Conclusion
This review spotlights common issues in the application of theoretical frameworks in HPV vaccine interventions in the US. Our results suggest we are still in a developmental phase on several aspects of theory application to HPV vaccination.
... [3][4][5][6][7][8][9][10] While tremendous progress has been made in extending lifespan and reducing morbidity in persons living with HIV/AIDS, the phenomenon of HIV and HPV co-infection has led to increasing rates of anal intraepithelial neoplasia, 11 anal cancers, and rectal cancers in these groups. 10,[12][13][14][15][16][17] Despite advances in implementing highly active antiretroviral therapy (HAART) among persons living with HIV, reduction in incidences of these cancers has not been observed, and in fact have increased. [18][19][20] HPV-associated anal, rectal, and penile cancers carry a significant burden of morbidity in these populations. ...
Gay, bisexual, and other men who have sex with men (MSM) experience disproportionately high burdens of Human Papilloma Virus (HPV)-associated anal cancers. Recent focus has shifted to anorectal cancer prevention through high-resolution anoscopy (HRA); however, little is known about sexual minority men’s perceptions, attitudes, or beliefs regarding HRA. We conducted 4 qualitative Focus Group Discussions (FGDs) (n = 15) with sexual minority men, focusing on their beliefs, attitudes, and perceptions of undergoing HRA. Participants discussed their experiences of HPV/HRA as influenced by both their gender and sexuality, including unawareness of HPV disease as a male health issue, challenges relating to female-oriented HPV/HRA language, conception of HPV/HRA as related to prostate health, and connecting their sexual behavior identification as “bottoms” to their need for HRA. As efforts to improve HRA knowledge, access, and uptake among sexual and gender minority communities increase, special attention should be paid to language and messaging choices around HRA.
... The incidence of anal squamous cell carcinoma (ASCC) is elevated in HIV-infected patients, especially in men who have sex with men (MSM) and in women with cervical disease [1], being much higher than in the general population [2]. ASCC progresses rapidly in the absence of medical treatment, and some authors have proposed its early diagnosis by the cytological analysis of anal swabs as a cost-effective strategy [3]. ...
Anal squamous cell carcinoma is the most frequent virus-related non-AIDS-defining neoplasia among HIV-infected individuals, especially MSM. The objectives of this study were to analyze the effectiveness of the quadrivalent HPV (qHPV) vaccine to prevent anal ≥ high-grade squamous intraepithelial lesions (≥HSILs), external ano-genital lesions (EAGLs), and infection by qHPV vaccine genotypes in HIV+ MSM, and to study the immunogenicity of the vaccine and risk factors for ≥ HSILs. This study is nested within a randomized, double-blind, placebo-controlled trial of the qHPV vaccine, which enrolled participants between May 2012 and May 2014, with a 48-month follow-up. A vaccine or placebo was administered at 0, 2, and 6 months, and vaccine antibody titers were evaluated at 7, 12, 24, 36, and 48 months. Data were gathered at 12, 24, 36, and 48 months on sexual habits, CD4/CD8 cell/counts, HIV viral load, and the results of cytology (Thin Prep® Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc© colposcope). The study included 129 patients (mean age of 38.8 years, 40 [31%] with a history of AIDS, 119 [92.2%] receiving ART, and 4 [3.3%] with virological failure), 66 (51.2%) in vaccine arm and 63 (48.4%) in placebo arm. The vaccine and placebo groups did not differ in ≥ HSILs (14.1 vs. 13.1%, respectively, p = 0.98) or EAGL (11.1 vs. 6.8%, p = 0.4) rates during follow-up; however, a protective effect against HPV 6 was observed during the first year of follow-up in the vaccine versus placebo group (7.5% vs. 23.4%; p = 0.047). A between-arm difference (p = 0.0001) in antibodies against qHPV vaccine genotypes was observed at 7 months (76.9% in vaccine arm vs. 30.2% in placebo arm), 12 months (68.1% vs. 26.5%), 24 months (75% vs. 32.5%), 36 months (90% vs. 24.4%), and 48 months (87.2% vs. 30%). Finally, the factor associated with the risk of anal ≥ HSIL onset during the four-year follow-up was the receipt of the last dose of the vaccine less than 6 months earlier in comparison to those vaccinated for a longer period (82.4% vs. 17.6% (OR 0.869 [95% CI, 0.825–0.917]). Vaccine and placebo arms did not significantly differ in ≥ HSIL or EAGL rates or in protection against infection by HPV genotype vaccine except for HPV6 at 12 months after the first dose. A long-lasting immune response was observed in almost all the vaccinated men. The main protective factor against ≥ HSIL was to have completed the vaccination regimen more than 6 months earlier.
... The incidence of anal squamous cell carcinoma (ASCC) is elevated in HIV-infected patients, especially in men who have sex with men (MSM) and in women with cervical disease (1), being much higher than in the general population [2]. ASCC progresses rapidly in the absence of medical treatment, and its early detection is of vital importance [3]. ...
Background: Anal squamous cell carcinoma is the most frequent virus-related non-AIDS-defining neoplasia among HIV-infected individuals, especially MSM. The objectives of this study were: to analyze the effectiveness of the quadrivalent HPV (qHPV) vaccine to prevent anal ≥ high-grade squamous intraepithelial lesions (≥HSILs), external ano-genital lesions (EAGLs), and infection by qHPV vaccine genotypes in HIV+ MSM; and to study the immunogenicity of the vaccine and risk factors for ≥HSILs
Methods: This study is nested within a randomized, double-blind, placebo-controlled trial of the qHPV vaccine, which enrolled participants between May 2012 and May 2014, with a 48-month follow-up. Vaccine or placebo was administered at 0, 2, and 6 months, and vaccine antibody titers were evaluated at 7, 12, 24, 36, and 48 months. Data were gathered at 12, 24, 36, and 48 months on sexual habits, CD4/CD8 cell/counts, HIV viral load, and the results of cytology (Thin Prep® Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc© colposcope).
Results: The study included 129 patients, 66 (51.2%) in vaccine arm and 63 (48.4%) in placebo arm. The vaccine and placebo groups did not differ in ≥ HSILs (14.1 vs. 13.1%, respectively, p=0.98) or EAGL (14.3 vs. 13.6%, p=0.98) rates during follow-up; however, a protective effect against HPV 6 was observed during the first year of follow-up in the vaccine versus placebo group (7.5% vs. 23.4%; p=0.047). A between-arm difference (p=0.0001) in antibody formation was observed at 7 months (76.9% in vaccine arm vs. 30.2% in placebo arm), 12 months (68.1% vs. 26.5%), 24 months (75% vs. 32.5%), 36 months (90% vs. 24.4%), and 48 months (87.2% vs. 30%). Finally, receipt of the full vaccine 6 months earlier was a risk factor for ≥ HSIL (82.4% vs. 17.6%, OR 0.869 [95% CI 0.825-0.917]).
Conclusions: Vaccine and placebo arms did not significantly differ in ≥HSIL or EAGL rates or in protection against infection by HPV genotype vaccine except for HPV6 at 12 months after the first dose. A long-lasting immune response was observed in almost all of the vaccinated men. The main protective factor against ≥ HSIL was to have completed the vaccination regimen more than 6 months earlier.
Clinical trial registration: ISRCTN14732216 (http://www.isrctn.com/ISRCTN14732216)
... 6 When compared with at-risk groups, such as men living with human immunodeficiency virus (HIV) and men who have sex with men (MSM), this incidence is disproportionately higher. 7,8 Studies from Europe and the United States demonstrated an increased incidence of anal cancer, with rates ranging from 75 to 137:100,000 people/year for MSM living with HIV/AIDS after the introduction of antiretroviral therapy (ART). 8,9 Historically, anal cancer was believed to develop as a result of chronic irritation of benign conditions such as hemorrhoids, fissures, and inflammatory bowel disease. ...
Study objectives
To perform anal lesion and anal cancer screening in men living with HIV/AIDS.
Methods
This is a descriptive, observational, cross-sectional study. Data were obtained from the Specialized Assistance Service (SAE) in Divinópolis, Minas Gerais. A sociodemographic, epidemiological, and sexual behavior questionnaire was applied; material was collected for cytology, high-resolution anoscopy (AAR) was performed, and an acceptability questionnaire applied.
Main results
Of the 50 men living with HIV/AIDS invited to participate in this study, 6% were excluded because they were illiterate, 40% refused to participate, and 54% participated in the survey. Among these, all answered the self-administered questionnaire. However, ten (37.0%) underwent proctological examination and anal cytology. Of these, two did not respond to the acceptability questionnaire. No anal lesions were identified during AAR and no biopsy was required. A 10% change in anal cytology was found.
Conclusions
Through the study it was possible to construct a flow of referrals from the SAE to the UFSJ Coloproctology outpatient clinic. Moreover, the existence of internal stigmas on the part of the participants regarding the proctological examination and the lack of information about anal cancer screening are challenges to be overcome.
... 2,8 Women and men living with HIV are disproportionately affected by HPV infection and associated diseases. 49,50 In their vaccination recommendations, the Centers for Disease Control and Prevention (CDC) have proposed the introduction of the HPV vaccine for people living with HIV, irrespective of the CD4 lymphocyte count. 51 In Mexico, the National Center for the Prevention and Control of HIV and AIDS (Censida, by its acronym in Spanish) is studying the possibility of universal introduction of vaccination against HPV in people living with HIV. ...
Materials and methods. A total of 1 329 men and women, with and without HIV, participated in one of three intervention studies, offering HPV vaccination, carried out in the states of Morelos, Tlaxcala and Mexico City; either the bivalent (Morelos n=103, Tlaxcala n=127) or quadrivalent HPV-vaccine (Mexico City n=1 099) was offered. Results. HPV vaccine was accepted by 80.3% of participants; ac- ceptance was higher in people living with HIV than those without (84.4 vs. 78%, p=0.004). Women had greater HPV infection knowledge (p<0.0001) than men and slightly higher (p=0.4) vaccine acceptance. The main reason for vaccine non-acceptance among HIV-positive participants was their doctor recommended they not get vaccinated. Conclusion. Acceptance of HPV-vaccine was high in men and women regardless of HIV status. Even higher rates of acceptability may be achieved by educating healthcare providers to recommend HPV vaccine to their patients.
Material y métodos. 1 329 hombres y mujeres con y sin VIH participaron en tres estudios de intervención, realizados en los estados de Morelos,Tlaxcala y Ciudad de México. Se ofreció la vacuna bivalente (Morelos n=103,Tlaxcala n=127) o la cuadrivalente (Ciudad de México n=1 099) contra VPH. Resultados. La vacuna fue aceptada por 80.3% de los participantes; la aceptación fue mayor en personas que viven con VIH que en aquéllas que no (84.4 vs. 78%, p=0.004). Las mujeres (p<0.0001) tenían mayor conocimientos sobreVPH que los hombres y una aceptación de la vacuna ligeramente mayor (p=0.4). El motivo principal de la no aceptación de la vacuna entre personas con VIH fue que su médico reco- mendó que no se vacunaran. Conclusión. La aceptación de la vacuna contra el VPH fue alta en hombres y mujeres, independientemente del estado de VIH. Se pueden lograr mayores tasas de aceptabilidad educando a los proveedores de atención médica para que recomienden la vacuna contra el VPH a sus pacientes.
... Most anal cancers are caused by high-risk human papillomavirus (HR-HPV), with a majority attributed to HPV16 [4]. Like cervical cancer, anal cancer is thought to develop through squamous epithelial precursor lesions that can be detected by exfoliative cellular sampling and diagnosed by high-resolution anoscopy (HRA) with directed biopsy [5]. Although there are no formal guidelines for anal cancer screening, some clinics use anal cytology for screening HIV+ MSM [6]. ...
Background:
Human papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal precancer detection in HIV-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 mRNA, and p16/Ki-67 dual stain in a population of HIV+ MSM.
Methods:
We enrolled 363 HIV+ MSM between 2009-2010 with passive follow-up through 2015. All had anal cytology and high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models.
Results:
One hundred twenty-nine men were diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity, but the lowest specificity of all assays. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. Two- and 5-year risks of HSIL/AIN2+ were highest for testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by dual stain-positive. Testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+.
Conclusions:
HPV-related biomarkers provide long-term risk stratification for anal precancers. HR-HPV- and dual stain-negativity indicate low risk of HSIL/AIN2+ for at least 2 years compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.
... Так, у ВИЧ-негативных ГМ заболеваемость ПРАК оценивается как 5,1 на 100 тыс., а у ВИЧ-позитивных ГМ -повышается до 49,5-100 на 100 тыс. контингента и может объективно рассматриваться как одна из важнейших проблем здоровья в данной популяции [22,23]. ...
The history of association between HPV and cancer, risk factors, pathogenesis, diagnostics, treatment and prophylaxis of anal intraelithelial neoplasia (AIN) and squamous-cell anal cancer are discussed in this article. Although these conditions are rare, they may become some of the main health hazards in certain groups of patients, such as HIV-infected patients, patients with history of other HPV-related malignancies, patients practicing anal sexual intercourse and patients receiving systemic immunosuppressive therapy. A collaboration of different specialists is necessary in order to develop effective prophylactic measures for HPV-associated malignancies of anal region. There are no estabilished methods for AIN treatment. The use of ointments and local destruction are the most researched treatment methods. Vaccination is already developed as a prophylactic measure. However, a more thorogh research of HPV types in russian population is necessary prior to its wide implementation. Preliminary data favors the use of polivalent vaccines in russian population.
BACKGROUND
People living with HIV (PLWH) have substantially increased incidence of anal precancer and cancer. There are very little data regarding genomic disturbances in anal precancers among PLWH. Here, we identified specific chromosomal variants in anal squamous intraepithelial lesions.
METHODS
We collected 63 anal biopsy specimens (27 low-grade intraepithelial lesions [LSIL] and 36 high-grade intraepithelial lesions [HSIL]) from PLWH obtained as part of anal cancer screening in our NYC-based health system. Data on patient demographics, anal cytological and high-risk human papillomavirus (HR-HPV) diagnoses were collected. Specimens were tested for a panel of chromosomal alterations associated with HPV-induced oncogenesis using Fluorescence In-Situ Hybridization (FISH) and analyses compared the associations of these alterations with clinical characteristics.
RESULTS
Gains of 3q26, 5p15, 20q13 and cen7 were detected in 42%, 31%, 31%, and 19% of HSIL compared to 7%, 0%, 4%, and 0% of LSIL, respectively. Where at least one abnormality was seen, 89% had a 3q26 gain. In lesions with 5p15 gains, 20q13 gains co-occurred in 91% of cases, while cen7 gain only co-occurred with the other three alterations. Sensitivity and specificity of any alteration to predict HSIL was 47% (95% CI: 30-65%) and 93% (95% CI: 76%-99%) respectively.
CONCLUSIONS
Genomic alterations seen in HPV-associated cancers may help distinguish anal LSIL from HSIL. 3q26 amplification may be an early component of anal carcinogenesis, preceding 5p16, 20q13 and/or chr7.
IMPACT
We share insights on potential genomic biomarkers for discriminating high-risk anal precancers.
Background
Due to the heterogeneity of risk for invasive anal cancer (IAC) among people with human immunodeficiency virus (PWH), we investigated predictors of IAC and described outcomes among those with a cancer diagnosis.
Methods
Using a longitudinal inception cohort of anal cancer screening, we evaluated risk factors and outcome probabilities for incident IAC in Cox models. Screening included anal cytology and digital anorectal examination, and, if results of either were abnormal, high-resolution anoscopy.
Results
Between 30 November 2006 and 3 March 2021, a total of 8139 PWH received care at the University of California, San Diego, with 4105 individuals undergoing screening and subsequently followed up over a median of 5.5 years. Anal cancer developed in 33 of them. IAC was more likely to develop in patients with anal high-grade squamous intraepithelial lesions (aHSILs) on initial or subsequent follow-up cytology (hazard ratio, 4.54) and a nadir CD4 cell count ≤200/µL (2.99). The joint effect of aHSILs and nadir CD4 cell count ≤200/µL amplified the hazard of IAC by 9-fold compared with the absence of both. PWH with time-updated cytology aHSIL and CD4 cell counts ≤200/µL had 5- and 10-year probabilities of IAC of 3.40% and 4.27%, respectively. Twelve individuals with cancer died, 7 (21% of the total 33) due to cancer progression, and they had clinical stage IIIA or higher cancer at initial diagnosis.
Conclusions
PWH with both aHSIL and a nadir CD4 cell count ≤200/µL have the highest risk of IAC. PWH who died due to IAC progression had clinical stage IIIA cancer or higher at diagnosis, highlighting the importance of early diagnosis through high-resolution anoscopic screening.
Background:
Anal canal squamous cell carcinoma (SCC) is a relatively uncommon neoplasia, and it is mostly a local-regional cancer, of low metastatic potential (only 15%), resulting in cure in most cases treated with definitive chemoradiation. On the other hand, its incidence has been steadily increasing over the last decades, which makes it an important public health problem. In an effort to provide surgeons and oncologists who treat patients with anal cancer with the most updated information based on the best scientific evidence, the Brazilian Society of Surgical Oncology (SBCO) has produced the present guideline for the management of anal canal SCC, focused on the main topics related to daily clinical practice.
Objectives:
The SBCO developed the present guidelines to provide recommendations on the main topics related to the management of anal canal squamous cell carcinoma (SCC) based on current scientific evidence.
Methods:
Between October 2022 and January 2023, 14 experts met to develop the guidelines for the management of anal canal cancer. A total of 30 relevant topics were distributed among the participants. The methodological quality of a final list with 121 sources was evaluated, all the evidence was examined and revised, and the management guidelines were formulated by the 14-expert committee. To reach a final consensus, all the topics were reviewed in a meeting that was attended by all the experts.
Results:
The proposed guidelines contained 30 topics considered to be highly relevant in the management of anal canal cancer, covering subjects related to screening recommendations, preventive measures, tests required for diagnosing and staging, treatment strategies, response assessment after chemoradiotherapy, surgical technique-related aspects, and follow-up recommendations. In addition, screening and response assessment algorithms, and a checklist were proposed to summarize the important information and offer an updated tool to assist surgeons and oncologists who treat anal canal cancer and in providing the best care to their patients.
Conclusion:
These guidelines summarize recommendations based on the most current scientific evidence on relevant aspects of anal canal cancer management and are a practical guide to help surgeons and oncologists who treat anal canal cancer make the best therapeutic decisions.
Background and aim:
Anal intraepithelial neoplasia (AIN) is the precursor of anal squamous carcinoma, frequently underappreciated by most gastroenterologists. Purpose of the study is to assess the diagnostic accuracy of narrow-band imaging (NBI) in predicting the histology of anal lesions, considering a new NBI classification.
Methods:
This is a retrospective analysis of consecutive patients with suspected anal squamous intraepithelial lesions (SILs) and superficially invasive squamous cell carcinoma (SISCCA) who underwent anorectal-sigmoidoscopy. Three expert endoscopists reviewed all the images collected during colonoscopies in white light and NBI in order to generate a practical classification of three main different NBI patterns.
Results:
After the modified Delphi process, the final NBI classification, mainly based on intrapapillary capillary loops (IPCL) changes included three different NBI pattern. NBI pattern I: elongation of IPCL toward epithelial surface; NBI pattern 2: thickened and tortuous IPCL; NBI pattern 3: mosaic-like disposition of IPCL. We found that NBI pattern positively correlated to the histologic type of the lesions and tumor grade (Spearman's rho = 0.9671, P = 0.0000). Among 58 anal lesions included, 41/41 (100%) LSILs have been classified as NBI pattern I, 10/11 (90.91%) HSILs as NBI pattern II, 1/11 HSIL as NBI pattern I, 4/4 SISCCA as NBI pattern III and 2/2 invasive cancer as NBI pattern III. Diagnostic accuracy of NBI pattern II or III in predicting histology differentiating HSIL or SISCCA/IC versus LSIL showed a sensitivity of 100%, (95% CI: 92.3-100%) and a specificity of 94.1% (95% CI: 83.8-98.3%).
Conclusion:
The accuracy of this new NBI score system in predicting the histology of anal lesions showed encouraging data in term of sensitivity and specificity in differentiating HSIL or SISCCA/IC versus LSIL, but the clinical usefulness and application of these findings should be evaluated in a prospective larger study.
Objective:
This study aimed to evaluate factors associated with anal high-grade intraepithelial lesions (HSIL) and anal carcinoma among young men who have sex with men (MSM) and transgender women (TW) with HIV in Atlanta, GA, to better inform screening guidelines and preventative measures.
Materials and methods:
Cross-sectional retrospective chart review was completed for cisgender MSM and TW with HIV aged 13-25 years at the Grady Ponce and Family Youth Clinic in Atlanta, GA, from 2009 to 2020. High-grade anal disease was defined as anal intraepithelial neoplasia (AIN) 2, 3, or anal carcinoma (AIN 2+). Associations between clinical and demographic factors with AIN 2+ were estimated using logistic regression. Adjusted odds ratios (aORs) and associated 90% CIs are reported.
Results:
One hundred nine MSM and TW with HIV who underwent anoscopy were included. One hundred three participants received anal biopsies, and 62% had AIN 2+. Being incompletely or unvaccinated against human papillomavirus (HPV, 0-2 doses) relative to being fully vaccinated (3 doses; aOR = 5.85; 90% CI = 1.28-26.83; p = .06) and having ever received surgical treatment for anogenital HPV (aOR = 2.89; 90% CI = 1.10-7.65; p = .07) were associated with AIN 2+, controlling for age and CD4 T-cell count at time of biopsy.
Conclusions:
Our study found a high prevalence of anal HSIL among young MSM and TW with HIV. Those who had ever received surgical treatment for anogenital HPV and those who were incompletely or unvaccinated against HPV were more likely to have HSIL. Our data emphasize the urgent need to improve HPV vaccination efforts and to pursue larger surveillance studies of anal HSIL and carcinoma among young MSM and TW with HIV.
Globally, human papillomavirus (HPV) and human immunodeficiency virus (HIV) are the most common sexually transmitted diseases (STDs). World Health Organization (WHO) says there are around 17.4 million women living with HIV and over 291 million HPV-infected women worldwide. The co-existence of HPV with HIV is very common which is due to frequent suppression of immune activation and increased inflammation during these viral infections. The present chapter discusses the role of several types of immune cells, such as natural killer cells (NKCs), macrophages, dendritic cells (DCs), CD4⁺/CD8⁺ T cells, regulatory T cells (Treg), and cytokines in HPV and HIV infections. The understanding of immune modulation can be helpful in developing and stimulating cell immune response against the pathogens.
Multiple variants of oncogenic human papilloma viruses (HPVs) are the one of the main causes of genital cancers, most specifically cervical cancer, oral cancer, vaginal cancer along with the increasing incidences of head and neck cancers. In spite of the accessibility of numerous prophylactic vaccines against the most prevalent subtypes of oncogenic HPV, HPV-induced carcinomas are still a major public health and economic burden. However, standard therapeutical regimen involving surgery, chemotherapy radiation, and immunotherapy is coming out as an effectual adjuvant option. Here, in this book chapter, we have reviewed available literature on current immunotherapeutic interventions against HPV-associated malignancies as well as various ongoing clinical studies using immune checkpoint inhibitors, therapeutic vaccines, cell-based therapies, and novel immunotherapies which are demonstrating beneficial outcomes and could lead to substantial amelioration in the therapeutic and management of HPV-associated carcinomas.
Objectives
Human papillomavirus (HPV) is the most common STI and is associated with a wide range of diseases from anogenital warts to malignancies. Anal HPV infection is considerably more common in men who have sex with men (MSM) living with HIV. Aims of the present study are to (i) describe the prevalence of anal HPV infection in MSM who started pre-exposure prophylaxis (PrEP) and (ii) analyse factors associated with anal infection from genotypes that would be covered by nonavalent vaccination.
Methods
This monocentric, cross-sectional study included all subjects who started PrEP from May 2018 to November 2021. PrEP candidates underwent full behavioural and clinical evaluation, including digital anal rectal examination and swabbing for HPV determination. Descriptive statistics, Mann-Whitney U test for continuous and χ ² tests for categorical variables were adopted. Unadjusted and adjusted regression analyses were performed to assess factors associated with positive anal swabs and to the presence of genotypes covered by the nonavalent vaccination.
Results
The analysis included 288 subjects: anal swabs tested positive in 87.2% of cases, 79.2% of the subjects had a high-risk genotype (mainly 16), whereas 67.4% had a genotype covered by nonavalent vaccine. Sexual role was the only factor associated with anal HPV infection. Use of recreational drugs and a diagnosis of ≥2 STIs correlated with the presence of genotypes that would have been covered by vaccine, while previous vaccination had a protective role.
Conclusions
PrEP candidates showed a high prevalence of anal HPV infection, especially due to high-risk genotypes, comparable to what has been reported in MSM living with HIV.
Background
Anal cancer (AC) screening is justified in high-risk populations, particularly HIV-positive men having sex with men (MSM). HR-HPV testing could improve the efficiency of cytologically based screening of AC, as in the screening of biologically analogical cervical cancer. The specificity of HR-HPV testing is influenced by the prevalence of HR-HPV infection in the screened population. Reported anal HR-HPV DNA prevalence in MSM is high, but HR-HPV mRNA reflects rather long-term infections and is more specific for high-grade lesions. However, no data were published about HR-HPV DNA and mRNA prevalence in the Czech AC screening population.
Method
Results of liquid-based anal cytology of 203 predominantly HIV-positive MSM from the Czech AC screening cohort were correlated with results of DNA and E6/E7 mRNA testing of 14 HR-HPV types, and HPV16 genotyping. Eighty-one MSM underwent a standard anoscopy.
Results
A total of 109 (53.7%) samples had abnormal cytology, with 12 (5.9%) ASC-H/HSIL, 67 (33.0%) samples cytologically negative, and 27 (13.3%) unsatisfactory. HR-HPV DNA was detected in 134 (66.0%) and HR-HPV RNA in 72 (35.5%) anal smears. HR-HPV mRNA and HPV16 mRNA positivity were associated with abnormal cytology (p = .0037, p = .0021). No significant association was found between HR-HPV DNA or HPV16 DNA positivity and abnormal cytology. No high-grade lesions were revealed by anoscopy.
Conclusion
Prevalence of anal HR-HPV DNA among Czech MSM is high, however, the prevalence of HR-HPV mRNA is half and associated with abnormal cytology. Our results indicate an increased efficiency of cytological screening when combined with HR-HPV mRNA testing.
Background:
Ablative treatment of anal high-grade squamous intraepithelial lesions (HSIL) reduces the risk of progression to anal squamous cell carcinoma.
Objectives:
To identify factors that influence the response to treatment of anal HSIL by electrocautery ablation (ECA) in a population of HIV-positive men who have sex with men (MSM).
Design:
Retrospective study of ECA treatment response in a prospectively followed anal dysplasia cohort. HIV-positive MSM diagnosed with anal HSIL were included. Demographic and HIV data were recorded. Response to treatment was assessed by biopsy after at least 18 months of follow-up.
Results:
One hundred and twenty-eight HSILs in 91 men were included in this study. The overall response rate at 18 months was 70.3%. The number of electrocautery sessions required (2 ECA sessions vs 1: adjusted odds ratio [aOR] = 0.36 (95%CI 0.13-1.01); >=3 sessions vs 1: aOR = 0.10 (95%CI 0.04-0.29); p < 0.001]) and the history of previous HPV-related anal pathology (previous anal lesions vs no previous lesions AOR = 2.83 (95%CI 1.14-7.02), p = 0.024) were independently associated with response at 18 months. No serious adverse events were reported.
Conclusions:
Consideration should be given to alternative therapies in patients with unresolved HSIL after 1 ECA treatment.
Background:
The Department of Veterans Affairs cares for the largest population of patients with HIV of any healthcare system in the United States. Screening for anal dysplasia/cancer is recommended for all veterans with HIV. Exams are invasive, burdensome, and resource intensive. We currently lack markers of disease to tailor screening.
Objective:
The purpose of this study was to establish the prevalence of advanced anal disease (high-grade dysplasia and anal cancer) and to determine whether CD4/CD8 ratio correlates with risk.
Design:
This was a retrospective regional cohort study of veterans with HIV.
Settings:
The study was conducted at eight medical centers between 2001 and 2019.
Patients:
Patients with advanced disease were compared with patients with nonadvanced anal pathology.
Main outcome measures:
Logistic regression modeling was used to estimate adjusted odds of disease as a function of CD4/CD8. Lowest (nadir) CD4/CD8 and nearest CD4/CD8 ratio in each cohort were evaluated.
Results:
A total of 2267 veterans were included. Fifteen percent had anal pathology (112 with advanced disease (37 cancer and 75 high-grade), 222 with nonadvanced disease). Nadir and nearest ratio were lower in patients with advanced disease versus nonadvanced (0.24 vs 0.45 (p < 0.001) and 0.50 vs 0.88 (p < 0.001)). In adjusted models, a 1-unit increase in nadir or nearest ratio conferred decreased risk of advanced disease (OR = 0.19 (95% CI, 0.07-0.53); p < 0.001; OR = 0.22 (95% CI, 0.12-0.43); p < 0.001). Using a minimum sensitivity analysis, a cutoff nadir ratio of 0.42 or nearest ratio of 0.76 could be used to risk stratify.
Limitations:
This was a retrospective analysis with a low screening rate.
Conclusions:
In a regional cohort of veterans with HIV, 15% were formally assessed for anal dysplasia. Advanced anal disease was present in 33% of those screened, 5% of the HIV-positive population. A strong predictor of advanced disease in this cohort is the CD4/CD8 ratio, which is a promising marker to stratify screening practices. Risk stratification using CD4/CD8 has the potential to decrease burdensome invasive examinations for low-risk patients and to intensify examinations for those at high risk. See Video Abstract at http://links.lww.com/DCR/B528.
Prevalencia de displasia anal de alto grado y cncer anal en veteranos que viven con el vih y la relacin cd / cd como marcador de mayor riesgo un estudio de cohorte regional retrospective:
ANTECEDENTES:El Departamento de Asuntos de Veteranos atiende a la población más grande de pacientes con el virus de inmunodeficiencia humana (VIH) de cualquier sistema de salud en los Estados Unidos. Se recomienda la detección de displasia / cáncer anal para todos los veteranos con VIH. Los exámenes son invasivos, onerosos y requieren muchos recursos. Actualmente carecemos de marcadores de enfermedad para adaptar la detección.OBJETIVO:Establecer la prevalencia de enfermedad anal avanzada (displasia de alto grado y cáncer anal) y determinar si la relación CD4 / CD8 se correlaciona con el riesgo.DISEÑO:Estudio de cohorte regional retrospectivo de veteranos con VIH.AJUSTE:Ocho centros médicos entre 2001-2019.PACIENTES:Se comparó a pacientes con enfermedad avanzada con pacientes con patología anal no avanzada.PRINCIPALES MEDIDAS DE RESULTADO:Se utilizó un modelo de regresión logística para estimar las probabilidades ajustadas de enfermedad en función de CD4 / CD8. Se evaluó la relación CD4 / CD8 más baja (nadir) y la relación CD4 / CD8 más cercana en cada cohorte.RESULTADOS:Se incluyeron un total de 2267 veteranos. El 15% tenía patología anal (112 enfermedad avanzada (37 cáncer, 75 de alto grado), 222 enfermedad no avanzada). El nadir y el cociente más cercano fueron menores en los pacientes con enfermedad avanzada frente a los no avanzados (0,24 frente a 0,45 (p <0,001) y 0,50 frente a 0,88 (p <0,001)), respectivamente. En modelos ajustados, el aumento de una unidad en el nadir o el cociente más cercano confirió una disminución del riesgo de enfermedad avanzada (OR 0,19 (IC del 95%: 0,07, 0,53, p <0,001)) y (OR 0,22 (IC del 95%: 0,12, 0,43, p <0,001))), respectivamente. Utilizando un análisis de sensibilidad mínima, se podría utilizar un cociente del nadir de corte de 0,42 o el cociente más cercano de 0,76 para estratificar el riesgo.LIMITACIONES:Análisis retrospectivo con una tasa de detección baja.CONCLUSIONES:En una cohorte regional de veteranos con VIH, el 15% fueron evaluados formalmente por displasia anal. La enfermedad anal avanzada estuvo presente en el 33% de los examinados, el 5% de la población VIH +. Un fuerte predictor de enfermedad avanzada en esta cohorte es la relación CD4 / CD8, que es un marcador prometedor para estratificar las prácticas de detección. La estratificación del riesgo usando CD4 / CD8 tiene el potencial de disminuir los exámenes invasivos onerosos para los pacientes de bajo riesgo e intensificar los exámenes para los de alto riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B528.
Aim:
to evaluate the presence of subclinical HPV-induced anal lesions with anal cytology, High-Resolution Anoscopy (HRA) and HPV genotyping by polymerase chain reaction (PCR) in the follow-up of treated condylomata acuminata (CA).
Methods:
seventy-nine male patients were included. One month after anal CA eradication, the patients underwent brush samples collection for anal cytology and PCR, and HRA with biopsy of acetowhite lesions. These methods were compared within all patients and between groups, according to Human Immunodeficiency Virus (HIV) infection status: HIV-negative; HIV-positive with TCD4 count above and below 350 cells/mm3.
Results:
the most frequent HPV types were 6 and 16. HPV DNA was isolated in 92%. HIV infection was associated with a higher number of oncogenic HPV types (p=0.038). All patients with negative PCR had negative HRA and cytology. There were no differences in cytological, HRA or histopathological findings between groups.
Conclusion:
the association of the findings of cytopathology, HRA and genotyping of HPV refined the diagnosis of HPV-induced lesions. The degree of immunodeficiency was not associated with increase in remnant HPV-induced anal lesions.
Human papillomavirus (HPV) is a double stranded DNA (dsDNA) virus that often causes an asymptomatic infection and clears spontaneously. However, HPV infection may result in genital warts, dysplasia, and squamous cell carcinoma of the head, neck and genitalia. Genital HPV is the most common sexually transmitted infection (STI) in the United States. HPV infection may lead to significant morbidity for both immunocompetent and immunocompromised persons. Immunocompromised persons, including those with human immunodeficiency virus (HIV) infection, are more likely to develop persistent HPV infection and its associated complications. All adolescents and young adults should get the HPV vaccine, ideally prior to initiation of sexual intercourse, in order to prevent infection and the subsequent potential for progression to malignancy.
The field of dermatology and syphilology has relied on diagnostic laboratory and pathology tools to aid in the clinician in care of the patient for the better part of two centuries. The purpose of the diagnostics in dermatology column is to highlight commonly encountered diagnostic tools in dermatology and review the indications for use and result interpretation. This article discusses the anal Pap smear, a useful and cost-effective tool to screen for anal intraepithelial neoplasia in at-risk groups.
The natural history of squamous intraepithelial lesions (SILs) in the anal canal of HIV-infected men is incompletely understood. We assessed the incidence and factors associated with SIL and invasive anal squamous cell carcinoma (IASCC) among HIV-infected men with normal cytology at baseline. We performed a single-center prospective cohort study [men who have sex with men (MSM) and men who have sex with women (MSW)]. The incidence of anal canal SIL (low grade and high grade) and IASCC were estimated and predictive factors analyzed. The study population comprised 297 HIV-infected men with a normal cytology result and no anal human papillomavirus (HPV)-related diseases. Of these, 251 (85%) had at least one evaluable set of cytology data during follow-up (172 MSM, 79 MSW). The median follow-up time was 4 years. The cumulative incidence of SIL was 43% (107/251): 52% in MSM (90/172) and 22% in MSW (17/79), p < 0.0001. The incidence rate of SILs was 109 (95% confidence interval = 90-132) per 1000 person-years: 142 in MSM and 49 in MSW, p < 0.0001. HPV infection, receiving antiretroviral treatment (ART), and being MSM were independently associated risk factors. The incidence of IASCC was 0.15 per 1000 person-years among MSM and 0 in MSW. HIV-infected men, both MSM and MSW, are at high risk of developing SIL despite having a normal anal cytology at baseline. The incidence of anal canal SIL was higher among MSM, but was also remarkable among MSW. Independent risk factors associated with SIL were being HIV-infected MSM at high risk for acquisition of STIs, time on ART, and HPV infection.
Pap test has been an excellent example of success in medicine because of its role in remarkably reducing the incidence and death rate of cervical cancer. However, it is not a perfect test, and to certain degree, it became the victim of its success due to overexpectation of the public that led to a stringent government regulation of the practice. With the evolving of our knowledge of high-risk HPV infection in the development of cervical cancer, HPV molecular tests have been developed to enhance the Pap test in the early detection of cervical cancer. HPV vaccination has further advanced the battle against the development of cervical cancer by blocking the initial viral infection. This chapter briefly updates the current status of cervical cancer prevention and early detection, and the government regulation on pertinent cytology practice. Anal smear has recently emerged as a new approach to detect anal epithelial dysplastic changes; common questions in daily anal-rectal cytology are also discussed.
Background:
Anal cytology is used as a screening tool in the detection of precancerous anal squamous lesions. Follow-up clinical examination after abnormal anal cytology is recommended. The objective of this study was to determine how often abnormal cytology was followed by a clinical examination at our institution and how often cytology predicted histologic outcome.
Materials and methods:
A retrospective chart review was performed (2008-2018) on patients with anal cytology, demonstrating either low-grade or high-grade squamous intraepithelial lesion. Clinical examination within 1 y (digital rectal examination, anoscopy, or high-resolution anoscopy) was recorded. The probability of anal intraepithelial neoplasm on biopsy after dysplasia on cytology was calculated, and McNemar's test was used to determine if there was correspondence between cytology and histology.
Results:
A total of 327 anal cytology results demonstrated dysplasia (75% low grade and 25% high grade) in 182 patients. Seventy-five percent of dysplastic anal cytology were followed by clinical examination within 1 y, and 50% were biopsied. The probability of dysplasia on histology after dysplasia on cytology was 72% (95% confidence interval: 64%-78.5%). Twenty-eight percent of low-grade cytology results were upgraded to advanced disease (high-grade or invasive cancer) on histology. A low-grade cytology result was unable to preclude high-grade histology in our population.
Conclusions:
There is room for improvement at our institution to consistently follow-up with clinical examination after abnormal anal cytology. Our data suggest this is especially important considering anal cytology is an imperfect predictor of histologic anal intraepithelial neoplasia and invasive disease. Clinical examination is a critical component of anal dysplasia screening and follow-up.
These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of Human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer causing strains. Organ transplant recipients should be screened for HPV associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.
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Introduction
Anal cytology (AC) can be used as a screening tool for detection of anal HPV associated lesions, mainly in men who have sex with men and in immunosuppressed patients. Our aim is to review our experience with AC in women.
Material & methods: We have retrospectively reviewed all AC diagnosed between 2010–2017 in a single tertiary hospital (n = 644) and selected those performed in women (n = 158).
Results
24.53% of AC were performed in women. 14.7% of all women were HIV positive and 56.7% referred anal intercourse. Squamous lesions were found in 27.2% of women, most of them ASCUS and LSIL (14% and 11.5%). HPV DNA was detected in 38.6% of patients, and 63.9% of them showed positivity for multiple high-risk types. Anal biopsy showed high grade lesions in 20% of biopsied patients. We observed a significant relationship between HPV status and receptive anal sex, and the association between HPV status and anal histological diagnosis tended to significance. Sensitivity, specificity, negative predictive value and positive predictive value for anal cytology were 57%; 83%; 28% and 94%, respectively. 70.9% of women had synchronous cervical cytology, and squamous cervical lesions were detected in 46.4% of the cases, most of them LSIL or ASCUS (21.4% and 15.2%). We did not confirm a significant association between cytological diagnosis of cervical and anal samples.
Conclusions
AC is less widely used in women than in homosexual men. However, women show important rates of anal lesions, regardless of their HIV status. More studies should be performed to assess the potential impact of screening protocols in this population.
Background:
More than 90% of anal cancers are caused by human papillomavirus, and human papillomavirus strains 16 and 18 are the most oncogenic. Anal high-grade squamous intraepithelial lesions are cancer precursors. Treating these high-grade intraepithelial lesions likely reduces the risk of cancer, but cytology is an imperfect screening test.
Objective:
The purpose of this study was to determine whether human papillomavirus 16 and/or 18 testing better predicts the presence of high-grade squamous intraepithelial lesions.
Design:
In this retrospective study, 894 consecutive patients underwent anal dysplasia screening with digital anorectal examination, anal cytology, high-risk human papillomavirus testing, and high-resolution anoscopy with biopsy. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of each test and for a novel screening protocol. The absolute and relative risk of high-grade squamous intraepithelial lesions for all of the cytology/human papillomavirus combinations were also calculated.
Settings:
The study was conducted at a single practice specializing in anal dysplasia.
Patients:
Ninety-two percent of participants were men who have sex with men. Forty-four percent were HIV-positive individuals who were well controlled on antiretroviral therapy. The median age was 50 years.
Main outcome measures:
The presence of high-grade squamous intraepithelial lesions as a function of human papillomavirus and the cytology results were measured.
Results:
High-risk human papillomavirus testing alone demonstrated better sensitivity (96% vs 89%; p = 0.03) and negative predictive value (99% vs 96%; p = 0.008) over cytology. Human papillomavirus 16/18 testing increased specificity (48% to 71%; p < 0.0001) and positive predictive value (24% to 37%; p = 0.003) over testing for all of the high-risk strains. For each cytology category, high-grade squamous intraepithelial lesions were more prevalent when human papillomavirus 16/18 was detected. Benign cytology with 16/18 had a 31-fold increased risk of high-grade squamous intraepithelial lesions.
Limitations:
This study was conducted in a single private practice specializing in anal dysplasia screening with a mostly male population, and results might not be generalizable.
Conclusions:
Testing of high-risk human papillomavirus strains 16/18 improves specificity and positive predictive value over cytology for anal dysplasia screening. Patients testing positive for strains 16/18 are at a high risk for high-grade squamous intraepithelial lesions and should undergo high-resolution anoscopy regardless of the cytology result. See Video Abstract at http://links.lww.com/DCR/A654.
CDC has revised the classification system for HIV infection to emphasize the clinical importance of the CD4+ T-lymphocyte count in the categorization of HIV-related clinical conditions. This classification system replaces the system
published by CDC in 1986 [1] and is primarily intended for use in public health practice. Consistent with the 1993 revised
classification system, CDC has also expanded the AIDS surveillance case definition to include all HIV-infected persons who
have <200 CD4+ T-lymphocytes/µL, or a CD4+ T-lymphocyte percentage of total lymphocytes of <14. This expansion includes the addition of three clinical conditions—pulmonary
tuberculosis, recurrent pneumonia, and invasive cervical cancer—and retains the 23 clinical conditions in the AIDS surveillance
case definition published in 1987 [2]; it is to be used by all states for AIDS case reporting effective January 1, 1993.
One of the groups at highest risk of anal cancer is homosexual and bisexual men. Like cervical cancer, anal cancer is associated
with human papillomavirus (HPV) infection. Anal HPV infection was characterized in a study of 346 human immunodeficiency virus
(HIV)-positive and 262 HIVnegative homosexual and bisexual men. Anal HPV DNA was detected in 93% of HIV-positive and 61% of
HIV-negative men by polymerase chain reaction. The spectrum of HPV types was similar in HIV-positive and HIV-negative men,
with HPV-16 the most common type. Infection with multiple HPV types was found in 73% of HIV-positive and 23% of HIV-negative
men. Among HIV-positive men who were positive by hybrid capture for group B HPV types (16/18/31/33/35/39/45/51/52/56/ 58)
or group A types (6/11/42/43/44), lower CD4 cell levels were associated with higher levels of group B DNA (P = .004) but not group A DNA. These data suggest increased replication of the more oncogenic HPV types with more advanced
immunosuppression.
Background: The risk of Kaposi's sarcoma and non-Hodgkin's lymphoma is increased in people infected with the human immunodeficiency virus-1
(HIV). Highly active antiretroviral therapy (HAART) has been widely used by HIV-infected people in North America, Europe,
and Australia since about 1997. Acquired immunodeficiency syndrome (AIDS) incidence and mortality rates have fallen markedly
in association with the use of HAART, but its impact on the incidence of cancer in HIV-infected people is less clear. Methods: Cancer incidence data from 23 prospective studies that included 47 936 HIV-seropositive individuals from North America, Europe,
and Australia were collated, checked, and analyzed centrally. Adjusted incidence rates (expressed as number of cancers per
1000 person-years) for Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, cervical cancer, and 20 other cancer types
or sites were calculated. Rate ratios were estimated, comparing incidence rates from 1997 through 1999 with rates from 1992
through 1996, after adjustment for study, age, sex, and HIV transmission group. All statistical tests were two-sided. Results: For the period from 1992 through 1999, 2702 incident cancers were reported in 138 148 person-years of observation, and more
than 90% of them were either Kaposi's sarcoma or non-Hodgkin's lymphoma. The adjusted incidence rate for Kaposi's sarcoma
declined from 15.2 in 1992 through 1996 to 4.9 in 1997 through 1999 (rate ratio = 0.32; 99% confidence interval [CI] = 0.26–0.40;
based on 1489 and 190 cases, respectively; P<.0001). The incidence rates for non-Hodgkin's lymphoma also declined, from 6.2 to 3.6 (rate ratio = 0.58; 99% CI = 0.45–0.74;
based on 623 and 134 cases, respectively; P<.0001). Among the lymphomas, the rate ratios were 0.42 (99% CI = 0.24–0.75) for cerebral lymphoma, 0.57 (99% CI = 0.39–0.85)
for immunoblastic lymphoma, and 1.18 (99% CI = 0.48–2.88) for Burkitt's lymphoma (χ22 for heterogeneity = 6.2; P = .05). There was no statistically significant change in the incidence rates for Hodgkin's disease (rate ratio = 0.77; 99%
CI = 0.32–1.85; based on 38 and 12 cases, respectively; P = .4) or for cervical cancer (rate ratio = 1.87; 99% CI = 0.77–4.56; based on 19 and 17 cases, respectively; P = .07). The adjusted incidence rate for all other cancers combined was 1.7 in each time period (rate ratio = 0.96; 99% CI
= 0.62–1.47; based on 126 and 54 cases, respectively). Conclusions: Since the widespread use of HAART, there have been substantial reductions in the incidence Kaposi's sarcoma and non-Hodgkin's
lymphoma in HIV-infected people but, so far, no substantial change in the incidence of other cancers.
Background: Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active antiretroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment. Objective: To assess the benefit of HAART in patients with advanced AIDS and anemia. Design: Prospective, multicenter cohort study. Setting: The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999. Patients: 528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia. Measurements: In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use. Results: At baseline, patients had a median CD4 + lymphocyte count of 0.015 x 10 9 cell/L, median plasma HIV RNA level of 4.8 logo copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P 0.2]). Results were similar in patients with baseline CD4 + lymphocyte counts less than 0.010 × 10 9 cells/L. Conclusions: The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.
Context Large-scale studies are needed to determine if cancers other than Kaposi
sarcoma, non-Hodgkin lymphoma, and cervical cancer occur in excess in persons
with human immunodeficiency virus (HIV) infection or acquired immunodeficiency
syndrome (AIDS).Objectives To examine the general cancer pattern among adults with HIV/AIDS and
to distinguish immunosuppression-associated cancers from other cancers that
may occur in excess among persons with HIV/AIDS.Design, Setting, and Subjects Analysis of linked population-based AIDS and cancer registry data from
11 geographically diverse areas in the United States, including 302 834
adults aged 15 to 69 years with HIV/AIDS. The period of study varied by registry
between 1978 and 1996.Main Outcome Measure Relative risks (RRs) of cancers, calculated by dividing the number of
observed cancer cases by the number expected based on contemporaneous population-based
incidence rates. We defined cancers potentially influenced by immunosuppression
by 3 criteria: (1) elevated overall RR in the period from 60 months before
to 27 months after AIDS; (2) elevated RR in the 4- to 27-month post-AIDS period;
and (3) increasing trend in RR from before to after AIDS onset.Results Expected excesses were observed for the AIDS-defining cancers, but non–AIDS-defining
cancers also occurred in statistically significant excess (n = 4422; overall
RR, 2.7; 95% confidence interval [CI], 2.7-2.8). Of individual cancers, only
Hodgkin disease (n = 612; RR, 11.5; 95% CI, 10.6-12.5), particularly of the
mixed cellularity (n = 217; RR, 18.3; 95% CI, 15.9-20.9) and lymphocytic depletion
(n = 36; RR, 35.3; 95% CI, 24.7-48.8) subtypes; lung cancer (n = 808; RR,
4.5; 95% CI, 4.2-4.8); penile cancer (n = 14; RR, 3.9; 95% CI, 2.1-6.5); soft
tissue malignancies (n = 78; RR, 3.3; 95% CI, 2.6-4.1); lip cancer (n = 20;
RR, 3.1; 95% CI, 1.9-4.8); and testicular seminoma (n = 115; RR, 2.0; 95%
CI, 1.7-2.4) met all 3 criteria for potential association with immunosuppression.Conclusion Although occurring in overall excess, most non–AIDS-defining cancers
do not appear to be influenced by the advancing immunosuppression associated
with HIV disease progression. Some cancers that met our criteria for potential
association with immunosuppression may have occurred in excess in persons
with HIV/AIDS because of heavy smoking (lung cancer), frequent exposure to
human papillomavirus (penile cancer), or inaccurately recorded cases of Kaposi
sarcoma (soft tissue malignancies) in these persons. However, Hodgkin disease,
notably of the mixed cellularity and lymphocytic depletion subtypes, and possibly
lip cancer and testicular seminoma may be genuinely influenced by immunosuppression.
Anal cancer may be preceded by anal squamous intraepithelial lesions (ASIL), but the natural history of ASIL is poorly understood. In this report, we characterize the 2-year incidence and progression of low-grade SIL (LSIL) and highgrade SIL (HSIL) in a cohort study in 346 HIV-positive and 262 HIV-negative homosexual or bisexual men. Subjects were studied at defined intervals using anal cytology, anoscopy with biopsy of visible lesions, human papillomavirus (HPV) testing, HIV serostatus, CD4 level, and data on medical history and lifestyle. The incidence of HSIL within 2 years was 20% in HIV-positive men and 8% in HIV-negative men who were normal at baseline. In total, 62% of HIV-positive and 36% of HIV-negative men with LSIL at baseline progressed to HSIL. The relative risk (RR) for anal disease progression in HIV-positive men was 2.4 (95% confidence interval [CI], 1.8-3.2) when compared with HIV-negative men. The RR increased to 3.1 (95% CI, 2.3-4.1) in HIV-positive men with CD4 counts <200/mm3. Infection with multiple HPV types was a risk factor for anal disease progression in both HIV-positive (RR = 2.0; 95% CI, 1.0-4.1) and HIV-negative (RR = 5.1; 95% CI, 2.3-11) men. The incidence of anal HSIL and progression of LSIL to HSIL within 2 years of follow-up is high in HIV-positive homosexual or bisexual men and to a lesser extent, in HIV-negative men. Men with the above risk factors may be at increased risk of developing anal cancer.
In 1959, Graham and Helwig reported that 80 percent of patients with Bowen's disease developed associated cutaneous or internal
malignancies. Subsequent to the publication of this report, extensive and invasive workup of patients with Bowen's disease
became the standard of practice. The authors' personal experience with perianal Bowen's disease suggested a substantially
lower correlation between that disease and associated malignancies. Therefore a survey was initiated by contacting active
members of the American Society of Colon and Rectal Surgeons to investigate further. Analysis of 106 cases demonstrated a
lower incidence of associated malignancies (4.7 percent) subsequent to diagnosis of perianal Bowen's disease. The data further
indicated, however, that these patients are at risk to develop recurrent Bowen's disease (9.4 percent) and invasive carcinoma
(5.7 percent). It is concluded that an extensive and invasive workup of patients with perianal Bowen's disease is not indicated
and that the patient's greatest risk is development of recurrent or invasive disease.
PURPOSE: The prevalence of anal squamous intraepithelial lesions is high among human immunodeficiency virus-positive homosexual males and, to a lesser extent, among human immunodeficiency virus-negative homosexual males. Furthermore, the incidence of high-grade squamous intraepithelial lesions, the putative precursor lesion to invasive cancer, is also high. We report the first prospective study of high-resolution anoscopy-directed surgical treatment of high-grade squamous intraepithelial lesions.
METHODS: A prospective study of patients undergoing surgical treatment of high-grade squamous intraepithelial lesions (excision/cauterization of lesions visualized with high-resolution anoscopy) was performed. Follow-up anoscopy with biopsy and Papanicolaou smear was performed every three to six months.
RESULTS: Patients diagnosed with high-grade squamous intraepithelial lesions during the course of their participation in a prospective cohort study of anal squamous intraepithelial lesions were identified. From this group, 37 patients who were treated surgically between 1995 and 1999 were studied. Of these, 29 had tested positive for human immunodeficiency virus and 8 were negative for the virus. Mean patient age was 45 8 years. Mean duration of follow-up was 32.3 20.6 months in the human immunodeficiency virus-negative group and 28.6 12.9 months in the human immunodeficiency virus-positive group. No human immunodeficiency virus-negative patient developed recurrent high-grade squamous intraepithelial lesions. Twenty-three of 29 human immunodeficiency virus-positive patients had persistent or recurrent high-grade squamous intraepithelial lesions (P = 0.003; mean time to recurrence, 12 months). Six patients underwent reoperation for high-grade squamous intraepithelial lesions (4 recurred by 6 months). No patients developed incontinence, stenosis, postoperative infection, or significant bleeding after surgical treatment.
CONCLUSIONS: Surgical intervention directed by high-resolution anoscopy is safe and eliminates high-grade squamous intraepithelial lesions in human immunodeficiency virus-negative patients. The high persistence or recurrence rate in human immunodeficiency virus-positive patients suggests that multiple staged procedures and continued surveillance may be necessary.
The incidence of anal cancer among homosexual men exceeds that of cervical cancer in women, and HIV-positive homosexual men may be at even higher risk than HIV-negative men. Cervical cancer is preceded by high-grade squamous intra-epithelial lesions (HSIL) and anal HSIL may similarly be the precursor to anal cancer. In this study, we describe the incidence of and risk factors for HSIL in HIV-positive and HIV-negative homosexual and bisexual men.
Prospective cohort study of HIV-positive and HIV-negative homosexual men.
The University of California, San Francisco.
346 HIV-positive and 262 HIV-negative men enrolled at baseline, 277 HIV-positive and 221 HIV-negative homosexual men followed after baseline.
A questionnaire was administered detailing lifestyle habits, medical history and sexual practices. Anal swabs for cytology and human papillomavirus studies were obtained, followed by biopsies of visible lesions. Human papillomavirus testing was performed using polymerase chain reaction (PCR) and 'hybrid capture'. Blood was obtained for HIV testing and measurement of CD4 levels.
Incident HSIL.
HIV-positive men were more likely to develop HSIL than HIV-negative men relative risk (RR), 3.7; 95% confidence interval (CI), 2.6-5.7. Life-table estimates of the 4-year incidence of HSIL was 49% (95% CI, 41-56) among HIV-positive men and 17% (95% CI, 12-23) among HIV-negative men. Among HIV-positive men, those with lower baseline CD4 counts (P = 0.007) and persistent infection with one or more human papillomavirus types, determined using PCR (P = 0.0001), were more likely to develop HSIL.
HIV infection, lower CD4 levels and human papillomavirus infection were associated with high rates of incident HSIL among homosexual men. However, high rates were found at all CD4 levels among HIV-positive men and among HIV-negative men.
Anal cancer may be preceded by anal squamous intraepithelial lesions (ASIL), but the natural history of ASIL is poorly understood. In this report, we characterize the 2-year incidence and progression of low-grade SIL (LSIL) and high-grade SIL (HSIL) in a cohort study in 346 HIV-positive and 262 HIV-negative homosexual or bisexual men. Subjects were studied at defined intervals using anal cytology, anoscopy with biopsy of visible lesions, human papillomavirus (HPV) testing, HIV serostatus, CD4 level, and data on medical history and lifestyle. The incidence of HSIL within 2 years was 20% in HIV-positive men and 8% in HIV-negative men who were normal at baseline. In total, 62% of HIV-positive and 36% of HIV-negative men with LSIL at baseline progressed to HSIL. The relative risk (RR) for anal disease progression in HIV-positive men was 2.4 (95% confidence interval [CI], 1.8-3.2) when compared with HIV-negative men. The RR increased to 3.1 (95% CI, 2.3-4.1) in HIV-positive men with CD4 counts <200/mm3. Infection with multiple HPV types was a risk factor for anal disease progression in both HIV-positive (RR = 2.0; 95% CI, 1.0-4.1) and HIV-negative (RR = 5.1; 95% CI, 2.3-11) men. The incidence of anal HSIL and progression of LSIL to HSIL within 2 years of follow-up is high in HIV-positive homosexual or bisexual men and to a lesser extent, in HIV-negative men. Men with the above risk factors may be at increased risk of developing anal cancer.
Background:
Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
Purpose:
Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
Methods:
More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
Results:
HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
Conclusions:
Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.
Implication:
The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.
Breast and cervical cancer incidence and mortality rates were reviewed for the period 1973-1987. For breast cancer, mortality has been relatively stable, increasing from 26.9/100,000 women in 1973 to 27.1 in 1987. Alternatively, data from the National Cancer Institute's Surveillance, Epidemiology, End Results Program (SEER) showed a 36% increase in the incidence of this malignancy over the same period. In 1987, overall incidence of invasive breast cancer was 111.9/100,000 women. White women experienced lower overall mortality rates and higher overall incidence than black women; however, these differences varied by age. Examination of breast cancer incidence by stage of disease at diagnosis revealed that rates for distant and regional disease have remained relatively stable since 1973. In contrast, rates of localized and in situ cancers exhibited an increase in the 1980s that may correspond to increased use of mammography in this country. The rate of decline in cervical cancer incidence and mortality has slowed in recent years. In 1987, 3.0 cervical cancer deaths/100,000 women occurred. SEER incidence for invasive disease for that year was 8.2/100,000. Rates varied by race, age, state, and stage of disease. In general, black women experienced much higher incidence and mortality from invasive cervical cancer than white women. For both races, rates of in situ disease were highest among young women and decreased rapidly with age. Rates of in situ cervical cancer were consistently higher than rates of invasive cancer for the time period studied.
In 1959, Graham and Helwig reported that 80 percent of patients with Bowen's disease developed associated cutaneous or internal malignancies. Subsequent to the publication of this report, extensive and invasive workup of patients with Bowen's disease became the standard of practice. The authors' personal experience with perianal Bowen's disease suggested a substantially lower correlation between that disease and associated malignancies. Therefore a survey was initiated by contacting active members of the American Society of Colon and Rectal Surgeons to investigate further. Analysis of 106 cases demonstrated a lower incidence of associated malignancies (4.7 percent) subsequent to diagnosis of perianal Bowen's disease. The data further indicated, however, that these patients are at risk to develop recurrent Bowen's disease (9.4 percent) and invasive carcinoma (5.7 percent). It is concluded that an extensive and invasive workup of patients with perianal Bowen's disease is not indicated and that the patient's greatest risk is development of recurrent or invasive disease.
Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.
The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.
To determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection.
Prospective cohort study of 158 HIV-seropositive and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic and colposcopic findings.
Subjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIN. Anal specimens were screened for HPV DNA.
HG-AIN developed in eight (5.4%) and 24 (15.2%) HIV-seronegative and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 count < or = 500 x 10(6)/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests.
The association of HG-AIN with HIV, independent of HPV type, level of HPV detection and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.
Anal squamous intraepithelial lesions (ASIL) are common in homosexual and bisexual men, and high-grade ASIL (HSIL) in particular may represent an anal cancer precursor. Cervical cytology is a useful screening tool for detection of cervical HSIL to prevent cervical cancer. To assess anal cytology as a screening tool for anal disease, we compared anal cytology with anoscopy and histopathology of anal biopsies. A total of 2958 anal examinations were performed on 407 HIV-positive and 251 HIV-negative homosexual or bisexual men participating in a prospective study of ASIL. The examination consisted of a swab for anal cytology and anoscopy with 3% acetic acid and biopsy of visible lesions. Defining abnormal cytology as including atypical squamous cells of undetermined significance and ASIL, the sensitivity of anal cytology for detection of biopsy-proven ASIL was 69% (95% confidence interval: 60 to 78) in HIV-positive and 47% (95% confidence interval; 26 to 68) in HIV-negative men at their first visit and was 81% and 50%, respectively, for all subsequent visits combined. The absence of columnar cells did not affect the sensitivity, specificity, or predictive value of anal cytology. Anal cytology may be a useful screening tool to detect ASIL, particularly in HIV-positive men. The grade of disease on anal cytology did not always correspond to the histologic grade, and anal cytology should be used in conjunction with histopathologic confirmation.
The incidence of anal cancer is increased in men with a history of anal receptive intercourse. Analogous to cervical cancer, whose precursor is cervical high-grade squamous intraepithelial lesion (HSIL), anal cancer may be preceded by anal HSIL. Although not yet proven, detection, follow-up, and treatment of HSIL may prevent development of anal cancer. Cervical colposcopic methodology was used to describe anal lesions and to determine if HSIL could be distinguished from low-grade squamous intraepithelial lesion (LSIL).
The colposcopic characteristics of 385 biopsied anal lesions were described and correlated with results of histopathology in a cohort of 121 human immunodeficiency virus-positive and 31 human immunodeficiency-negative homosexual/bisexual men with anal lesions followed as part of a longitudinal study of anal squamous intraepithelial lesions. Color, contour, surface, and vascular patterns of anal lesions were analyzed and correlated with histologic diagnosis.
Sixty-seven percent of biopsies showed LSIL and 26 percent showed HSIL. The positive predictive value for anal HSIL in lesions with characteristics typical of cervical LSIL was 7.7 percent (95 percent confidence interval, 1.8-14), whereas the positive predictive value for anal HSIL in lesions with characteristics typical of cervical HSIL was 49 percent (95 percent confidence interval, 40-58).
The colposcopic appearance of different grades of anal squamous intraepithelial lesions was similar to those described for the cervix. Incorporation of colposcopy into assessment of anal disease could aid in distinguishing anal LSIL from HSIL.
To clarify which types of cancer result from AIDS, we compared the cancer experiences of people with AIDS with those of the general population by matching population-based cancer and AIDS registries in the USA and Puerto Rico.
We used a probabilistic matching algorithm to compare names, birth dates, and, where available, social-security numbers of 98,336 people with AIDS and 1,125,098 people with cancer aged less than 70 years. We defined AIDS-related cancers as those with both significantly raised incidence post-AIDS and increasing prevalence from 5 years pre-AIDS to 2 years post-AIDS.
Among people with AIDS, we found 7028 cases of Kaposi's sarcoma (KS), 1793 of non-Hodgkin lymphoma (NHL), and 712 other cases of histologically defined cancer. Incidence rates among people with AIDS were increased 310-fold for KS, 113-fold for NHL, and 1.9-fold (95% CI 1.5-2.3) for other cancers. Of 38 malignant disorders other than KS and NHL, only angiosarcoma (36.7-fold), Hodgkin's disease (7.6-fold), multiple myeloma (4.5-fold), brain cancer (3.5-fold), and seminoma (2.9-fold) were raised and increasing significantly (p<0.02) from the pre-AIDS to the post-AIDS period.
Interpretation is complicated by screening and shared risk factors, such as sexual behaviour and cigarette smoking. However, our data indicate that AIDS leads to a significantly increased risk of Hodgkin's disease, multiple myeloma, brain cancer, and seminoma. Immunological failure to control herpes or other viral infections may contribute to these malignant diseases.
Ano-genital neoplasia is about 20 x more common in renal transplant patients than the general population. Neoplasms in the immunosuppressed are more morbid and mortal because: patients are younger; tumors are more undifferentiated; they have more and larger foci; more sites are involved; neoplasms tend to persist, recur and progress; and there are more complications from treatments. Intraepithelial neoplasia engenders some morbidity. Invasion is rarer, but when it occurs, it is always morbid, and all too often mortal. Invasive ano-genital cancer is primarily preventable because the lower genital and anal tracts are accessible to inspection, cytologic screening, endoscopy and biopsy. Prime prevention is avoiding infection with the Human Papilloma Virus (HPV). Next best is detecting HPV/intraepithelial neoplasia early with frequent inspection, cytology and liberal biopsies; and then removing any condylomas or intraepithelial neoplasia that develop.
Homosexual and bisexual men infected with human immunodeficiency virus (HIV) are at increased risk for human papillomavirus-related anal neoplasia and anal squamous cell carcinoma (SCC).
To estimate the clinical benefits and cost-effectiveness of screening HIV-positive homosexual and bisexual men foranal squamous intraepithelial lesions (ASIL) and anal SCC.
Cost-effectiveness analysis performed from a societal perspective that used reference case recommendations from the Panel on Cost-Effectiveness in Health and Medicine. A state-transition Markov model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening vs several screening strategies for ASIL and anal SCC using anal Papanicolaou (Pap) testing at different intervals. Values for incidence, progression, and regression of anal neoplasia; efficacy of screening and treatment; natural history of HIV; health-related quality of life; and costs were obtained from the literature.
Hypothetical cohort of homosexual and bisexual HIV-positive men living in the United States.
Life expectancy, quality-adjusted life expectancy, quality-adjusted years of life saved, lifetime costs, and incremental cost-effectiveness ratio.
Screening for ASIL increased quality-adjusted life expectancy at all stages of HIV disease. Screening with anal Pap tests every 2 years, beginning in early HIV disease (CD4 cell count >0.50 x 10(9)/L), resulted in a 2.7-month gain in quality-adjusted life expectancy for an incremental cost-effectiveness ratio of $13,000 per quality-adjusted life year saved. Screening with anal Pap tests yearly provided additional benefit at an incremental cost of $16,600 per quality-adjusted life year saved. If screening was not initiated until later in the course of HIV disease (CD4 cell count <0.50 x 10(9)/L), then yearly Pap test screening was preferred due to the greater amount of prevalent anal disease (cost-effectiveness ratio of less than $25,000 per quality-adjusted life year saved compared with no screening). Screening every 6 months provided little additional benefit over that of yearly screening. Results were most sensitive to the rate of progression of ASIL to anal SCC and the effectiveness of treatment of precancerous lesions.
Screening HIV-positive homosexual and bisexual men for ASIL and anal SCC with anal Pap tests offers quality-adjusted life expectancy benefits at a cost comparable with other accepted clinical preventive interventions.
The aim of this study was to review the literature with regard to perianal Bowen's disease and anal intraepithelial neoplasia.
A literature review was conducted from 1960 to 1999 using MEDLINE.
Perianal Bowen's disease and anal intraepithelial neoplasia are precursors to squamous carcinoma of the anus. They are analogous to and are associated with cervical and vulvar intraepithelial neoplasia, and have human papillomavirus as a common cause. Biopsy and histopathologic examination is required for diagnosis and to distinguish other perianal dermatoses. Treatment options range from aggressive wide local excision of all disease with negative margins to observation alone for microscopic lesions not visible to the naked eye. The disease has a proclivity for recurrence and recalcitrance.
Most surgeons caring for patients with perianal Bowen's disease and high-grade anal epithelial neoplasia use wide local excision, with an effort to obtain disease-free margins. Some authors have reported the advantages of ablative procedures such as laser ablation and cryotherapy. Microscopic disease found serendipitously in hemorrhoidectomy specimens can probably be treated conservatively with serial examinations alone. There is a lack of controlled data supporting an optimal treatment strategy. A multicenter controlled study comparing wide local excision with ablative procedures may be warranted.
Studies from the era prior to the introduction of highly active antiretroviral therapy (HAART) have shown that the prevalence of anal infection with human papillomavirus (HPV) and anal squamous intraepithelial lesions (ASIL) were high among HIV-positive homosexual men, and to a lesser extent, among HIV-negative homosexual men. The data also show that the incidence of high-grade ASIL (HSIL), the putative invasive cancer precursor lesion, was high in these groups. Early data suggest that at least 75% of those with HSIL lesions do not regress while receiving HAART. Given that progression of HSIL to invasive cancer may require several years, lengthened survival associated with HAART may paradoxically lead to an increased risk of anal cancer. The potential to prevent anal cancer through detection and treatment of anal HSIL suggests a need to screen high-risk individuals with anal cytology, similar to cervical cytology screening to prevent cervical cancer. Cost-effectiveness analyses suggest that anal screening programs may be cost-effective in HIV-positive men. However, barriers to implementation of screening include inadequate numbers of clinicians skilled in diagnosis and treatment of HSIL and lack of medical alternatives to surgical excision. Recent progress in understanding the pathogenesis of ASIL in HIV-positive men points to a role for decreased cell-mediated immunity to HPV antigens as well as the effects of the HIV-1 tat protein in modulating the biology of HPV-infected keratinocytes.
Homosexual and bisexual men are at an increased risk for human papillomavirus-induced squamous intraepithelial lesions and cancer of the anus. Our objective was to estimate the cost-effectiveness of screening for anal squamous intraepithelial lesions in these high-risk patients.
A Markov model was developed to evaluate alternative screening strategies using anal cytology in a hypothetical cohort of homosexual and bisexual men. Data were obtained from prospective cohort studies, national databases, Medicare reimbursement rates, and the published literature. Model outcomes included life expectancy, quality-adjusted life expectancy, total lifetime costs, and incremental cost-effectiveness ratios.
The undiscounted life expectancy gain associated with anal cytology screening every 3 years was 5.5 months. Compared with no screening, screening every 3 years increased the discounted quality-adjusted life expectancy by 1.8 months and cost $7,000 per quality-adjusted life year (QALY) gained. Screening every 2 years cost $15,100 per QALY gained compared with screening every 3 years. Annual screening provided incremental benefits of less than 0.5 quality-adjusted months and had an incremental cost of $34,800 per QALY gained. Screening every 6 months provided little additional benefit (i.e, 5 days) over that of annual screening and had an incremental cost of $143,500 per QALY gained.
In homosexual and bisexual men, screening every 2 or 3 years for anal squamous intraepithelial lesions with anal cytology would provide life-expectancy benefits comparable with other accepted preventive health measures, and would be cost-effective.
Human papillomavirus (HPV)-associated anogenital malignancies occur frequently in patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). The purpose of our study was to determine if the high frequency of these cancers is due to lifestyle factors associated with both HPV and HIV infections or to immunosuppression following HIV infection.
We studied invasive and in situ HPV-associated cancers among 309 365 U.S. patients with HIV infection/AIDS (257 605 males and 51 760 females) from 5 years before the date of AIDS onset to 5 years after this date. Sex-, race-, and age-standardized ratios of observed-to-expected cancers served as measures of relative risk (RR). Trend tests were used to evaluate changes in the RRs during the 10 years spanning AIDS onset. All statistical tests were two-sided.
All HPV-associated cancers in AIDS patients occurred in statistically significant excess compared with the expected numbers of cancers. For in situ cancers, overall risks were significantly increased for cervical (RR = 4.6; 95% confidence interval [CI] = 4.3-5.0), vulvar/vaginal (RR = 3.9; 95% CI = 2.0-7. 0), anal (in females, RR = 7.8 [95% CI = 0.2-43.6]; in males, RR = 60.1 [95% CI = 49.2-72.7]), and penile (RR = 6.9; 95% CI = 4.2-10.6) cancers, and RRs increased during the 10 years spanning AIDS onset for carcinomas in situ of the cervix (P: for trend <.001), vulva/vagina (P: for trend =.04), and penis (P: for trend =.04). For invasive cancers, overall risks were significantly increased for cervical (RR = 5.4; 95% CI = 3.9-7.2), vulvar/vaginal (RR = 5.8; 95% CI = 3.0-10.2), and anal (RR = 6.8; 95% CI = 2.7-14.0) cancers in females and for anal (RR = 37.9; 95% CI = 33.0-43.4), penile (RR = 3. 7; 95% CI = 2.0-6.2), tonsillar (RR = 2.6; 95% CI = 1.8-3.8), and conjunctival (RR = 14.6; 95% CI = 5.8-30.0) cancers in males. However, RRs for invasive cancers changed little during the 10 years spanning AIDS onset.
HPV-associated malignancies occur at increased rates in persons with HIV/AIDS. Increasing RRs for in situ cancers to and beyond the time of AIDS onset may reflect the gradual loss of control over HPV-infected keratinocytes with advancing immunosuppression. However, the lack of a similar increase for invasive HPV-associated cancers suggests that late-stage cancer invasion is not greatly influenced by immune status.
Compared with HIV-negative individuals, HIV-positive individuals have a higher prevalence of anogenital human papillomavirus (HPV) infection, as well as a higher incidence of HPV-associated anal cancer. Little is currently known of chromosomal changes occurring in anal intraepithelial neoplasia (AIN), the probable precursor to anal cancer. Genetic changes in AIN were characterized by comparative genomic hybridization (CGH) in a study of samples obtained from 19 HIV-positive and 11 HIV-negative men. The proportion with genetic changes significantly increased with the severity of the histopathologic grade with none diagnosed as (0%) AIN 1; 5 of 17 (29%) as AIN 2; and 5 of 9 (56%) AIN 3 showing genetic changes (p = .02). This correlation was also found in study subjects who had multiple biopsies with different grades of pathology concurrently or serially over time. The most common regional DNA copy number change was gain mapped to chromosome arm 3q (12% of AIN 2 and 33% of AIN 3). This alteration was previously reported to be commonest alteration in cervical cancer, which suggests a common molecular pathway for these two HPV-associated anogenital neoplasias.
Large-scale studies are needed to determine if cancers other than Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer occur in excess in persons with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
To examine the general cancer pattern among adults with HIV/AIDS and to distinguish immunosuppression-associated cancers from other cancers that may occur in excess among persons with HIV/AIDS.
Analysis of linked population-based AIDS and cancer registry data from 11 geographically diverse areas in the United States, including 302 834 adults aged 15 to 69 years with HIV/AIDS. The period of study varied by registry between 1978 and 1996.
Relative risks (RRs) of cancers, calculated by dividing the number of observed cancer cases by the number expected based on contemporaneous population-based incidence rates. We defined cancers potentially influenced by immunosuppression by 3 criteria: (1) elevated overall RR in the period from 60 months before to 27 months after AIDS; (2) elevated RR in the 4- to 27-month post-AIDS period; and (3) increasing trend in RR from before to after AIDS onset.
Expected excesses were observed for the AIDS-defining cancers, but non-AIDS-defining cancers also occurred in statistically significant excess (n = 4422; overall RR, 2.7; 95% confidence interval [CI], 2.7-2.8). Of individual cancers, only Hodgkin disease (n = 612; RR, 11.5; 95% CI, 10.6-12.5), particularly of the mixed cellularity (n = 217; RR, 18.3; 95% CI, 15.9-20.9) and lymphocytic depletion (n = 36; RR, 35.3; 95% CI, 24.7-48.8) subtypes; lung cancer (n = 808; RR, 4.5; 95% CI, 4.2-4.8); penile cancer (n = 14; RR, 3.9; 95% CI, 2.1-6.5); soft tissue malignancies (n = 78; RR, 3.3; 95% CI, 2.6-4.1); lip cancer (n = 20; RR, 3.1; 95% CI, 1.9-4.8); and testicular seminoma (n = 115; RR, 2.0; 95% CI, 1.7-2.4) met all 3 criteria for potential association with immunosuppression.
Although occurring in overall excess, most non-AIDS-defining cancers do not appear to be influenced by the advancing immunosuppression associated with HIV disease progression. Some cancers that met our criteria for potential association with immunosuppression may have occurred in excess in persons with HIV/AIDS because of heavy smoking (lung cancer), frequent exposure to human papillomavirus (penile cancer), or inaccurately recorded cases of Kaposi sarcoma (soft tissue malignancies) in these persons. However, Hodgkin disease, notably of the mixed cellularity and lymphocytic depletion subtypes, and possibly lip cancer and testicular seminoma may be genuinely influenced by immunosuppression.
Anal cancers are thought to arise from squamous intraepithelial lesions in the anal canal, and women infected with human immunodeficiency virus-1 (HIV) may be at higher risk of anal cancer. Our aim was to determine the prevalence of human papillomavirus (HPV)-related abnormalities of the anal canal in women and to characterize risk factors for these lesions.
We evaluated HPV-related abnormalities in 251 HIV-positive and in 68 HIV-negative women. We completed physical examinations and obtained questionnaire data on medical history and relevant sexual practices. Univariate and adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed using the Mantel-Haenszel procedure and regression techniques. All statistical tests were two-sided.
Abnormal anal cytology, including atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions (HSILs), was diagnosed in 26% of HIV-positive and in 8% of HIV-negative women. HSILs were detected by histology or cytology in 6% of HIV-positive and in 2% of HIV-negative women. HIV-positive women showed increased risk of anal disease as the CD4 count decreased (P<.0001) and as the plasma HIV RNA viral load increased (P =.02). HIV-positive women with abnormal cervical cytology had an increased risk of abnormal anal cytology at the same visit (RR = 2.2; 95% CI = 1.4 to 3.3). Abnormal anal cytology in HIV-positive women was associated with anal HPV RNA detected by the polymerase chain reaction and by a nonamplification-based test (RR = 4.3; 95% CI = 1.6 to 11). In a multivariate analysis, the history of anal intercourse and concurrent abnormal cervical cytology also were statistically significantly (P =.05) associated with abnormal anal cytology.
HIV-positive women had a higher risk of abnormal anal cytology than did HIV-negative women with high-risk lifestyle factors. These data provide strong support for anoscopic and histologic assessment and careful follow-up of women with abnormal anal lesions.
Mortality and morbidity related to AIDS have decreased among HIV-infected patients taking highly active anti-retroviral therapy (HAART), but previous studies may have been confounded by other changes in treatment.
To assess the benefit of HAART in patients with advanced AIDS and anemia.
Prospective, multicenter cohort study.
The Viral Activation Transfusion Study (VATS), with enrollment from August 1995 through July 1998 and follow-up through June 1999.
528 HIV-infected patients with cytomegalovirus (CMV) seropositivity or disease who were receiving a first red blood cell transfusion for anemia.
In a person-year analysis of follow-up before and after initiation of HAART, Poisson regression was used to calculate crude rate ratios and rate ratios adjusted for CD4 count, HIV RNA level, calendar period, time on study, sex, ethnicity, and injection drug use.
At baseline, patients had a median CD4(+) lymphocyte count of 0.015 x 10(9) cell/L, median plasma HIV RNA level of 4.8 log(10) copies/mL, and median hemoglobin concentration of 73 g/L. Use of HAART increased from 1% of active patients in January 1996 to 79% of active patients in January 1999. The crude death rate was 0.24 event/person-year among patients taking HAART and 0.88 event/person-year among those not taking HAART (rate ratio, 0.26; adjusted rate ratio, 0.38; P < 0.001 for both comparisons). Rates of non-CMV disease were 0.15 event/ person-year after HAART and 0.45 event/person-year before HAART (crude rate ratio, 0.34 [ P < 0.001]; adjusted rate ratio, 0.66 [ P < 0.05]). Rates of CMV disease were 0.10 event/person-year after HAART and 0.25 before HAART (crude rate ratio, 0.42 [ P < 0.01]; adjusted rate ratio, 1.01 [ P > 0.2]). Results were similar in patients with baseline CD4(+) lymphocyte counts less than 0.010 x 10(9) cells/L.
The data support an independent reduction in mortality and opportunistic events attributable to HAART, even in patients with very advanced HIV disease. However, patients with CMV infection or disease may not have a reduction in new CMV events due to HAART.
The prevalence of anal squamous intraepithelial lesions is high among human immunodeficiency virus-positive homosexual males and, to a lesser extent, among human immunodeficiency virus-negative homosexual males. Furthermore, the incidence of high-grade squamous intraepithelial lesions, the putative precursor lesion to invasive cancer, is also high. We report the first prospective study of high-resolution anoscopy-directed surgical treatment of high-grade squamous intraepithelial lesions.
A prospective study of patients undergoing surgical treatment of high-grade squamous intraepithelial lesions (excision/cauterization of lesions visualized with high-resolution anoscopy) was performed. Follow-up anoscopy with biopsy and Papanicolaou smear was performed every three to six months.
Patients diagnosed with high-grade squamous intraepithelial lesions during the course of their participation in a prospective cohort study of anal squamous intraepithelial lesions were identified. From this group, 37 patients who were treated surgically between 1995 and 1999 were studied. Of these, 29 had tested positive for human immunodeficiency virus and 8 were negative for the virus. Mean patient age was 45 +/- 8 years. Mean duration of follow-up was 32.3 +/- 20.6 months in the human immunodeficiency virus-negative group and 28.6 +/- 12.9 months in the human immunodeficiency virus-positive group. No human immunodeficiency virus-negative patient developed recurrent high-grade squamous intraepithelial lesions. Twenty-three of 29 human immunodeficiency virus-positive patients had persistent or recurrent high-grade squamous intraepithelial lesions (P = 0.003; mean time to recurrence, 12 months). Six patients underwent reoperation for high-grade squamous intraepithelial lesions (4 recurred by 6 months). No patients developed incontinence, stenosis, postoperative infection, or significant bleeding after surgical treatment.
Surgical intervention directed by high-resolution anoscopy is safe and eliminates high-grade squamous intraepithelial lesions in human immunodeficiency virus-negative patients. The high persistence or recurrence rate in human immunodeficiency virus-positive patients suggests that multiple staged procedures and continued surveillance may be necessary.
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