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1.  The impact of highly active antiretroviral therapy on prevalence and incidence of cervical human papillomavirus infections in HIV-positive adolescents 
BMC Infectious Diseases  2010;10:295.
Background
The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial.
Methods
HIV-positive and high-risk HIV-negative female adolescents were enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) longitudinal cohort study. At each semi-annual clinical visit, cervical lavage samples were tested for 30 HPV types. Type-specific and carcinogenic risk-specific HPV prevalence and incidence were compared in 373 eligible participants: 146 HIV-negative female adolescents with a median follow-up of 721.5 [IQR: 483-1301] days and 227 HIV-positive female adolescents. Of the 227 HIV-positive participants, a fixed set (n = 100) were examined both before and after HAART initiation; 70 were examined only before HAART initiation; and 57 were examined only after HAART initiation, with overall median follow-up of 271 [IQR: 86.5-473] and 427.25 [IQR: 200-871] days respectively for before and after HAART initiation.
Results
Of the 373 eligible participants, 262 (70%) were infected with at least one type of HPV at baseline, and 78 of the remaining 111 (70%) became infected with at least one type of HPV by the end of the study. Overall, the incidence and prevalence of HPV types 58, 53/66, 68/70, and 31/33/35 were much higher than the established carcinogenic and HPV vaccine types 16 and 18, especially in HIV-positive females both before and after HAART initiation. Baseline prevalence for individual high-risk HPV types ranged, depending on type, from 0.7-10%, 1-17%, and 1-18% in the HIV-negative group, the HIV-positive before HAART initiation group, and the HIV-positive after HAART initiation group, respectively. Likewise, the incidence ranged, depending on HPV type, from 0.64-9.83 cases/100 PY, 3.00-12.80 cases/100 PY, and 1.49-17.05 cases/100 PY in the three groups, respectively. The patterns of each HPV type infection, clearance, and persistence did not differ considerably before or after the introduction of HAART and were clearly independent of CD4+ change within the short post-HAART follow-up period.
Conclusions
HAART did not immediately affect the incidence of type-specific HPV infections within a short-period follow-up; however, future studies are warranted in larger populations to evaluate HAART's impact over longer periods.
doi:10.1186/1471-2334-10-295
PMCID: PMC2965148  PMID: 20946655
2.  Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in Rakai, Uganda 
AIDS (London, England)  2012;26(12):1555-1565.
Objectives
High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men.
Design
HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15–49 who participated in male circumcision trials in Rakai, Uganda.
Methods
Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRR) and clearance risk ratios (adjRR).
Results
HR-HPV incidence was 66.5/100 py in HIV-positive men and 32.9/100 py among HIV-negative men (IRR=2.0, 95%CI 1.7–2.4). Incidence was higher with non-marital status (adjIRR=1.7, 95%CI 1.2–2.5), and decreased with age (adjIRR=0.6, 95%CI 0.4–1.0) and male circumcision (adjIRR=0.7, 95%CI 0.6–0.9). HR-HPV clearance was 114.7/100 py for HIV-positive men and 170.2/100 py for HIV-negative men (RR=0.7, 95%I 0.6–0.8). Clearance in HIV-negative men was increased with circumcision (adjRR=1.5, 95%CI 1.3–1.7), HSV-2 infection (adjRR=1.2, 95%CI 1.0–1.4), and symptoms of urethral discharge (adjRR=1.4, 95%CI 1.1–1.7).
Conclusions
HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and HPV vaccination is critical in sub-Saharan Africa.
doi:10.1097/QAD.0b013e328353b83c
PMCID: PMC3442933  PMID: 22441255
Human papillomavirus (HPV); HIV; male circumcision; Uganda
3.  Clustering patterns of human papillomavirus infections among HIV-positive women in Kenya 
Background
HIV-positive women are at increased risk of human papillomavirus (HPV) infection, and, especially, multiple infections compared to HIV-negative women. Whether certain HPV types have a tendency to cluster in multiple infections beyond or below what would be expected by shared risk factors (e.g., sexual behavior and the degree of immunosuppression) is unclear. We, therefore, investigated clustering patterns of 44 HPV types in HIV-positive women from Kenya.
Findings
HPV status was assessed on cervical scrapings from 498 women using GP5+/6+ PCR and reverse line blot. Logistic regression was used to model type-specific HPV positivity, adjusted for age, specific HPV type prevalence, CD4, combination antiretroviral therapy, and, in the Full Model, individual-level random effects that represent unobservable risk factors common to all HPV types. We found a modest excess of women with co-infections with 2 HPV types (1.12; 95% credible intervals: 1.03-1.21) in the Full Model but no significant associations of individual types. No significant deviations of observed/expected counts were observed for any 2-way combination of HPV types at either the chosen level of significance, p = 0.00005, or at p = 0.01. Findings were substantially similar when women with CIN2/3 were excluded and when they were stratified by use of anti-retroviral therapy or CD4 count.
Conclusions
HPV co-infections occurred at random in the cervix of HIV-positive women as previously found in HIV-negative women. The removal of HPV types through vaccination should not result, therefore, in an increase or decrease in the prevalence of HPV types not targeted by vaccination in immunosuppressed women.
doi:10.1186/1750-9378-8-50
PMCID: PMC3878246  PMID: 24355034
Human papillomavirus; HIV; Prevalence; Women; Multiple infections
4.  Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults 
Introduction
Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.
Methods
This study was nested within the MACS (men) and WIHS (women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope™ mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations (GEE) in this cross-sectional analysis.
Results
Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared to HIV-negative individuals (aOR=2.1, 95%CI=1.6–2.8). Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each p-trend<0.01). In contrast, among HIV-positive individuals lower CD4 T-cell count (p-trend<0.001) and higher number of lifetime sexual partners (p-trend=0.03) were strong risk factors.
Conclusions
Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV.
Impact
Immunosuppression may contribute to increased persistence or progression of oral HPV infection.
doi:10.1158/1055-9965.EPI-11-0734
PMCID: PMC3280125  PMID: 22045700
Oral HPV; HIV; risk factors; Head and Neck/Oral Cancer; Epidemiology; Infections and the etiology of cancer, Diet, Alcohol, Smoking, and other Lifestyle Factors; Biomarkers of Human Exposure to carcinogens and DNA damaging agents; DNA tumor viruses
5.  Evidence for an Epistatic Effect between TP53 R72P and MDM2 T309G SNPs in HIV Infection: A Cross-Sectional Study in Women from South Brazil 
PLoS ONE  2014;9(2):e89489.
Objective
To investigate the associations of TP53 R72P and MDM2 T309G SNPs with HPV infection status, HPV oncogenic risk and HIV infection status.
Design
Cross-sectional study combining two groups (150 HIV-negative and 100 HIV-positive) of women.
Methods
Data was collected using a closed questionnaire. DNA was extracted from cervical samples. HPV infection status was determined by nested-PCR, and HPV oncogenic risk group by Sanger sequencing. Both SNPS were genotyped by PCR-RFLP. Crude and adjusted associations involving each exposure (R72P and T309G SNPs, as well as 13 models of epistasis) and each outcome (HPV status, HPV oncogenic risk group and HIV infection) were assessed using logistic regression.
Results
R72P SNP was protectively associated with HPV status (overdominant model), as well as T309G SNP with HPV oncogenic risk (strongest in the overdominant model). No epistatic model was associated with HPV status, but a dominant (R72P over T309G) protective epistatic effect was observed for HPV oncogenic risk. HIV status was strongly associated (risk factor) with different epistatic models, especially in models based on a visual inspection of the results. Moreover, HIV status was evidenced to be an effect mediator of the associations involving HPV oncogenic risk.
Conclusions
We found evidence for a role of R72P and T309G SNPs in HPV status and HPV oncogenic risk (respectively), and strong associations were found for an epistatic effect in HIV status. Prospective studies in larger samples are warranted to validate our findings, which point to a novel role of these SNPs in HIV infection.
doi:10.1371/journal.pone.0089489
PMCID: PMC3938491  PMID: 24586820
6.  Association of HIV Viral Load and CD4 with HPV Detection and Clearance in HIV Infected Women Initiating HAART 
HIV medicine  2012;13(6):372-378.
Objectives
The extent to which highly active antiretroviral therapy (HAART) affects HPV acquisition and clearance in HIV-infected women is not well-understood. We sought to describe high risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4+ T-cell count (CD4) using novel statistical methods.
Methods
We conducted retrospective analysis of data from completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high risk HPV types from 2003 and 2009 publications were considered.
Results
There was some evidence that VL>400 copies/mL was marginally associated with higher rate of HPV detection (p=0.068, hazard ratio [HR]=4.67), using the older set of high risk HPV types. Such association was not identified using the latest set of HPV types (p=0.343, HR=2.64). CD4>350 cells/mm3 was significantly associated with more rapid HPV clearance with both sets of HPV types (p=0.001, HR=3.93; p=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 in all analyses.
Conclusions
High risk HPV types vary in studies, and they can affect analysis results. Use of HAART to improve CD4 may have an impact in the control of HPV infection, and the decrease in VL to a lesser degree.
doi:10.1111/j.1468-1293.2011.00979.x
PMCID: PMC3500098  PMID: 22257000
HIV; human papillomavirus; HAART; cervical cancer; Markov models
7.  Reduced acquisition and reactivation of human papillomavirus infections among older women treated with cryotherapy: results from a randomized trial in South Africa 
BMC Medicine  2010;8:40.
Background
Treatment of women for high-grade cervical cancer precursors frequently results in clearance of the associated high-risk human papillomavirus (hrHPV) infection but the role of treatment among women without hrHPV is unknown. We investigated whether cervical cryotherapy reduces newly detected hrHPV infections among HIV-positive and HIV-negative women who were hrHPV negative when treated.
Methods
The impact of cryotherapy on newly detected hrHPV infections was examined among 612 women of known HIV serostatus, aged 35 to 65 years, who were negative for hrHPV DNA, and randomized to either undergo cryotherapy (n = 309) or not (n = 303). All women underwent repeat hrHPV DNA testing 6, 12, 24, and 36 months later.
Results
Among 540 HIV-negative women, cryotherapy was associated with a significant reduction in newly detected hrHPV infections. Women in the cryotherapy group were 55% less likely to have newly detected hrHPV than women in the control group (95% CI 0.28 to 0.71). This association was independent of the influence of changes in sexual behaviors following therapy (adjusted hazards ratio (HR) = 0.49, 95% CI 0.29 to 0.81). Among 72 HIV-positive women, similar reductions were not observed (HR = 1.10, 95% CI 0.53 to 2.29).
Conclusions
Cervical cryotherapy significantly reduced newly detected hrHPV infections among HIV-negative, but not HIV-positive women. These results raise intriguing questions about immunological responses and biological mechanisms underlying the apparent prophylactic benefits of cryotherapy.
doi:10.1186/1741-7015-8-40
PMCID: PMC2907297  PMID: 20587028
8.  The Effect of Circumcision of HIV-Infected Men on Human Papillomavirus Infection in Female Partners: Analyses Using Data from a Randomized Trial in Rakai, Uganda 
The Lancet infectious diseases  2011;11(8):604-612.
Background
Male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) in HIV-uninfected men and their female partners. We assessed whether MC of HIV-infected men reduces HR-HPV infection in their female partners.
Methods
Female partners of married HIV-infected men with CD4 counts >350 cells/mL randomized to immediate MC (intervention, n=211) and delayed MC (control, n=171) were evaluated for HR-HPV in vaginal swabs by Roche HPV Linear Array. Prevalence risk and incident rate ratios (PRR and IRR) and 95% confidence intervals (95%CI) of HR-HPV were estimated by Poisson multiple regression using an intention-to-treat analysis. In women with pre-existing HR-HPV, we estimated the risk ratio (RR) of clearance of infection (i.e., loss of detection). The trial was registered with ClinicalTrials.gov, NCT00124878.
Findings
Female characteristics and HPV prevalence were generally similar between arms at enrollment, except the intervention arm women were younger (p=0.04). Female HR-HPV prevalence at enrollment was 67.0% in intervention arm and 61.9% in control arm p=0.33. Two year female retention rates were 75.8% (160/211) in the intervention arm and 77.2% (132/171) in the control arm. Female HR-HPV prevalence at year two was 55.4% in intervention arm and 51.9% in control arm (PRR = 1.07, 95%CI0.86–1.32, p=0.64). HR-HPV incidence over 2 years was 32.0/100py in intervention arm and 30.6/100py in control arm female partners (IRR=1.05, 95%CI 0.77–1.43, p=0.78). There was no difference in female genotype-specific HR-HPV clearance by study arm (RR=0.96, 95%CI 0.83–1.11, p=0.61).
Interpretation
Contrary to findings in HIV-negative men, male circumcision of HIV-infected men did not affect HR-HPV transmission to female partners.
Funding
Bill & Melinda Gates Foundation and National Institutes of Health.
doi:10.1016/S1473-3099(11)70038-X
PMCID: PMC3146628  PMID: 21489882
Male circumcision; transmission; female partners; human papillomavirus (HPV); cervical cancer; HIV; Uganda; sexually transmitted infections
9.  The epidemiology of human papillomavirus infection in HIV-positive and HIV-negative high-risk women in Kigali, Rwanda 
BMC Infectious Diseases  2011;11:333.
Background
The prevalence, incidence and persistence of human papillomavirus (HPV) types in sub-Saharan Africa are not well established. The objectives of the current study are to describe (predictors of) the epidemiology of HPV among high-risk women in Kigali, Rwanda.
Methods
HIV-negative, high-risk women were seen quarterly for one year, and once in Year 2. HIV serostatus, clinical, and behavioral information were assessed at each visit, HPV types at Month 6 and Year 2, and other sexually transmitted infections (STI) at selected visits. HPV prevalence was also assessed in HIV-positive, high-risk women.
Results
Prevalence of any HPV was 47.0% in HIV-negative women (median age 25 years) compared to 72.2% in HIV-positive women (median age 27 years; OR 2.9, 95% CI 1.9-4.6). Among HIV-negative women, cumulative incidence of high-risk (HR)-HPV was 28.0% and persistence 32.0% after a mean period of 16.6 and 16.9 months, respectively. Prior Chlamydia trachomatis and Neisseria gonorrhoeae infection, concurrent low-risk (LR)-HPV infection and incident HSV-2 were associated with HR-HPV prevalence among HIV-negative women; prior C. trachomatis infection and co-infection with LR-HPV and HPV16-related HPV types with HR-HPV acquisition. HPV16-related types were the most prevalent and persistent.
Conclusions
High HPV prevalence, incidence and persistence were found among high-risk women in Kigali. HPV52 had the highest incidence; and, together with HPV33 and HPV58, were strongly associated with acquisition of other HR-HPV types in HIV-negative women.
doi:10.1186/1471-2334-11-333
PMCID: PMC3247865  PMID: 22136570
10.  Factors Affecting the Prevalence of Strongly and Weakly Carcinogenic and Lower-Risk Human Papillomaviruses in Anal Specimens in a Cohort of Men Who Have Sex with Men (MSM) 
PLoS ONE  2013;8(11):e79492.
Background
MSM are at higher risk for invasive anal cancer. Twelve human papillomaviruses (HPVs) cause cervical cancer in women (Group 1 high-risk HPVs (hrHPVs)) and 13 HPVs are probable/possible causes (Group 2 hrHPVs) of cervical malignancy. HPVs rarely associated with malignancy are classified as lower-risk HPVs (lrHPVs).
Materials and Methods
Dacron-swab anal-cytology specimens were collected from and data complete for 97% (1262/1296) of Multicenter AIDS Cohort Study (MACS) men tested for HPVs using the Linear Array assay. Multivariate Poisson regression analyses estimated adjusted prevalence ratios for Group 1/2 hrHPVs and lrHPVs, controlling for the effects of age, race, ethnicity, sexual partnerships, smoking; HIV-infection characteristics, treatment, and immune status among HIV-infected men.
Results
HIV-infected men showed 35–90% higher prevalence of Group 1/2 hrHPVs and lrHPVs than HIV-uninfected men, and higher prevalence of multi-Type, and multiple risk-group infections. CD4+ T-cell count was inversely associated with HPV Group 2 prevalence (p<0.0001). The number of receptive anal intercourse (RAI) partners reported in the 24 months preceding HPV testing predicted higher prevalence of Group 1/2 hrHPVs. Men reporting ≥30 lifetime male sex partners before their first MACS visit and men reporting ≥1 RAI partners during the 24 months before HPV testing showed 17–24% and 13–17% higher prevalence of lrHPVs (p-values ≤0.05). Men reporting smoking between MACS visit 1 and 24 months before HPV testing showed 1.2-fold higher prevalence of Group 2 hrHPVs (p = 0.03). Both complete adherence to CART (p = 0.02) and HIV load <50 copies/mL (p = 0.04) were protective for Group 1 hrHPVs among HIV-infected men.
Conclusions
HIV-infected men more often show multi-type and multi-group HPV infections HIV-uninfected men. Long-term mutual monogamy and smoking cessation, generally, and CART-adherence that promotes (HIV) viremia control and prevents immunosuppression, specifically among HIV-infected MSM, are important prevention strategies for HPV infections that are relevant to anal cancer.
doi:10.1371/journal.pone.0079492
PMCID: PMC3835810  PMID: 24278140
11.  High Prevalence of Human Papillomavirus Infections in Urine Samples from Human Immunodeficiency Virus-Infected Men 
Journal of Clinical Microbiology  2005;43(12):5936-5939.
Infection with human immunodeficiency virus (HIV) and the resulting immunosuppression are associated with an increased risk for human papillomavirus (HPV) persistence and related malignancies. In the present study we investigated the prevalence of HPV in urine samples from 104 HIV-infected men with low CD4+ cell counts (<100 per mm3) and 115 urine samples from HIV-negative men. A high prevalence of HPV DNA (39.4%) was found in the HIV patients. Most of the HPV types were high risk (81.4%), with HPV 52 as the most prevalent type (12.5%), followed by HPV 18 (6.7%), HPV 35 (5.8%), and HPV 70 (4.8%). Multiple HPV genotypes were observed in 17 (41%) of the 41 HPV- and HIV-positive men. In contrast, only 11 (9.6%) HPV DNA-positive cases were observed among the 115 HIV-uninfected men, and 3 (27.3%) contained multiple genotypes. Quantitative analyses indicated that the HPV viral load, as measured in urine samples, is significantly higher in HIV-positive men compared to HIV-negative men. In the present study we show that urine samples are useful for detecting HPV DNA, there is a high prevalence of HPV in HIV-positive men, and the HPV viral load is substantially higher in HIV-positive than in HIV-negative men. More studies are needed to evaluate the risk and natural development of HPV-related malignancies in HIV-positive men.
doi:10.1128/JCM.43.12.5936-5939.2005
PMCID: PMC1317195  PMID: 16333078
12.  Determinants of incidence and clearance of high-risk HPV infections in rural Rakai, Uganda 
Background
We used self-administered vaginal swabs to assess the incidence and clearance of carcinogenic HPV infections in rural Rakai, Uganda.
Methods
Women provided self-administered vaginal swab at annual, home-based visits. Type-specific carcinogenic HPV incidence and clearance, and risk-factors were assessed.
Results
Carcinogenic HPV incidence was 17.3/100 person-years (PY) among HIV-positive, compared with 7.0/100 PY among HIV-negative women (p<0.001). HPV-51 had the highest incidence followed by HPV-16 (1.8/100 PY, and 1.5/100 PY, respectively). In multivariate model, HIV-positive women were twice as likely to have incident infection compared to HIV-negatives. Younger women were at higher risk for incident infection, as were women with higher lifetime and recent sexual partners, and high perception of AIDS. Married women were less likely to have incident infection. Approximately half of all carcinogenic HPV infections cleared over the study follow-up of three years. HPV-31, 35, and 16 had the lowest clearance (16.7%, 27.9%, and 38.3%, respectively). In multivariate model, HIV-positives, women over 30, higher HPV viral burden, and more lifetime sex partners were less likely to clear infections.
Conclusions
Self-collected vaginal swabs provide accurate HPV exposure assessment for studying the HPV exposure and epidemiology, and can be an important tool for research in populations unwilling to undergo pelvic exam.
doi:10.1158/1055-9965.EPI-07-2678
PMCID: PMC3158656  PMID: 18559545
HIV; incident; clearance; risk factors; carcinogenic HPV
13.  Oral HPV infection before and after treatment for HPV16-positive and negative head and neck squamous cell carcinoma 
Purpose
Oral human papillomavirus (HPV) infection is a risk factor for head and neck squamous cell carcinoma (HNSCC), and is a concern for patients with HPV-positive HNSCC and their partners. The prevalence of oral HPV infection before and after cancer therapy was investigated among patients with HPV16-positive and -negative HNSCC.
Experimental design
Serial oral rinse samples (ORS) were collected from a cohort of 135 HNSCC cases as frequently as every three months for up to three years. Tumor HPV status was determined by HPV16 in situ hybridization. HPV was detected in ORS by consensus PCR and line-blot hybridization. The HPV16 variants in positive oral rinse-tumor pairs were determined by sequencing. The odds of oral HPV infection among HPV16-positive and -negative cases were compared by use of generalized estimating equations.
Results
Patients were followed for a median of 21 months and provided a median of four samples. Forty-four of 135 patients had HPV16-positive tumors. HPV16-positive cases were more likely than HPV16-negative cases to have an oral HPV infection detected before (OR=8.6, 95%CI=3.5–21) and after therapy (OR=2.9, 95%CI=1.1–7.4). Oral infections by HPV16 and other high-risk, but not low-risk, types were more common among HPV16-positive cases both before and after therapy. Most HPV16 variants in ORS were European, unique, and identical to that in the tumor. Persistence of a type-specific oral infection was demonstrable for as long as five years.
Conclusion
Oral high-risk HPV infections are more frequent among patients with HPV16-positive than HPV16-negative HNSCC, consistent with a behavioral and/or biological disposition to infection.
doi:10.1158/1078-0432.CCR-08-0498
PMCID: PMC2598779  PMID: 18981014
human papillomavirus; oral infection; head and neck cancer
14.  The Impact of HAART on HPV-Related Cervical Disease 
Current HIV research  2010;8(7):493-497.
Purpose of Review
Highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposi’s sarcoma and non-Hodgkin’s lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease.
Relevant Findings
Compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression.
Summary
The incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV-related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices.
PMCID: PMC3108243  PMID: 20946095
HPV; Human papillomavirus; HAART; Cervical dysplasia; Cervical cancer; HIV
15.  Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study 
Lancet  2011;377(9769):932-940.
Summary
Background
Human papillomaviruses (HPVs) cause genital warts and cancers in men. The natural history of HPV infection in men is largely unknown, and that information is needed to inform prevention strategies. The goal in this study was to estimate incidence and clearance of type-specific genital HPV infection in men, and to assess the associated factors.
Methods
Men (aged 18–70 years), residing in Brazil, Mexico, and the USA, who were HIV negative and reported no history of cancer were recruited from the general population, universities, and organised health-care systems. They were assessed every 6 months for a median follow-up of 27·5 months (18·0–31·2). Specimens from the coronal sulcus, glans penis, shaft, and scrotum were obtained for the assessment of the status of HPV genotypes.
Findings
In 1159 men, the incidence of a new genital HPV infection was 38·4 per 1000 person months (95% CI 34·3–43·0). Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners (hazard ratio 2·40, 1·38–4·18, for at least 50 partners vs not more than one partner), and number of male anal-sexual partners (2·57, 1·46–4·49, for at least three male partners vs no recent partners). Median duration of HPV infection was 7·52 months (6·80–8·61) for any HPV and 12·19 months (7·16–18·17) for HPV 16. Clearance of oncogenic HPV infection decreased in men with a high number of lifetime female partners (0·49, 0·31–0·76, for at least 50 female partners vs not more than one partner), and in men in Brazil (0·71, 0·56–0·91) and Mexico (0·73, 0·57–0·94) compared with the USA. Clearance of oncogenic HPV was more rapid with increasing age (1·02, 1·01–1·03).
Interpretation
The data from this study are useful for the development of realistic cost-effectiveness models for male HPV vaccination internationally.
Funding
National Cancer Institute.
doi:10.1016/S0140-6736(10)62342-2
PMCID: PMC3231998  PMID: 21367446
16.  Increased risk of HIV acquisition among Kenyan men with human papillomavirus infection 
The Journal of infectious diseases  2010;201(11):1677-1685.
Background
Few data are available concerning the effect of human papillomavirus (HPV) infection on HIV acquisition.
Methods
HIV-seronegative, sexually active 18-24 year-old Kenyan men within a randomized trial of male circumcision provided penile exfoliated cells from two anatomical sites (glans/coronal sulcus, and shaft) at baseline. The GP5+/6+ PCR assay ascertained a wide range of HPV DNA types at the baseline visit. Risk of HIV infection [95% confidence interval (CI)] was estimated using Kaplan-Meier methods, and hazard ratios (HR)[95% CI] from proportional hazards models.
Results
Among 2,168 uncircumcised men with baseline HPV data, 1,089 (50%) were HPV DNA positive. Cumulative incidence of HIV infection by 42-months was 5.8% [95% CI 3.6, 7.9] in men with HPV-positive glans specimens versus 3.7% [1.8, 5.6] in men with HPV-negative glans specimens (p=0.01). Controlling for subsequent circumcision status, baseline HSV-2 serostatus, and sexual and sociodemographic risk factors, the HR of HIV infection in men with HPV-positive glans specimens was 1.8 [1.1, 2.9] compared to men with HPV-negative glans specimens.
Conclusion
Results suggest an independent, increased risk of HIV seroconversion among HPV positive men. If confirmed in other studies, HPV prevention could be another tool for HIV prevention.
doi:10.1086/652408
PMCID: PMC2873838  PMID: 20415595
Human immunodeficiency virus (HIV); human papillomavirus (HPV); circumcision; Kenya; men; acquisition; risk factors
17.  Prevalence and determinants of human papillomavirus infection and cervical lesions in HIV-positive women in Kenya 
British Journal of Cancer  2012;107(9):1624-1630.
Background:
We assessed the association of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) with various characteristics, CD4 count and use of combination antiretroviral therapy (cART) among HIV-positive women.
Methods:
Cross-sectional study of 498 HIV-positive women who underwent HPV PCR-based testing, cytology, and systematic cervical biopsy.
Results:
In all, 68.7% of women were HPV-positive, 52.6% had high-risk (hr) HPV, and 40.2% multiple type infections. High-risk human papillomavirus-positivity did not vary significantly by age but it was negatively associated with education level. The most frequent types in 113 CIN2/3 were HPV16 (26.5%), HPV35 (19.5%), and HPV58 (12.4%). CD4 count was negatively associated with prevalence of hrHPV (P<0.001) and CIN2/3 among non-users of cART (P=0.013). Combination antiretroviral therapies users (⩾2 year) had lower hrHPV prevalence (prevalence ratio (PR) vs non-users=0.77, 95% confidence interval (CI): 0.61–0.96) and multiple infections (PR=0.68, 95% CI: 0.53–0.88), but not fewer CIN2/3. The positive predictive value of hrHPV-positivity for CIN2/3 increased from 28.9% at age <35 years to 53.3% in ⩾45 years.
Conclusion:
The burden of hrHPV and CIN2/3 was high and it was related to immunosuppression level. Combination antiretroviral therapies ( ⩾2 year) use had a favourable effect on hrHPV prevalence but cART in our population may have been started too late to prevent CIN2/3.
doi:10.1038/bjc.2012.441
PMCID: PMC3493776  PMID: 23033006
HIV; cervical neoplasia; human papillomavirus; combination antiretroviral therapy; Africa
18.  High prevalence of high risk human papillomavirus-capsid antibodies in human immunodeficiency virus-seropositive men: a serological study 
Background
Serological study of human papillomavirus (HPV)-antibodies in order to estimate the HPV-prevalence as risk factor for the development of HPV-associated malignancies in human immunodeficiency virus (HIV)-positive men.
Methods
Sera from 168 HIV-positive men and 330 HIV-negative individuals (including 198 controls) were tested using a direct HPV-ELISA specific to HPV-6, -11, -16, -18, -31 and bovine PV-1 L1-virus-like particles. Serological results were correlated with the presence of HPV-associated lesions, the history of other sexually transmitted diseases (STD) and HIV classification groups.
Results
In HIV-negative men low risk HPV-antibodies were prevailing and associated with condylomatous warts (25.4%). Strikingly, HIV-positive men were more likely to have antibodies to the high-risk HPV types -16, -18, -31, and low risk antibodies were not increased in a comparable range. Even those HIV-positive heterosexual individuals without any HPV-associated lesions exhibited preferentially antibody responses to the oncogenic HPV-types (cumulative 31.1%). The highest antibody detection rate (88,8%) was observed within the subgroup of nine HIV-positive homosexual men with anogenital warts. Three HIV-positive patients had HPV-associated carcinomas, in all of them HPV-16 antibodies were detected. Drug use and mean CD4-cell counts on the day of serologic testing had no influence on HPV-IgG antibody prevalence, as had prior antiretroviral therapy or clinical category of HIV-disease.
Conclusion
High risk HPV-antibodies in HIV-infected and homosexual men suggest a continuous exposure to HPV-proteins throughout the course of their HIV infection, reflecting the known increased risk for anogenital malignancies in these populations. The extensive increase of high risk antibodies (compared to low risk antibodies) in HIV-positive patients cannot be explained by differences in exposure history alone, but suggests defects of the immunological control of oncogenic HPV-types. HPV-serology is economic and can detect past or present HPV-infection, independently of an anatomical region. Therefore HPV-serology could help to better understand the natural history of anogenital HPV-infection in HIV-positive men in the era of antiretroviral therapy.
doi:10.1186/1471-2334-3-6
PMCID: PMC156631  PMID: 12723991
AIDS; human papillomavirus; serology
19.  Male Circumcision Reduces Human Papillomavirus Transmission to HIV-Negative Female Partners: A Randomized Trial in Rakai, Uganda 
Lancet  2011;377(9761):209-218.
Background
Randomized trials show that medical male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in men. We assessed the efficacy of MC to reduce HR-HPV in female partners.
Methods
HIV-negative men were randomized to immediate MC (intervention) or MC delayed for 24 months (control). HIV-uninfected female partners of married men (648 intervention and 597 control arm) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 and 24 months. Female HPV infection was a secondary trial end point. Vaginal swabs were evaluated for HR-HPV by Roche HPV Linear Array. An intention-to-treat analysis estimated prevalence risk and incident rate ratios (PRR and IRR) and 95% confidence intervals (95%CI) of HR-HPV by Poisson multiple regression. In women with pre-existing HR-HPV, we estimated the risk ratio (RR) of cleared infection (i.e., loss of detection). The trials were registered with ClinicalTrials.gov, NCT00425984 and NCT00124878.)
Findings
Female characteristics and HPV prevalence were similar between arms at enrollment. Two year retention rates were 84.7% (549/648) in intervention arm and 84.1% (502/597) in control arm spouses. Year 2 female HR-HPV prevalence was 27.8% (151/544) in the intervention and 38.7% (189/488) in the control arm (PRR=0.72, 95%CI 0.60–0.85, p=0.001). HR-HPV incidence was 20.7/100py in the intervention arm and 26.9/100py in the control arm wives (IRR=0.77, 95%CI 0.63-0.93, p=0.008). HR-HPV incidence was lower in intervention than control arm wives for 13 of 14 (92.9%) HR-HPV genotypes and in most demographic/behavioral subgroups. Genotype specific HR-HPV clearance was higher in the wives of men in the intervention arm (66.2%, 376/568) than the control arm (59.2%, 339/573, RR=1.12, 95%CI 1.02-1.22).
Interpretation
MC reduces the prevalence and incidence and increases clearance of HR-HPV infections in female partners.
Funding
Bill & Melinda Gates Foundation with additional laboratory and training support from National Institutes of Health and Fogarty International Center.
doi:10.1016/S0140-6736(10)61967-8
PMCID: PMC3119044  PMID: 21216000
Male circumcision; transmission; female partners; human papillomavirus (HPV); cervical cancer; HIV; Uganda; sexually transmitted infections
20.  Cervical, Anal and Oral HPV in an Adolescent Inner-City Health Clinic Providing Free Vaccinations 
PLoS ONE  2012;7(5):e37419.
Objectives
Published human papillomavirus (HPV) vaccine trials indicate efficacy is strongest for those naive to the vaccine-types. However, few high-risk young women have been followed and cervical HPV has been the predominant outcome measure.
Methods
We collected cervical and anal swabs, as well as oral rinse specimens from 645 sexually active inner-city young females attending a large adolescent health-clinic in New York City that offers free care and HPV vaccination. Specimens were tested for HPV-DNA using a MY09/MY11-PCR system. Type-specific prevalence of HPV at each anatomic site was compared for individuals by vaccination dose using generalized estimating equation logistic regression models.
Results
The majority of subjects reported being of non-Caucasian (92%) and/or Hispanic ethnicity (61%). Median age was 18 years (range:14–20). All had practiced vaginal sex, a third (33%) practiced anal sex, and most (77%) had also engaged in oral sex. At enrollment, 21% had not received the vaccine and 51% had received three doses. Prevalent HPV infection at enrollment was detected in 54% of cervical, 42% of anal and 20% of oral specimens, with vaccine types present in 7%, 6% and 1% of specimens, respectively. Comparing prevalence for vaccine types, the detection of HPV in the cervix of vaccinated compared to unvaccinated adolescents was significantly reduced: HPV6/11 (odds ratio [OR] = 0.19, 95%CI:0.06–0.75), HPV16 (OR = 0.31, 95%CI:0.11–0.88) and HPV18 (OR = 0.14, 95%CI:0.03–0.75). For anal HPV, the risk of detecting vaccine types HPV6/11 (OR = 0.27, 95%CI:0.10–0.72) and HPV18(OR = 0.12, 95%CI:0.01–1.16) were significantly reduced for vaccinated adolescents however, the risk for HPV16 was not significantly decreased (OR = 0.63, 95%CI:0.18–2.20).
Conclusion
HPV Prevalence is extremely high in inner-city female adolescents. Administration of the HPV vaccine reduced the risk for cervical HPV; however continued follow-up is required to assess the protection for HPV at all sites in young women with high exposure.
doi:10.1371/journal.pone.0037419
PMCID: PMC3356254  PMID: 22624027
21.  REDUCTION OF HPV INFECTIONS THROUGH VACCINATION AMONG AT-RISK URBAN ADOLESCENTS 
Vaccine  2012;30(37):5496-5499.
Introduction
Human papillomavirus (HPV) vaccine trials have demonstrated high efficacy in preventing HPV infections and HPV related disease in females ages 16–26. However, there is no source data to demonstrate the impact of the vaccine in other populations who may be at higher risk for HPV related disease. This study examines the impact of HPV vaccination on subsequent HPV detection and sexual behaviors among urban adolescents in a clinical setting.
Methods
A cohort of adolescent women, ages 14 to 17, were recruited prospectively and matched to historical controls to assess the impact of HPV vaccination. All women completed the same questionnaire and face-to-face interview that assessed sexual behaviors; all provided a clinician or self-collected vaginal swab that was used to test for sexually transmitted infections, including HPV. Logistic regression models, incorporating random pair effects, were used to assess the impact of the HPV vaccine on HPV detection and sexual behaviors between the two groups.
Results
Each woman recruited (N=75) was matched to 2 historical controls (HC); most of the recruited women (89.3%) had received one or more doses of the HPV vaccine. At enrollment, detection of quadrivalent vaccine types (HPV 6, 11, 16 and 18) was significantly less in the recruited group (5.3%) as compared to the HC (24%): OR=5.6 (CI=1.9, 16.5), p=.002. Adolescent women in the HC had a 9.5 times greater odds of HPV infection when the analysis was adjusted to compare those who had 2 or more vaccine doses to their matched controls. The only behavioral difference found was that the recruited women used condoms more frequently.
Conclusion
This study demonstrates that HPV vaccination was associated with fewer vaccine-type HPV infections despite incomplete vaccination and high risk sexual behaviors. These data also suggest that sexual behaviors were not altered because of the vaccine.
doi:10.1016/j.vaccine.2012.06.057
PMCID: PMC3423324  PMID: 22750043
Human papillomavirus vaccination; human papillomavirus infection; adolescent
22.  Human papillomavirus-related disease in people with HIV 
Purpose of the review
The incidence of human papillomavirus (HPV)-related cancers is increased among people with HIV infection compared with the general population. This review will describe recent findings in HPV-associated cancer incidence since the introduction of antiretroviral therapy (ART), HPV/disease prevalence at sites other than cervix and anus, and recent data on screening and treatment of anal intraepithelial neoplasia (AIN).
Recent findings
Consistent with high prevalence of anogenital HPV infection, cervical intraepithelial neoplasia (CIN) and AIN in HIV-positive men and women, new data show that the incidence of cervical cancer has not declined since the introduction of ART and that the incidence of anal cancer is rising. Several studies also highlight high rates of HPV infection and HPV-associated disease at sites other than the cervix and anus, including the penis and mouth. Treatment methods for AIN have been described and show reasonable efficacy.
Summary
New data imply that the problem of HPV-related cancers will not decline among HIV-positive men and women in the ART era, highlighting the need to perform studies to determine if screening and treatment of AIN will prevent development of anal cancer. Recent data show progress in both of these areas.
doi:10.1097/COH.0b013e32831a7246
PMCID: PMC2756707  PMID: 19339939
Human papillomavirus; anal cancer; cervical cancer; anal intraepithelial neoplasia; cervical intraepithelial neoplasia
23.  Human Papillomavirus Genotype Attribution and Estimation of Preventable Fraction of Anal Intraepithelial Neoplasia Cases Among HIV-Infected Men Who Have Sex With Men 
The Journal of Infectious Diseases  2012;207(3):392-401.
Background. The prevention of human papillomavirus (HPV)–induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use.
Methods. HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines.
Results. HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (Ptrend < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%.
Conclusions. Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.
doi:10.1093/infdis/jis694
PMCID: PMC3537447  PMID: 23162133
Anal cancer; human papillomavirus; human immunodeficiency virus; anal intraepithelial neoplasia; men who have sex with men; genotypes; attribution
24.  Genotype-Specific Clearance of Genital Human Papillomavirus (HPV) Infections among Mothers in the Finnish Family HPV Study▿  
Journal of Clinical Microbiology  2010;48(8):2665-2671.
The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.
doi:10.1128/JCM.00783-10
PMCID: PMC2916623  PMID: 20554830
25.  Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study 
Journal of Clinical Pathology  2005;58(9):946-950.
Aims: To monitor the association between the course of high risk human papillomavirus (HR-HPV) infection and the development of cervical neoplasia over time, from a baseline of normal cervical cytology.
Methods: This paper presents the follow up data from a previous cross sectional analysis. Women from a screening population who had normal cytology and who were HR-HPV positive were recalled after two to three years for cytology and HPV genotyping. The development of cervical neoplasia at follow up was related to the course of HPV infection (clearance, persistence, or sequential infection) and the presence of single or multiple HPV infections at baseline. A comparator control group of women who were HPV and cytologically negative at baseline were selected from the same population.
Results: Twelve cases of dyskaryosis were found in women who were HPV positive at baseline; four were high grade. Only three cases of low grade dyskaryosis were found in the control group. Women with type specific persistent infections were significantly more likely to develop cervical neoplasia than women who cleared the infection (p = 0.0001) or were sequentially infected with different types (p = 0.001). Women with multiple HPV infections at baseline were no more likely to develop cervical dyskaryosis than those with a single infection.
Conclusions: Type specific persistent HR-HPV infection as monitored by genotyping can identify women at increased risk of cervical neoplasia more accurately than a single or repeated presence/absence HPV test. The cost effectiveness of such an approach should be investigated by an appropriate, large scale cost–benefit analysis.
doi:10.1136/jcp.2004.022863
PMCID: PMC1770812  PMID: 16126875
human papillomavirus; genotyping; longitudinal study; persistent infection; cervical neoplasia

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