Isabelle Heard

High Prevalence of Anal Human Papillomavirus Infection and Anal Cancer Precursors among HIV-Infected Persons in the Absence of Anal Intercourse

Context Anal cancer is associated with human papillomavirus (HPV) infection and receptive anal intercourse and is more common in HIV-positive than HIV-negative homosexual men. Little is known about HPV infection and anal lesions in HIV-positive men with no history of receptive anal intercourse. Contribution In this cross-sectional study of HIV-positive men, 46% of 50 heterosexual men who reported no history of receptive anal intercourse had anal HPV infection and 36% had anal squamous intraepithelial lesions. Low CD4+ cell counts were associated with an increased risk for anal lesions. Implications Anal HPV infection and precancerous lesions occur without receptive anal intercourse in HIV-positive men. The Editors The incidence of anal cancer among men with a history of receptive anal intercourse before the HIV epidemic was several times higher than the current rate of cervical cancer in women in the United States; the incidence of anal cancer is estimated to be as high as 35 per 100 000 in this population (1, 2). Anal cancer is associated with human papillomavirus (HPV) infection (3, 4). Earlier studies of the risk for anal cancer in HIV-negative populations showed that a history of receptive anal intercourse was an important risk factor (2, 5), presumably because it increased the risk for acquiring anal HPV infection. Both anal squamous intraepithelial lesions (SILs) and anal HPV infection are more common in HIV-positive than in HIV-negative men who have sex with men (6-13). Recent studies estimated that the incidence of anal cancer was twofold higher in HIV-infected than in HIV-negative men who had sex with men (14, 15); in addition, the relative risk for developing anal cancer among HIV-positive men was 37-fold higher than in the general population (16). Human immunodeficiency virus-positive men who had sex with men were at 60-fold higher risk. Human immunodeficiency virus-positive injection drug users were also at increased risk (6-fold), although less so than the HIV-positive men who had sex with men. In HIV-positive men who have sex with men, it is difficult to ascertain the role of anal intercourse as a risk factor for anal HPV infection or anal SIL, given the high prevalence of this behavior in this population. Immunosuppression probably plays a role, as indicated in studies showing an association between anal SIL and low CD4+ cell counts (6, 10, 13). In addition, evidence shows that the risk for anal SIL is increased in renal allograft recipients in the absence of receptive anal intercourse (17-19). Cervical cytologic screening to detect cervical high-grade SIL (HSIL) followed by treatment of the lesions substantially reduces the incidence of cervical cancer. Studies of anal cytologic screening to determine whether the incidence of anal cancer can similarly be reduced have not yet been done. However, according to costbenefit modeling over a wide range of assumptions, anal cytologic screening in HIV-positive men who have sex with men has been projected to be cost-effective for preventing anal cancer (20, 21). In this cross-sectional study, we compared the prevalence of and risk factors for abnormal anal histologic or cytologic findings in HIV-positive men who have sex with men with male HIV-positive injection drug users who reported no history of anal intercourse. This was done to assess the role of HIV-related immunodeficiency in detecting anal HPV infection and anal disease in the absence of anal intercourse. In addition, we sought to determine whether the prevalence of anal HPV infection and anal SIL was high enough in HIV-positive injection drug users to warrant additional studies of potential benefit from anal cytologic screening in this population. Methods Study Design Between June 1999 and October 2000, 120 HIV-seropositive men attending the outpatient clinic of Hpital Europen Georges Pompidou, Paris, France, were recruited in a cross-sectional study of anal HPV infection and anal SIL in HIV-seropositive men. Men were eligible for the study if they had acquired HIV through homosexual or bisexual contact or through injection drug use, were older than 18 years of age, and had absolute CD4+ cell counts less than 500 106 cells/L. Injection drug users who had sex with men were excluded from the study. The patients were recruited from a cohort of 1198 HIV-infected patients who were followed at the Clinical Immunology unit of Hpital Europen Georges Pompidou. All patients were consecutively enrolled into the study. No eligible patient declined participation. The Ethics Review Board of Hpital Piti-Salpetrire, Paris, and the Committee on Human Research of the University of California, San Francisco, approved the protocol and written informed consent documents. Patients provided signed written consent before inclusion in the study. All men were interviewed by using a standardized, comprehensive, self-administered questionnaire that included questions on age, education status, professional activity, tobacco use, route of HIV infection, medical history, history of sexually transmitted diseases, history of HPV-related disease, history of treatment for anal disease, drug use, age at first intercourse, total number of sexual partners, total number of receptive and insertive anal intercourse, and history of commercial sex work with men. The questionnaire was a French translation of a questionnaire used in other published studies conducted at the University of California, San Francisco (10). The questionnaires were self-administered, and the investigators were blinded to the results to better ensure patient privacy and accuracy of the data. Cytologic and Histologic Analyses Patients had a thorough anal examination that included insertion of a Dacron swab (Eurotubo, Rubi, Spain) for anal cytologic and HPV testing. The swab was immediately rinsed in a vial of PreservCyt fixative fluid (Cytyc Corp., Boxborough, Massachusetts). Each vial was used for HPV testing and ThinPrep cytologic screening (Cytyc Corp.). An aliquot was taken from the vial for HPV testing; slides were then prepared from the vial by using the ThinPrep 2000 processor (Cytyc Corp.). When cytologic abnormalities were found, consenting patients underwent anoscopic examination and biopsy with the use of a colposcope (22). Biopsy specimens were fixed in 10% formalin for routine histopathologic examination. Anal cytologic and histologic results were evaluated independently of each other, without knowledge of clinical status and HIV risk group of the patient or HPV results. Anal cytologic results were classified as normal, atypical squamous cell of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or HSIL by using the Bethesda system criteria for evaluation of cervical cytologic results. If both cytologic and histologic results were available for analysis, a patients diagnosis was categorized as the more severe result. Detection of Anal HPV DNA Polymerase chain reaction (PCR) for anal HPV DNA detection was performed in a blinded fashion. To determine specimen adequacy, genomic DNA was isolated from the ThinPrep vial and amplified by using MY09/MY11 consensus HPV L1 primers as well as primers to amplify the human -globin gene (9). After 40 amplification cycles, specimens were probed with a biotin-labeled HPV L1 consensus probe mixture. A separate membrane was probed with biotin-labeled probes for the human -globin gene. We performed type-specific probing for the following HPV types individually: 6; 11; 16; 18; 26; 31; 32; 33; 35; 39; 40; 45; 51; 52; 53; 54; 55; 56; 58; 59; 61; 66; 68; 69; 70; 73; Pap 155; Pap 291; AE2; and a mix containing 2, 13, 34, 42, 57, 62, 64, 67, 72, and W13B. We designated samples that were positive with the consensus probes but negative with the individual type-specific probes as having one or more other types. Polymerase chain reaction can be used to discriminate between low-level HPV infection and high-level HPV infection on the basis of intensity of the PCR signal on Southern blot analysis (23), which was recorded on a scale from 0 (negative) to 5. For the purpose of the analysis, a sample that was positive for more than one HPV high-risk types was categorized as the higher PCR signal from the sample. CD4+ Cell Count and Plasma HIV RNA Viral Load We used the CD4+ cell counts and plasma HIV RNA viral loads closest to the period within 2 months of the anal examination. The nadir CD4+ cell count was defined as the lowest count recorded before the study. Absolute numbers of CD4+ T cells were determined by standard flow cytometry. Plasma HIV RNA levels were determined by the branched-chain DNA signal amplification assay (Quantiplex HIV-RNA, Chiron Diagnostics Corp., Emeryville, California). Statistical Analysis We analyzed data by using StatView 5 software (SAS Institute, Inc., Cary, North Carolina). Because most variables had skewed distribution, data are presented as median and ranges. Differences across HIV risk groups were tested with the Fisher exact test (categorical variables) and the nonparametric Mann-Whitney U test (continuous variables). Patients with HPV infection and histologic or cytologic abnormalities were compared with patients with no evidence of HPV infection or anal disease. To identify risk factors for histologic or cytologic abnormalities, the following dichotomous variables were entered into a logistic regression model: age (<35 vs. 35 years), age at first intercourse (<16 vs. 16 years), number of lifetime sexual partners (<40 vs. 40), number of receptive anal intercourse episodes (<10 vs. 10), current smoking, history of anogenital warts, history of sexually transmitted disease (including anogenital herpes, gonorrhea, and syphilis), CD4+ cell count less than 250 106 cells/L, nadir CD4+ cell count less than 100 106 cells/L, plasma HIV RNA viral load greater than 1.7 log copies/mL, previous AIDS-defining event, current antiretroviral treatment, current protease inhibitor tr

Early regression of cervical lesions in HIV-seropositive women receiving highly active antiretroviral therapy

Objective:Advanced HIV disease is associated with a high prevalence of cervical squamous intra-epithelial lesions (SIL) and of infection with oncogenic human papillomavirus (HPV) genotypes. Triple-combination antiretroviral therapy results in decreased plasma HIV viral load, increased CD4 cell counts and partial restoration of immune functions in patients with severe HIV disease. This study investigated the outcome of SIL in HIV-seropositive women undergoing triple combination antiretroviral treatment. Methods:Forty-nine women who started triple-combination antiretroviral therapy, including a protease inhibitor, were examined prior to and after a median 5-month treatment. We collected cytological, colposcopic and histologic data and assessed the presence of HPV DNA in cervical smears by PCR and Southern blot hybridization (SBH). Results:The prevalence of SIL decreased from 69 to 53% during follow-up (P < 0.0001). Among 13 women who initially presented with high-grade SIL, conversion to lower grade was observed in two women and a full regression to normality was observed in one. Cytology also returned to normality in nine out of 21 women who initially presented with low-grade SIL. The high prevalence of HPV infection as detected by SBH and PCR was similar at the first and second examinations and the same high-risk viral genotypes were identified at both examinations in all infected patients but one. There was a higher increase in absolute CD4 cells in the subgroup of patients whose lesions regressed (99 versus 50 × 106/l, P = 0.03). Conclusion:Our observations demonstrate that active antiretroviral therapy may result in a reduced prevalence of cervical squamous intra-epithelial lesions despite the absence of clearance of HPV infection.

Comprehensive control of human papillomavirus infections and related diseases.

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph Comprehensive Control of HPV Infections and Related Diseases Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy.

Background The impact of highly active antiretroviral therapy (HAART) on the natural history of HPV infection and anal squamous intraepithelial lesions (SIL) in HIV-infected men who have sex with men (MSM) is poorly documented. Goal The goal of this study was to evaluate the prevalence of anal HPV infection and SIL inpatients under HAART. Study Design Forty-five HIV-infected protease inhibitor-experienced MSM were enrolled in a cross-sectional study. Each patient provided anal samples for anal cytology, histology, and human papillomavirus (HPV) DNA testing. Results The patients had previously received HAART for a median of 32 months. Anal cytology was abnormal in 32 of 45 (71%) patients, including high-grade SIL in 10 patients (22%), low-grade SIL in 19 patients (42%), and atypical squamous cells of undetermined significance in 3 patients (7%). HPV DNA was detected 36/45 men (80%). The prevalence of anal SIL and HPV infection were similar in patients exhibiting a significant increase in CD4+ cell count after HAART initiation compared with those who did not. Conclusion Our results demonstrate a high prevalence of anal SIL, including high-grade SIL, and anal HPV infection in HIV-infected MSM despite immune restoration under HAART.

Increased risk of cervical disease among human immunodeficiency virus–infected women with severe immunosuppression and high human papillomavirus load

Objective To investigate human papillomavirus (HPV) genotypes, HPV DNA load, and behavioral and sociodemographic factors in a series of human immunodeficiency virus (HIV)-seropositive women, and to correlate HPV infection with cervical disease according to immune status. Methods Three hundred seven HIV-seropositive women were tested for the presence of HPV DNA by polymerase chain reaction (PCR) and Southern blot hybridization. Cervical disease was assessed using Papanicolaou smears, colposcopy, and biopsies when necessary. Various risk factors for cervical intraepithelial neoplasia (CIN) were tested using multiple logistic regression analysis. Results Cervical disease was diagnosed in 83 (27.0%) of 307 women and HPV infection in 162 (52.8%). High HPV load (as detectable by Southern blot hybridization) was found in 90 (55.6%) of the 162 infected women. Potentially oncogenic or related genotypes were detected in 74 (82.2%) of these 90 cases. High-load HPV infection was twice as frequent in severely immunosuppressed women (CD4 cell count less than 200/μL) as in women with higher CD4 cell counts (P = .002). High-load HPV infection was associated with a high risk of cervical disease (adjusted odds ratio [OR] 16.8; 95% confidence interval [CI] 7.0, 40.3). The risk among severely immunosuppressed women was ten times greater than that among women with CD4 cell counts of at least 200/μL. Low-load HPV infection (detected by PCR only) was a risk factor for CIN in severely immunosuppressed women only (adjusted OR 7.4; 95% CI 1.3, 43.0). Conclusion Immunosuppression favors cervical high-load HPV infection with oncogenic genotypes and its clinical expression in HIV-seropositive women.

Human Papillomavirus, Human Immunodeficiency Virus and Immunosuppression

The vast majority of women infected with human immunodeficiency virus (HIV) will be co-infected with human papillomavirus (HPV). The interaction between the two sexually transmitted infections appears to be related to the alteration in cell-mediated immunity in HIV infected persons, increased susceptibility, and possibly reactivation of latent HPV infection. Linkage studies of HIV/AIDs and Cancer registries have indicated a 2- to 22-fold increase in cervical cancer in HIV-positive women compared to HIV-negative women. Data on the prevalence of HPV types in invasive cervical carcinoma (ICC) suggest that the proportion of infection with types HPV16/18 (responsible for over 70% of all cervical cancers) is similar in HIV-negative and HIV-positive women. The biological interaction between HIV and HPV needs further elucidation, although there is some evidence that the presence of HPV infection may be associated with increased HIV transmission. Adolescents perinatally infected by HIV are known to have higher rates of HPV infection and also have been shown to seroconvert in response to HPV vaccination with the quadrivalent vaccine, albeit to lower titers than HIV-negative individuals. Anal cancer incidence is greatly increased in HIV-positive individuals, particularly in HIV-positive men who have sex with men. Screening for anal cancer precursors is feasible and effective; however, the impact on reduction of anal cancer remains to be demonstrated. There are ongoing studies on the safety, immunogenicity, and efficacy of current HPV vaccines in HIV-positive individuals and mature data are awaited. Male circumcision may be another approach to prevention of HPV transmission, which also requires further study. This article forms part of a special supplement entitled Comprehensive Control of HPV Infections and Related Diseases Vaccine Volume 30, Supplement 5, 2012.

Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women.

ObjectiveThis study was undertaken to investigate the impact of highly active antiretroviral therapy (HAART) on the regression of cervical intraepithelial neoplasia (CIN) in HIV-infected women. DesignProspective study of 168 HIV-infected women with evidence of CIN until regression to a lower grade or to normality (end-point) or until surgical treatment or last visit. Ninety-six patients received HAART. MethodsWomen were examined every 6 months by Papanicolaou smears, colposcopy, and biopsy if required. The probability of CIN regression was calculated using survival analysis. HAART was entered as a time-dependent covariate according to the date of first prescription. ResultsRegression of CIN was observed in 67 (39.9%) women. The probability of regression at 12 months was significantly higher for high-grade CIN [23.8%; 95% confidence interval (CI), 14.2–33.5] than for low-grade lesions (14.8%; 95% CI, 7.0–22.6) (P = 0.04). The risk of regression of CIN was twice as high in women receiving HAART as compared with women not receiving HAART (relative hazard of regression, 1.93; 95% CI, 1.14–3.29). There was a trend for a larger increase in CD4 cell counts among those women taking HAART and who showed regression as compared with those who did not regress. ConclusionThe positive impact of HAART on CIN regression may be associated with some restoration of specific immune reactivity. This is not sufficient enough, however, to modify the gynecological follow-up of HIV-infected women.

Comparative prevalence, incidence and short-term prognosis of cervical squamous intraepithelial lesions amongst Hiv-positive and Hiv-negative women

Objective: To investigate the impact of HIV infection on the prevalence, incidence and short‐term prognosis of squamous intraepithelial lesions (SIL), in a prospective study with 1‐year follow‐up. Methods: Between 1993 and 1995, 271 HIV‐positive and 171 HIV‐negative women at high risk of HIV infection were recruited, 365 (82.6%) of whom completed the 1‐year follow‐up. The women underwent a Papanicolaou smear test at inclusion and at 6 and 12 months. Human papillomavirus (HPV) was detected at inclusion by Southern blot and PCR. Results: The SIL prevalence ranged from 7.5% for HIV‐negative to 31.3% for HIV‐positive women with CD4 cell counts < 500 × 106/l (P < 0.001). Other factors associated independently and significantly with SIL prevalence were HPV‐16, 18, 33 and related types, HPV‐31, ‐35, ‐39 and related types, lifetime number of partners, younger age, past history of SIL and lack of past cervical screening. The SIL incidence ranged from 4.9% in HIV‐negative women to 27% in HIV‐positive women with CD4 cells < 500 × 106/l (P < 0.001). Progression from low‐ to high‐grade SIL during follow‐up was detected in 38.1% of HIV‐positive women with CD4 cells ≤ 500 × 106/l but in no HIV‐negative nor HIV‐positive women with CD4 cells > 500 × 106/l. HPV‐16, 18, 33 and related types were also associated with higher incidence of SIL and progression from low‐ to high‐grade SIL. Conclusion: HIV‐induced immunodeficiency is associated with high prevalence, incidence and persistence/progression of SIL. A pejorative influence of HIV infection without marked immunodeficiency is less clear. HIV‐positive women with SIL may thus benefit from early treatment when a useful immune response is still present.

Selection of Drug-Resistant Variants in the Female Genital Tract of Human Immunodeficiency Virus Type 1-Infected Women Receiving Antiretroviral Therapy

We investigated human immunodeficiency virus (HIV) type 1 RNA, proviral DNA, and antiretroviral drug-resistant variants in cervicovaginal secretions of HIV-1-infected women receiving antiretroviral therapy. The prevalence of detectable HIV-1 RNA in genital secretions was inversely related to the number of antiretroviral drugs taken by the patients. Proviral DNA was detected in approximately half of all samples of cervicovaginal secretions from HIV-1-infected women, regardless of the presence or absence of HIV-1 RNA in cervicovaginal secretions and of the antiretroviral regimen. In cervicovaginal secretions of most women with persisting genital viral replication, HIV variants exhibiting mutations associated with drug resistance against protease and reverse-transcriptase pol genes were found. Our observations indicate that antiretroviral therapy is not effective in purging the female genital tract of cell-associated provirus and that antiretroviral drugs that penetrate the female genital tract at suboptimal concentrations exert a potent selective pressure on genital HIV variants when local replication of free HIV-1 RNA persists.

Reproductive choice in men and women living with HIV : evidence from a large representative sample of outpatients attending French hospitals (ANRS-EN12-VESPA Study)

Background:In France, the third decade of the HIV epidemic is characterized by a lower age among women who have been recently infected with HIV. This study analysed factors associated with the desire for a child in a sample of heterosexual women and men of reproductive age living with HIV. Methods:Individuals of reproductive age within the VESPA study were included in the analysis. Desire for a child was analysed according to reproductive potential, cultural aspects and HIV-related health condition (CD4 cell count, plasma HIV load and being on treatment). Results:A total of 555 women and 699 men who self-identified as heterosexual and did not report a medical diagnosis of infertility, were included in the analysis. Among them, 33% of the women and 20% of the men stated that they expected to have children in the future. In multivariate analysis, significant predictors of the desire for a child included factors associated with reproductive potential (younger age, already being a parent, regular relationship), the HIV status of the regular partner and ethnicity (African origin). HIV-related health status did not affect reproductive intentions among men and women. Conclusions:For both men and women, reproductive potential, ethnicity and partners HIV status influenced the desire for a child, whereas the persons own clinical condition in relation to HIV had low impact. Reproductive counselling integrated into HIV care should take into account cultural aspects in order to help people living with HIV examine issues of parenthood.