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3.  Cervical Precancer Risk in HIV-Infected Women Who Test Positive for Oncogenic Human Papillomavirus Despite a Normal Pap Test 
Human immunodeficiency virus-infected women with a normal Pap result who nonetheless test positive for human papillomavirus (HPV) type 16 have a high risk of cervical precancer that may warrant immediate colposcopy, whereas those positive for other oncogenic HPV types are at moderate risk.
Background. Determining cervical precancer risk among human immunodeficiency virus (HIV)–infected women who despite a normal Pap test are positive for oncogenic human papillomavirus (oncHPV) types is important for setting screening practices.
Methods. A total of 2791 HIV-infected and 975 HIV-uninfected women in the Women's Interagency HIV Study were followed semiannually with Pap tests and colposcopy. Cumulative risks of cervical intraepithelial neoplasia grade 2 or greater (CIN-2+; threshold used for CIN treatment) and grade 3 or greater (CIN-3+; threshold to set screening practices) were measured in HIV-infected and HIV-uninfected women with normal Pap tests, stratified by baseline HPV results, and also in HIV-infected women with a low-grade squamous intraepithelial lesion (LSIL; benchmark indication for colposcopy).
Results. At baseline, 1021 HIV-infected and 518 HIV-uninfected women had normal Pap tests, of whom 154 (15%) and 27 (5%), respectively, tested oncHPV positive. The 5-year CIN-2+ cumulative risk in the HIV-infected oncHPV-positive women was 22% (95% confidence interval [CI], 9%–34%), 12% (95% CI, 0%–22%), and 14% (95% CI, 2%–25%) among those with CD4 counts <350, 350–499, and ≥500 cells/µL, respectively, whereas it was 10% (95% CI, 0%–21%) in those without HIV. For CIN-3+, the cumulative risk averaged 4% (95% CI, 1%–8%) in HIV-infected oncHPV-positive women, and 10% (95% CI, 0%–23%) among those positive for HPV type 16. In HIV-infected women with LSIL, CIN-3+ risk was 7% (95% CI, 3%–11%). In multivariate analysis, HIV-infected HPV16-positive women had 13-fold (P = .001) greater CIN-3+ risk than oncHPV-negative women (referent), and HIV-infected women with LSIL had 9-fold (P < .0001) greater risk.
Conclusions. HIV-infected women with a normal Pap result who test HPV16 positive have high precancer risk (similar to those with LSIL), possibly warranting immediate colposcopy. Repeat screening in 1 year may be appropriate if non-16 oncHPV is detected.
PMCID: PMC4614409  PMID: 26187020
HIV; human papillomavirus; cervical cancer screening; Pap test
4.  Risk of Cancer among Commercially Insured HIV-Infected Adults on Antiretroviral Therapy 
Journal of Cancer Epidemiology  2016;2016:2138259.
The objective of this study was to explore the cancer incidence rates among HIV-infected persons with commercial insurance who were on antiretroviral therapy and compare them with those rates in the general population. Paid health insurance claims for 63,221 individuals 18 years or older, with at least one claim with a diagnostic code for HIV and at least one filled prescription for an antiretroviral medication between January 1, 2006, and September 30, 2012, were obtained from the LifeLink® Health Plan Claims Database. The expected number of cancer cases in the general population for each gender-age group (<30, 30–39, 40–49, 50–59, and >60 years) was estimated using incidence rates from the Surveillance Epidemiology and End Results (SEER) program. Standardized incidence ratios (SIRs) were estimated using their 95% confidence intervals (CIs). Compared to the general population, incidence rates for HIV-infected adults were elevated (SIR, 95% CI) for Kaposi sarcoma (46.08; 38.74–48.94), non-Hodgkin lymphoma (4.22; 3.63–4.45), Hodgkin lymphoma (9.83; 7.45–10.84), and anal cancer (30.54; 25.62–32.46) and lower for colorectal cancer (0.69; 0.52–0.76), lung cancer (0.70; 0.54, 0.77), and prostate cancer (0.54; 0.45–0.58). Commercially insured, treated HIV-infected adults had elevated rates for infection-related cancers, but not for common non-AIDS defining cancers.
PMCID: PMC5110893  PMID: 27882054
5.  Human Papillomavirus (HPV) Infections and the Importance of HPV Vaccination 
Current epidemiology reports  2015;2(2):101-109.
HPV persistence is necessary for the development of anogenital cancer. Studies show that cervical and anal HPV infections in women and in men who have sex with men are common. Clearance of HPV infection is similarly common; few individuals show persistence unless they are HIV-infected. HIV strongly influences the development of cervical and anal cancer, as well as their pre-malignant counterparts. Women with cervical and vulvar HPV-associated lesions have higher rates of anal cancer than the general population. HPV also plays an important role in pathogenesis of head and neck cancers, particularly oropharyngeal cancer. Two commercially available HPV vaccines have been proven to be safe and efficacious against cervical HPV16/18 infections and associated precancerous lesions; one of these has also been shown to prevent HPV16/18-associated anal lesions. The FDA has also just approved a new nonavalent HPV vaccine. HPV vaccines will play an important role in prevention of HPV-associated cancers.
PMCID: PMC4975546  PMID: 27500080
HPV; HPV vaccination; cervical cancer; anal cancer; HIV; immunosuppression
6.  Screening for Anal Cancer in Women 
Journal of lower genital tract disease  2015;19(3 0 1):S26-S41.
The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV) and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goal was to summarize the literature on anal cancer, HSIL and HPV infection in women, and provide screening recommendations in women.
A group of experts convened by the ASCCP and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL and anal cancer in women.
Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with HIV-infected women and those with a history of lower genital tract neoplasia (LGTN) at highest risk compared with the general population.
While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and have digital anorectal examinations to detect anal cancers. HIV-infected women and women with LGTN, may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL.
PMCID: PMC4479419  PMID: 26103446
Anal cancer; HIV infection; women; lower genital tract neoplasia
7.  Risk factors for anal human papillomavirus infection type 16 among HIV-positive men who have sex with men in San Francisco 
Background and Objective
HIV-positive men who have sex with men (MSM) are at high risk of anal cancer compared with the general population. Human papillomavirus (HPV) infection, particularly HPV 16, is causally associated with anal cancer. However, risk factors for anal HPV 16 infection are poorly understood. We determined the prevalence and risk factors for anal HPV 16 infection in a population of HIV-positive MSM, most of whom were being treated with antiretroviral therapy.
Cross-sectional data from the baseline visit of a 4-year prospective cohort study.
348 HIV-positive MSM were recruited in San Francisco and received a detailed sexual behavior risk-factor questionnaire. An anal swab was used to collect specimens for HPV type-specific DNA testing using L1 HPV DNA PCR. We used log-binomial multivariable models to determine risk factors for anal HPV 16 infection.
92% of HIV-positive MSM had at least one anal HPV type, 80% had at least one oncogenic HPV type and 42% had HPV 16. Non-Hispanic white race and higher level of education were associated with a decreased risk of HPV 16 infection. A higher number of total male partners was associated with HPV 16 (RR: 1.6, 95%CI 1.1–2.4, p=0.01) for 201–1000 partners compared with 1–200. Injection drug use (IDU) was independently associated with anal HPV 16 infection (RR: 1.5, 95%CI 1.2–1.9, p=0.003).
The prevalence of anal HPV infection, including HPV 16, is high in HIV-positive MSM. HIV-positive MSM should be counseled about the risk associated with increased partners and IDU.
PMCID: PMC4921229  PMID: 23614994
Human papillomavirus; HPV; HIV/AIDS; men who have sex with men; MSM; anal cancer
8.  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
9.  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
10.  Geographical Distribution and Risk Association of Human Papillomavirus Genotype 52–Variant Lineages 
The Journal of Infectious Diseases  2014;210(10):1600-1604.
Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%–5.5%; Pcorrected < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name “Asian lineage” be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.
PMCID: PMC4539913  PMID: 24879800
HPV; cervical cancer; phylogeny; oncogenic risk; Asia
11.  Anal human papillomavirus infection is associated with HIV acquisition in men who have sex with men 
AIDS (London, England)  2009;23(9):1135-1142.
Human papillomavirus (HPV) is a common sexually transmitted agent that causes anogenital cancer and precancer lesions that have an inflammatory infiltrate, may be friable and bleed. Our aim was to determine the association between anal HPV infection and HIV acquisition.
A prospective cohort study.
We recruited 1409 HIV-negative men who have sex with men recruited from a community-based setting in Boston, Denver, New York and San Francisco. We used Cox proportional hazards regression modeling and assessed the independent association of HPV infection with the rate of acquisition of HIV infection.
Of 1409 participants contributing 4375 person-years of follow-up, 51 HIV-seroconverted. The median number of HPV types in HPV-infected HIV-seroconverters was 2 (interquartile range 1–3) at the time of HIV seroconversion. After adjustment for sexual activity, substance use, occurrence of other sexually transmitted infections and demographic variables, there was evidence (P░=░0.002) for the effect of infection with at least two HPV types (hazard ratio 3.5, 95% confidence interval 1.2–10.6) in HIV seroconversion.
Anal HPV infection is independently associated with HIV acquisition. Studies that incorporate high-resolution anoscopy to more accurately identify HPV-associated disease are needed to determine the relationship between HPV-associated disease and HIV seroconversion.
PMCID: PMC4577294  PMID: 19390418
epidemiology; HIV incidence; human papillomavirus; men; risk factors
12.  Incidence of and risk factors for type-specific anal human papillomavirus infection among HIV-positive MSM 
AIDS (London, England)  2014;28(9):1341-1349.
HIV-positive MSM are at increased risk of anal human papillomavirus (HPV) infection compared with men in the general population, and little is known about the natural history of anal HPV infection in this population. The objective of this study was to determine the incidence of and risk factors for anal type-specific HPV infection.
Prospective cohort study.
HIV-positive MSM were evaluated for anal HPV DNA, lifestyle factors, and sexual risk behaviors every 6 months for at least 2 years.
The overall incidence rate of detectable type-specific anal HPV infection was 21.3 per 100 person-years [95% confidence interval (CI) 17.7–25.4] and was 13.3/100 person-years (10.5–16.6) for oncogenic HPV types. The most common incident infections were HPV 18 (3.7/100 person-years) and HPV 16 (3.5/100 person-years). An increased number of recent partners with whom the participant was the receptive partner [odds ratio (OR) 2.9 (1.6–5.1) 8+ partners vs. 0–1], an increased number of new partners in which the participant was the receptive partner [OR 1.03 (1.01–1.1) per partner], an increased number of new oral–anal contact partners in which the participant was the receptive partner [OR 1.1 (1.03–1.1) per partner], and the frequency of receptive anal intercourse [OR 1.1 (1.03–1.1) per act] all significantly increased the odds of incident HPV infection (P ≤ 0.05).
HIV-positive MSM have a high incidence of oncogenic anal HPV infection. Recent receptive anal sexual behaviors, including receptive anal intercourse and receptive oral–anal contact, are the most important risk factors for incident anal HPV infection.
PMCID: PMC4551512  PMID: 24959962
anus; HIV; HPV; human papillomavirus; incidence; men who have sex with men; receptive anal intercourse
13.  Trends in the Occurrence of High-Grade Anal Intraepithelial Neoplasia in San Francisco: 2000–2009 
Cancer  2013;119(19):3539-3545.
Although screening of human immunodeficiency virus (HIV)-positive individuals for anal intraepithelial neoplasia (AIN; a precursor of anal cancer) has been practiced in San Francisco among HIV health care providers since the early 1990s, to the authors’ knowledge no study to date has focused on evaluating recent AIN trends.
Cases of high-grade AIN 3 and invasive anal cancer from 2000 to 2009 were obtained from the San Francisco/Oakland Surveillance, Epidemiology, and End Results (SEER) population-based cancer registry. Age-standardized rates of AIN 3 and anal cancer were calculated overall and by demographic characteristics (sex, race, and age group). Log-linear regression calculated annual percent change in rates during 2000 to 2009, and rate ratios (RRs) and 95% confidence intervals (95% CIs), evaluated differences in rates during 2000 through 2004 and 2005 through 2009.
During 2000 through 2009, the majority of AIN 3 cases occurred among men (1152 of 1320 men; 87.3%). Rates of AIN 3 during the corresponding period increased by 11.48% per year (P <.05) among men and were stable among women. Comparing rates among men during 2000 to 2004 with those during 2005 to 2009, the largest increases were noted among those aged 50 years to 64 years (RR, 2.47; 95% CI, 1.93–3.17) and among black individuals (RR, 3.49; 95% CI, 2.14–5.85). During the same period, anal cancer rates were stable among men and women.
Rates of AIN 3 increased in San Francisco during 2000 through 2009, in conjunction with an anal cytology screening program for high-risk groups, whereas rates of invasive anal cancer were unchanged. Continued surveillance is necessary to evaluate the impact of screening and human papillomavirus vaccination on the prevention of human papillomavirus-related AIN and anal cancer.
PMCID: PMC4535426  PMID: 23861091
anal cancer; anal intraepithelial neoplasia; incidence; screening
14.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
15.  Immunogenicity and Safety of the Quadrivalent Human Papillomavirus Vaccine in HIV-1–Infected Women 
This multicenter prospective trial among HIV-1–infected women aged 13–45 years found that the quadrivalent human papillomavirus vaccine was highly immunogenic, but women with CD4 counts <200 cells/µL had lower seroconversion rates compared with women with higher CD4 cell counts.
Background. Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)–related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201–350 (stratum B), and ≤200 cells/µL (stratum C).
Methods. Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline.
Results. Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/µL, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C.
Conclusions. The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13–45 years. Women with HIV RNA load >10 000 copies/mL and/or CD4 count <200 cells/µL had lower rates of seroconversion rates.
Clinical Trials Registration. NCT00604175.
PMCID: PMC4305143  PMID: 24723284
HPV vaccine; HIV-infected women; immunogenicity; vaccine safety; anogenital disease
16.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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