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1.  Efficacy of trichloroacetic acid in the treatment of anal intraepithelial neoplasia in HIV-positive and HIV-negative men who have sex with men 
Anal intraepithelial neoplasia (AIN), particularly AIN 3 is a precursor to anal cancer. Most cases of AIN are intra-anal, but few treatments for intra-anal AIN are currently available. Topical 85% trichloroacetic acid (TCA) is an inexpensive method used to treat peri-anal condyloma, a form of AIN 1, but its efficacy to treat intra-anal AIN as first-line therapy is unknown.
Retrospective review of medical records was performed for all patients with AIN treated at the University of California San Francisco (UCSF) Anal Neoplasia Clinic with TCA as the first-line therapy from January 2000 to December 2004. Clearance was defined as the absence of AIN confirmed by high resolution anoscopy and cytology after up to four TCA treatments.
Thirty-five HIV-positive and 19 HIV-negative men met the enrollment criteria. In multivariate analysis, greater clearance was seen in patients 41–48 years of age versus >49 years (OR: 8.4, CI: 1.1– 94, p-value: 0.04). Among HIV-positive men, those with two or fewer lesions showed greater clearance (OR: 14.3, CI: 1.5–662, p-value: 0.01). 32% of patients with AIN 2/3 cleared to no lesions. On a per-lesion basis, 73% of AIN 1 and 71% AIN 2/3 cleared to no lesion or AIN 1 or less, respectively.
Topical 85% TCA was safe and well tolerated. It was more effective in younger patients and among HIV-positive patients, those with 2 or fewer lesions. A high proportion of AIN 2/3 lesions responded to TCA treatment.
PMCID: PMC2871540  PMID: 19779306
Trichloroacetic acid; anal intraepithelial neoplasia; HIV, anal cancer, therapy
2.  Prevalence and Risk Factors for Neutralizing Antibodies to Human Papillomavirus Types 16 and 18 in HIV-positive Men who have Sex with Men 
HPV vaccination is routinely recommended in HIV-positive MSM ≤ 26 years old. Levels of prior HPV exposure in older HIV-positive MSM are assumed to be too high to warrant routine HPV vaccination. However, little is known about the prevalence of and risk factors for neutralizing antibody seropositivity to HPV-16 or HPV-18, a key measure of prior exposure to these types.
Cross-sectional analysis of baseline visit for 296 HIV-positive MSM participating in a prospective cohort study of anal squamous intraepithelial lesions (ASIL) at a university-based research clinic. Participants completed a questionnaire detailing behaviors and medical history. Phlebotomy, anal cytology, HPV DNA testing with quantitation, and high resolution anoscopy with biopsy were performed. A pseudovirion-based neutralizing antibody (PBNA) assay was used to measure HPV-16 and HPV-18 neutralizing antibodies.
132/296 (45%) men were HPV-16-seropositive and 141/296 (48%) were HPV-18-seropositive. 175/296 (59%) of the men were positive for HPV-16 antibodies or DNA, and 167/296 (56%) were positive for HPV-18 antibodies or DNA. In multivariable analysis, HPV-16 seropositivity did not correlate with age, years of HIV positivity, CD4+ level or HIV viral load. Significant risk factors included HPV-16 DNA positivity with higher DNA levels (ptrend<.001) and higher number of receptive sexual partners in the last year (ptrend=.012).
A high proportion of HIV-positive MSM >26 years are DNA-negative and seronegative to HPV-16 and HPV-18 even when using a sensitive PBNA assay. Prospective studies are needed to determine the clinical- and cost-effectiveness of HPV vaccination in HIV-positive MSM > 26 years old.
PMCID: PMC4287402  PMID: 24231786
Human papillomavirus; pseudovirions; neutralizing antibodies; HIV; MSM
3.  High grade anal intraepithelial neoplasia among HIV-1-infected men screening for a multi-center clinical trial of a human papillomavirus vaccine 
HIV clinical trials  2013;14(2):75-79.
High-grade anal intraepithelial neoplasia (HGAIN) is the precursor lesion to invasive anal cancer. HPV vaccination holds great promise for preventing anal cancer.
We examined 235 HIV-1-infected men screening for participation in a multi-site clinical trial of a quadrivalent HPV vaccine. All participants had anal swabs obtained for HPV testing and cytology, and high resolution anoscopy with biopsies of visible lesions to assess for HGAIN.
HPV 16 and 18 were detected in 23% and 10%, respectively; abnormal anal cytology was found in 56% and HGAIN in 30%. HGAIN prevalence was significantly higher in those with HPV 16 detection compared to those without (38% vs. 17%, P=.01). Use of antiretroviral therapy, nadir and current CD4+ cell count were not associated with abnormal anal cytology or HGAIN.
HGAIN is highly prevalent in HIV-infected men. Further studies are needed on treatment and prevention of HGAIN.
PMCID: PMC3676177  PMID: 23611828
human papillomavirus; HIV-1 infection; male; anal intraepithelial neoplasia; anal infection
4.  HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus 
Virology  2013;446(0):10.1016/j.virol.2013.08.018.
The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral and anal epithelial cells and tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration into the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.
PMCID: PMC3809142  PMID: 24074602
5.  Cervical human papillomavirus infection in a sample of Hispanic women living in Puerto Rico: Comparison with cervical cytology reports 
Persistent infection with high-risk (HR) HPV is a necessary risk factor for the development of cervical cancer. Information on HPV infection is limited in Puerto Rico. This study determined the distribution of HPV types and the association of HR-HPV types with cervical pathology in a clinic-based sample of women in PR.
Data from 92 female participants aged 18 to 34 years and recruited from the University of Puerto Rico-Gynecology Clinic, were analyzed. Cervical cytology was performed. HPV testing was performed using L1 consensus primer PCR with MY09/MY11 primers and typed by dot-blot hybridization. Logistic regression modeling was used to determine the crude and covariate adjusted association between HR-HPV and cervical pathology.
Twenty percent (n=18) of the patients had abnormal cytology, 45.7% (n=42) were HPV positive, and 30.4% (n=28) were HR HPV-positive. Women infected with HR-risk HPV types were 7.9 (95% CI = 2.5–25.5) times likely to have abnormal cytology as compared to women without HR infection when adjusted by age and age at first sexual intercourse.
The burden of HPV infection was high, and, as expected, HR HPVs were strongly associated with dysplasia. A population-based study is needed to estimate HPV prevalence and its association with related malignancies in our population. This will be of great value in determining disease burden and will increase awareness of the HPV vaccination in our population.
PMCID: PMC4162397  PMID: 23556259
Cervical cancer; Prevention; Screening; Self-sampling
6.  HPV Infection in Men 
Disease Markers  2007;23(4):261-272.
While much is known about the natural history of cervical human papillomavirus (HPV) infection and its consequences, including cervical intraepithelial neoplasia and cervical cancer, relatively little is known about the natural history of anogenital HPV infection and diseases in men. In part this reflects difficulties in penile sampling and visual assessment of penile lesions. Anal HPV infection and disease also remain poorly understood. Although HPV is transmitted sexually and infects the genitals of both sexes, the cervix remains biologically more vulnerable to malignant transformation than does the penis or anus in men. An understanding of male HPV infection is therefore important in terms of reducing transmission of HPV to women and improving women's health. However, it is also important due to the burden of disease in men, who may develop both penile and anal cancer, particularly among HIV-positive men who have sex with men. Improved sampling techniques of the male genitalia and cohort studies in progress should provide important information on the natural history of anogenital HPV infection and disease in men, including risk factors for HPV acquisition and transmission. The impact of HPV vaccination in women on male anogenital HPV infection will also need to be assessed.
PMCID: PMC3851123  PMID: 17627061
Penile HPV infection; anal HPV infection; penile intraepithelial neoplasia; anal intraepithelial neoplasia; penile cancer; anal cancer; condyloma; HIV
7.  Anal human papillomavirus infection among Thai men who have sex with men with and without HIV infection: prevalence, incidence, and persistence 
HIV-positive men who have sex with men (MSM) have a higher prevalence of anal human papillomavirus (HPV) infection and anal cancer incidence than HIV-negative MSM. High-risk HPV persistence is an important risk factor for the development of anal cancer.
A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled from the Thai Red Cross AIDS Research Centre in Bangkok, Thailand, and followed for 12 months. Anal sample collection for HPV genotyping was performed at every visit. HPV prevalence, incidence, clearance and persistence were calculated. A logistic regression model was used to study factors associated with high-risk HPV persistence.
The prevalence of any anal HPV infection was 85% in HIV-positive and 58.5% in HIV-negative MSM (p<0.0001). The prevalence of high-risk HPV infection was 57.5% in HIV-positive and 36.6% in HIV-negative MSM (p=0.001). HPV 16 was the most common high-risk HPV type. HIV-positive MSM had a higher prevalence (22.5% vs. 9.8%, p=0.008) and persistence (16.7% vs. 1.3%, p<0.001) of HPV 16 than HIV-negative MSM, and a trend for higher incidence (16.1 vs. 6.1 episodes/1000 person-months, incidence rate ratio 2.6, p=0.058). HIV infection (OR 4.45, 95% CI 2.11–9.4, p<0.001) and smoking in HIV-positive MSM (OR 2.3, 95% CI 1.17–4.5, p=0.015) were independently associated with high-risk HPV persistence in multivariate models.
In addition to targeting HIV-positive MSM who are at higher risk for anal high-risk HPV persistence, anal cancer prevention programs should also integrate behavioral interventions such as smoking cessation to modify risk for high-risk HPV persistence.
PMCID: PMC3700660  PMID: 23514956
anal; human papillomavirus; persistence; MSM; HIV
8.  High prevalence and incidence of high-grade anal intraepithelial neoplasia among young Thai men who have sex with men with and without HIV 
AIDS (London, England)  2013;27(11):1753-1762.
Men who have sex with men (MSM) are at elevated risk of having anal cancer. However, the prevalence and incidence among MSM of high-grade anal intraepithelial neoplasia (HGAIN), the putative precursor of anal cancer, is understudied, particularly in Asians.
A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand, and followed for 12 months. Anal sample collection for human papillomavirus (HPV) genotyping and high-resolution anoscopy (HRA) with biopsies were performed at every visit.
Mean age at enrollment was 28.9 years. HIV-positive MSM were more commonly infected with high-risk HPV types in the anus than HIV-negative MSM (57.5% vs. 36.6%, p=0.001). The prevalence of HGAIN was 18.9% in HIV-positive and 11.4% in HIV-negative MSM (p=0.1). The incidence of HGAIN at 12 months was 29% in HIV-positive and 8% in HIV-negative MSM (p=0.001). The hazard ratios for incident HGAIN in multivariate models were 5.16 (95% CI 1.89–14.08, p<0.001) in MSM with persistent HPV 16 and/or 18 infection and 2.62 (95% CI 1.04–6.61, p=0.042) in HIV-positive MSM.
Approximately one-third of HIV-positive MSM developed incident HGAIN within 12 months. Given the relative increased prevalence of HIV among MSM worldwide, local HGAIN data are needed to guide practitioners, policy makers, and communities in planning for strategies to screen for and treat HGAIN in this population.
PMCID: PMC3706028  PMID: 23807271
high-grade anal intraepithelial neoplasia; human papillomavirus; men who have sex with men; HIV
9.  Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women 
AIDS (London, England)  2013;27(11):1743-1751.
To assess factors associated with concomitant anal and cervical human papillomavirus (HPV) infections in HIV-infected and at-risk women.
A study nested within the Women’s Interagency HIV Study (WIHS), a multi-center longitudinal study of HIV-1 infection in women conducted in six centers within the United States.
Four hundred and seventy HIV-infected and 185 HIV-uninfected WIHS participants were interviewed and examined with anal and cervical cytology testing. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV testing. Women with abnormal cytologic results had colposcopy or anoscopy-guided biopsy of visible lesions. Logistic regression analyses were performed and odds ratios (ORs) measured the association for concomitant anal and cervical HPV infection.
One hundred and sixty-three (42%) HIV-infected women had detectable anal and cervical HPV infection compared with 12 (8%) of the HIV-uninfected women (P <0.001). HIV-infected women were more likely to have the same human papillomavirus (HPV) genotype in the anus and cervix than HIV-uninfected women (18 vs. 3%, P <0.001). This was true for both oncogenic (9 vs. 2%, P = 0.003) and nononcogenic (12 vs. 1%, P <0.001) HPV types. In multivariable analysis, the strongest factor associated with both oncogenic and nononcogenic concomitant HPV infection was being HIV-infected (OR = 4.6 and OR = 16.9, respectively). In multivariable analysis of HIV-infected women, CD4+ cell count of less than 200 was the strongest factor associated with concomitant oncogenic (OR = 4.2) and nononcogenic (OR = 16.5) HPV infection.
HIV-infected women, particularly those women with low CD4+ cell counts, may be good candidates for HPV screening and monitoring for both cervical and anal disease
PMCID: PMC3917497  PMID: 23803793
anal intraepithelial neoplasia; cervical intraepithelial neoplasia; HIV-infection; human papillomavirus; women
10.  Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations 
Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.
PMCID: PMC3962828  PMID: 23136059
HPV; variant; cervical cancer; phylogeny; oncogenic risk
12.  Safety and Immunogenicity of the Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Men 
The Journal of infectious diseases  2010;202(8):1246-1253.
HIV-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types.
AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multi-center clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, 18) vaccine in HIV-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and 24. The primary endpoints were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination.
There were no Grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least one vaccine dose. Seroconversion was observed for all 4 types: type 6 (59/60, 98%), type 11 (67/68, 99%), type 16 (62/62, 100%), type 18 (74/78, 95%). No adverse effects on CD4 counts and plasma HIV-1 RNA were observed.
The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-infected men. Efficacy studies in HIV-infected men are warranted.
PMCID: PMC3118428  PMID: 20812850
human papillomavirus; HIV-1 infection; male; vaccine; anal infection
13.  Acceptability of Cervical and Anal HPV Self-sampling in a Sample of Hispanic Women in Puerto Rico 
Self-sampling techniques have been shown to be reliable in determining human papillomavirus (HPV) infection, although the acceptability of this method of sampling has not been studied in Puerto Rico (PR). The objective of this study was to determine the acceptability of cervicovaginal and anal self-sampling for HPV DNA testing among women in PR. One hundred women aged 18–34 years old and undergoing routine Pap smears in an OBGYN clinic in PR were recruited. Interviewer-administered and computer-based questionnaires were used to collect information on relevant risk factors. To assess acceptability, four-item acceptability Likert scales were used that measured comfort, pain, privacy, and embarrassment. Overall acceptability indexes were calculated as the sum of the Likert scores. Clinician-collected and self-collected cervicovaginal and anal samples for HPV-DNA testing were obtained from the participating women. Although the acceptability of both sampling methods was high, it was higher for self- rather than clinician-sampling of the cervix (difference in mean score = −0.71, p<0.05); contrarily, it was higher for clinician-sampling of the anus (difference in mean score = 0.64). When analyzing individual items within the scale, less embarrassment was observed with respect to the self-collection of cervical and anal samples. Nevertheless, most women reported that they preferred having a clinician collect cervical and anal samples (67% and 61%, respectively); and most of these women (86% for cervical samples and 92% for anal samples) felt more confident that this sample would be properly taken. Despite this, in this population, the high level of acceptability with regard to self-collected samples and the previously documented concordance between self- and clinician-collected samples support the use of cervical and anal HPV DNA self-sampling techniques in future HPV-related population-based studies and screening programs in PR.
PMCID: PMC3954748  PMID: 23844468
acceptability; cervix; anus; self-sampling; HPV
14.  Safety and efficacy of topical Cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women 
AIDS (London, England)  2013;27(4):545-551.
To evaluate the safety and efficacy of topical cidofovir for treatment of high-grade squamous perianal and vulvar intraepithelial neoplasia (PAIN and VIN) lesions in HIV-positive individuals.
Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium (AMC)
HIV-positive patients with biopsy-proven high-grade PAIN that was ≥ 3 cm2 were enrolled. PAIN biopsy specimens were assessed for HPV using PCR and type-specific HPV probing. Subjects applied 1% topical cidofovir to PAIN and VIN (if present) for 6 two-week cycles. Results were designated as complete response (CR), partial response (PR) (> 50% reduction in size), stable disease (SD), or progressive disease (PD).
Twenty-four men and 9 women (8 with high-grade VIN as well) were enrolled. Mean age was 44 years, mean CD4+ count was 412 cells/μl. HPV DNA (most commonly HPV16) was detected in all pre-treatment study specimens. Twenty six (79%) subjects completed treatment per protocol—CR: 5 (15%); PR: 12 (36%), SD: 7 (21%); PD: 2 (6%) (1 with a superficially invasive cancer and 1 with new area of high-grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/burning/irritation (25 subjects) and ulceration (13 subjects).
Topical cidofovir had 51% efficacy in the short-term treatment of high-grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed.
PMCID: PMC3759510  PMID: 23032420
Perianal intraepithelial neoplasia; Vulvar intraepithelial neoplasia; cidofovir; HIV; HPV; Bowen’s disease
15.  Epidemiology of Anal HPV Infection in High-Risk Men Attending a Sexually Transmitted Infection Clinic in Puerto Rico 
PLoS ONE  2014;9(1):e83209.
Recent studies in Puerto Rico have reported an increasing incidence of anal cancer in Puerto Rican men. The objective of this study was to determine the prevalence, genotype distribution and risk factors associated with anal HPV infection among men attending an STI clinic in Puerto Rico.
We conducted a cross-sectional study among 205 men 18 years and older. A comprehensive survey was administered that included a demographic and a behavioral assessment. Separate logistic regression models were performed to determine factors associated with any, high-risk (HR), and multiple anal HPV infection.
The mean age of the study sample was 38.0±13.5 years. The most common HR types were 58, 51 and 31. Overall, HR anal HPV infection was found in 53.5% of the participants. Multiple HPV types in the anal canal were found in 47.6% of the sample. A third (29.8%) of participants reported being men who had sex with men (MSM). MSM had a significantly higher prevalence of any, HR and multiple HPV infection (p-value<0.05). Separate multivariate logistic regression analyses showed that being MSM was associated with any (OR = 4.5; [95%CI: 1.9–10.7]), HR (OR = 3.4; [95%CI: 1.1–10.3) and multiple anal HPV infection (OR = 3.6; [95%CI: 1.5–9.1). HIV was marginally associated with multiple anal HPV infection in multivariate analysis (OR = 3.3; 95%CI = 1.0–11.0).
Anal HPV is common among sexually active men attending this STI clinic, with higher likelihood of anal HPV infection among MSM.
PMCID: PMC3882217  PMID: 24400071
16.  Epstein-Barr Virus Transcytosis through Polarized Oral Epithelial Cells 
Journal of Virology  2013;87(14):8179-8194.
Although Epstein-Barr virus (EBV) is an orally transmitted virus, viral transmission through the oropharyngeal mucosal epithelium is not well understood. In this study, we investigated how EBV traverses polarized human oral epithelial cells without causing productive infection. We found that EBV may be transcytosed through oral epithelial cells bidirectionally, from both the apical to the basolateral membranes and the basolateral to the apical membranes. Apical to basolateral EBV transcytosis was substantially reduced by amiloride, an inhibitor of macropinocytosis. Electron microscopy showed that virions were surrounded by apical surface protrusions and that virus was present in subapical vesicles. Inactivation of signaling molecules critical for macropinocytosis, including phosphatidylinositol 3-kinases, myosin light-chain kinase, Ras-related C3 botulinum toxin substrate 1, p21-activated kinase 1, ADP-ribosylation factor 6, and cell division control protein 42 homolog, led to significant reduction in EBV apical to basolateral transcytosis. In contrast, basolateral to apical EBV transcytosis was substantially reduced by nystatin, an inhibitor of caveolin-mediated virus entry. Caveolae were detected in the basolateral membranes of polarized human oral epithelial cells, and virions were detected in caveosome-like endosomes. Methyl β-cyclodextrin, an inhibitor of caveola formation, reduced EBV basolateral entry. EBV virions transcytosed in either direction were able to infect B lymphocytes. Together, these data show that EBV transmigrates across oral epithelial cells by (i) apical to basolateral transcytosis, potentially contributing to initial EBV penetration that leads to systemic infection, and (ii) basolateral to apical transcytosis, which may enable EBV secretion into saliva in EBV-infected individuals.
PMCID: PMC3700193  PMID: 23698302
17.  Use of Human Papillomavirus DNA, E6/E7 mRNA, and p16 Immunocytochemistry to Detect and Predict anal High-Grade Squamous Intraepithelial Lesions in HIV-Positive and HIV-Negative Men Who Have Sex with Men 
PLoS ONE  2013;8(11):e78291.
Men who have sex with men (MSM) are at high risk of having anal cancer. Anal high-grade squamous intraepithelial lesion (HSIL) is the precursor of anal cancer. We explored the use of different biomarkers associated with human papillomavirus (HPV) infection and HPV-mediated cell transformation to detect and predict HSIL among HIV-positive and HIV-negative MSM.
Methodology/Principal Findings
A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled and followed for 12 months. High-resolution anoscopy (HRA) with biopsies were performed at every visit along with anal sample collection for cytology, high-risk HPV DNA genotyping, HPV E6/E7 mRNA, and p16 immunocytochemistry. Performance characteristics and area under the receiver operator characteristics curve were calculated for these biomarkers at baseline, and Cox regression compared the usefulness of these biomarkers in predicting incident HSIL. High-risk HPV DNA, E6/E7 mRNA, and p16 immunocytochemistry each identified 43–46% of MSM whose baseline test positivity would trigger HRA referral. E6/E7 mRNA had the highest sensitivity (64.7%) and correctly classified the highest number of prevalent HSIL cases. With the exception of p16 immunochemistry, most tests showed significant increases in sensitivity but decreases specificity versus anal cytology, while the overall number of correctly classified cases was not significantly different. Baseline or persistent type 16 and/or 18 HPV DNA was the only test significantly predicting incident histologic HSIL within 12 months in models adjusted for HIV status and low-grade squamous intraepithelial lesions at baseline.
Countries with a high HIV prevalence among MSM and limited HRA resources may consider using biomarkers to identify individuals at high risk of HSIL. E6/E7 mRNA had the highest sensitivity for prevalent HSIL detection regardless of HIV status, whereas type 16 and/or 18 HPV DNA performed best in predicting development of incident HSIL within 12 months.
PMCID: PMC3827039  PMID: 24265682
18.  Cervicovaginal HPV Infection Before and After Hysterectomy: Evidence of Different Tissue Tropism for Oncogenic and Non-Oncogenic HPV Types in a Cohort of HIV-positive and HIV-negative Women 
Human papillomavirus (HPV) is detected in nearly all cervical cancers and approximately half of vaginal cancers. However, vaginal cancer is an order of magnitude less common than cervical cancer, not only in the general population but also among women with HIV/AIDS. It is interesting therefore that recent studies found that HPV was common in both normal vaginal and cervical tissue, with higher prevalence of non-oncogenic HPV types in the vagina. In the current investigation, we prospectively examined HPV infection in 86 HIV-positive and 17 HIV-negative women who underwent hysterectomy during follow-up in a longitudinal cohort. Cervicovaginal lavage specimens were obtained semi-annually and tested for HPV DNA by PCR. To address possible selection biases associated with having a hysterectomy, subjects acted as their own comparison group – before versus after hysterectomy. The average HPV prevalence was higher in HIV-positive than HIV-negative women both before (59% versus 12%; P<0.001) and after hysterectomy (56% versus 6%; P<0.001). Multivariate random effects models (within-individual comparisons) demonstrated significantly lower HPV prevalence (odds ratio [OR]=0.71; 95% confidence interval [CI]=0.59-0.85) after hysterectomy. The association of HPV prevalence with hysterectomy was similar among HIV-positive and HIV-negative women. However, hysterectomy had greater effects on oncogenic (OR=0.48; 95%CI=0.35-0.66) than non-oncogenic HPV types (OR=0.89; 95%CI=0.71-1.11; Pinteraction=0.002). Overall, we observed greater reductions in oncogenic than non-oncogenic HPV prevalence following hysterectomy. If correct, these data could suggest that oncogenic HPV have greater tropism for cervical compared with vaginal epithelium, consistent with the lower incidence of vaginal than cervical cancer.
PMCID: PMC3321069  PMID: 22120980
vaginal; HPV; hysterectomy; viral tropism; HIV
19.  HPV Awareness and Willingness to HPV Vaccination among High-Risk Men attending an STI Clinic in Puerto Rico 
An HPV vaccine has been approved for men aged 9 to 26 in the US for the prevention of genital warts and anal cancer. The purpose of this study is to describe 1) HPV vaccine awareness, 2) willingness to get the HPV vaccine and 3) perceived susceptibility to HPV-related cancers and genital warts among men 18–26 years old who attend an STI clinic in San Juan, Puerto Rico (PR).
A cross-sectional pilot study consisting of 206 HIV+/HIV− men. For purpose of this analysis, only those participants aged ≤26 years old were included in this analysis (n=46).
None of the study participants had been vaccinated against HPV. Fewer than a third knew about the HPV vaccine (28.3%). However, more than half (76.9%) were willing to be vaccinated against HPV. Information sources about the HPV vaccine included their female sexual partners (13.0%), a female sexual partner who received the vaccine (8.7%) and a male sexual partner (2.2%). Most participants reported that the main reason that would increase their willingness to get vaccinated was if a physician recommend the vaccine (95.7%). Perceived susceptibility was low, particularly for anal and oral cancer.
This pilot study shows poor awareness of the HPV vaccine, although willingness to getting the HPV vaccine was high among those who knew about the vaccine. Future studies should try to evaluate this paradox and study in depth willingness and barriers to vaccination among male sub-groups, such as men who have sex with men (MSM). These studies should also evaluate predictors of uptake of the HPV vaccine among men in this and other STI clinics in PR, in order to develop interventions to increase male vaccination.
PMCID: PMC3711188  PMID: 23844472
HPV Infection; HPV Vaccine; HPV Awareness; Men; Puerto Rico
20.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
PMCID: PMC3556987  PMID: 22820789
21.  Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males 
The New England journal of medicine  2011;364(5):401-411.
Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men.
We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status.
In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001).
Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; number, NCT00090285.)
PMCID: PMC3495065  PMID: 21288094
22.  Differential Transmission of HIV Traversing Fetal Oral/Intestinal Epithelia and Adult Oral Epithelia 
Journal of Virology  2012;86(5):2556-2570.
While human immunodeficiency virus (HIV) transmission through the adult oral route is rare, mother-to-child transmission (MTCT) through the neonatal/infant oral and/or gastrointestinal route is common. To study the mechanisms of cell-free and cell-associated HIV transmission across adult oral and neonatal/infant oral/intestinal epithelia, we established ex vivo organ tissue model systems of adult and fetal origin. Given the similarity of neonatal and fetal oral epithelia with respect to epithelial stratification and density of HIV-susceptible immune cells, we used fetal oral the epithelium as a model for neonatal/infant oral epithelium. We found that cell-free HIV traversed fetal oral and intestinal epithelia and infected HIV-susceptible CD4+ T lymphocytes, Langerhans/dendritic cells, and macrophages. To study the penetration of cell-associated virus into fetal oral and intestinal epithelia, HIV-infected macrophages and lymphocytes were added to the surfaces of fetal oral and intestinal epithelia. HIV-infected macrophages, but not lymphocytes, transmigrated across fetal oral epithelia. HIV-infected macrophages and, to a lesser extent, lymphocytes transmigrated across fetal intestinal epithelia. In contrast to the fetal oral/intestinal epithelia, cell-free HIV transmigration through adult oral epithelia was inefficient and virions did not infect intraepithelial and subepithelial HIV-susceptible cells. In addition, HIV-infected macrophages and lymphocytes did not transmigrate through intact adult oral epithelia. Transmigration of cell-free and cell-associated HIV across the fetal oral/intestinal mucosal epithelium may serve as an initial mechanism for HIV MTCT.
PMCID: PMC3302289  PMID: 22205732
23.  Anal cancer prevention in HIV-positive men and women 
Current opinion in oncology  2009;21(5):433-438.
Purpose of review
The incidence of human papillomavirus (HPV)-associated anal cancer is unacceptably high among HIV-positive men who have sex with men (MSM) and possibly in HIV-positive women. Unlike most other malignancies occurring in the HIV-positive population, anal cancer is potentially preventable, using methods similar to those used to prevent cervical cancer in women. This review discusses the issues around screening to prevent anal cancer.
Recent findings
Recent reports show that the incidence of anal cancer has increased since the introduction of highly active antiretroviral therapy (HAART) in this population and now exceeds the highest incidence of cervical cancer among women reported anywhere in the world.
The high incidence of anal cancer among HIV-positive individuals must not be ignored, since it may be preventable. Given the current evidence and analogy with cervical cancer prevention model, many clinicians believe that identification and treatment of HGAIN to prevent anal cancer are warranted. Where the expertise to do so exists, this is a reasonable approach, particularly if coupled with efforts to optimize further screening and treatment approaches, as well as efforts to document the efficacy of HGAIN treatment to reduce the incidence of anal cancer.
PMCID: PMC3415247  PMID: 19587592
Anal cancer; human papillomavirus; anal intraepithelial neoplasia; cancer prevention; screening; HIV
24.  Immunogenicity of the Quadrivalent Human Papillomavirus (Type 6/11/16/18) Vaccine in Males 16 to 26 Years Old 
Human papillomavirus (HPV) infection can lead to significant disease in males, including anogenital warts, intraepithelial neoplasias, and several types of oral and anogenital cancers. The quadrivalent HPV (type 6/11/16/18) L1 virus-like particle (VLP) vaccine (qHPV vaccine; Gardasil) has recently been demonstrated to prevent persistent infection and associated disease related to vaccine HPV types in males. We report the overall immunogenicity results from a trial of the quadrivalent HPV vaccine in males. Overall, 3,463 heterosexual men and 602 men who had sex with men were enrolled into a randomized, placebo-controlled, double-blind safety, immunogenicity, and efficacy study. Serum samples were collected prior to vaccination at day 1 and at months 7, 24, and 36 postvaccination. Immunogenicity was evaluated with a multiplex, competitive Luminex immunoassay. Almost all subjects (97.4 to 99.2%) seroconverted for vaccine HPV types by month 7. At month 36, 88.9%, 94.0%, 97.9%, and 57.0% of subjects were still seropositive for HPV-6, -11, -16, and -18, respectively. For all vaccine HPV types, black subjects had significantly higher antibody titers at month 7 than did both Caucasian and Asian subjects. An anamnestic antibody response was seen in men seropositive before vaccination. The vaccine was highly immunogenic in males 16 to 23 years of age; responses were comparable to those observed in women. Furthermore, the immune responses were consistent with the established efficacy of the vaccine in the prevention of incident and persistent HPV infection, anogenital warts, and anal intraepithelial neoplasia.
PMCID: PMC3272915  PMID: 22155768
25.  Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults 
Human Vaccines  2011;7(7):768-775.
Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16–26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2 and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs. 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs. 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16–26 years and had a favorable safety profile.
PMCID: PMC3219080  PMID: 21712645
human papillomavirus (HPV); vaccine; safety; male; adult; adolescent

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