High Human Papillomavirus Load Research Articles

Association between ТР53, MDM2 and NQO1 gene polymorphisms and viral load among women with human papillomavirus.

The risk of cervical cancer is caused by persistent human papillomavirus (HPV) infection. Cervical cancer is the most frequent cancer among women. Our purpose was to investigate the association between TP53 215C>G (Pro72Arg), MDM2 -410T>G, and NQO1 609C>T gene polymorphisms with a high HPV load and the inf luence of gene-gene interactions on prolonged HPV infection. Eighty-nine women with a high HPV viral load and 114 healthy women were involved in a case–control study. Genotyping for TP53 215C>G (Pro72Arg) and MDM2 -410T>G SNPs was carried out by allele-specif ic PCR and genotyping for NQO1 609C>T was performed by a TaqMan assay. Quantitative analysis of HPV DNA was performed by AmpliSens® HPV HCR screen-titer-FRT test system. Gene-gene interactions were analyzed using the multifactor dimensionality reduction (MDR) method. The study of separate SNPs of MDM2 -410T>G and NQO1 609C>T genes did not reveal any statistically signif icant difference in genotype and allele frequencies among women within the two groups. The frequency of the 215G (72Arg) allele and 215GG (72Arg/ Arg) genotype of the TP53 gene was signif icantly higher in the case group than in the control group (OR = 1.74, 95 % CI = 1.10–2.73; p = 0.02 and OR = 1.97, 95 % CI = 1.13–3.46; p = 0.04, respectively). MDR analysis showed the signif icance of intergenic interactions of the three studied loci TP53 (rs1042522) – MDM2 (rs2279744) – NQO1 (rs1800566) for the formation of a high HPV load (OR = 3.05, 95 % CI = 1.73–5.46; p = 0.0001).

Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: An observational study with a long-term follow-up.

ObjectiveTo investigate the prognostic value of pretreatment human papillomavirus (HPV) viral load for cervical cancer, and to develop nomograms based on HPV load and other clinicopathological factors for long-term survival.MethodsWe conducted a prospective study on cervical squamous cell carcinoma (SCC) patients diagnosed between January 2003 and December 2008. Cervical samples were tested for HPV viral load by the Hybrid Capture II (HCII) assay before treatment and 6 months after treatment. Clinical characteristics and follow-up information were also collected. A multivariable Cox proportional hazards model was used to adjust covariates in both the radical hysterectomy (RH) treatment group and concurrent chemoradiotherapy (CCRT) treatment group to identify relevant covariates, and then nomograms were constructed and used for internal validation.ResultsA total of 520 SCC patients enrolled in this study with a median follow-up of 127 months, 360 patients received RH, whereas 160 patients received CCRT. The median HPV viral load in RH and CCRT groups was 356.10 and 294.29, respectively. Tumor size was positively correlated with high pretreatment HPV load in both groups. In CCRT group, the advanced International Federation of Gynecology and Obstetrics (FIGO) stage and enlarged retroperitoneal lymph node status determined by computed tomography (LNSCT) were correlated with low HPV load group. Initial HPV viral load, FIGO stage and lymph node metastasis were prognostic factors for RH group, whereas HPV viral load, squamous cell carcinoma antigen (SCC-Ag) level and LNSCT were identified as prognostic factors for CCRT group. Nomograms incorporating these predictors for 10-year progression-free survival (PFS) were constructed [concordance index (C-index): 0.756, 0.749].ConclusionsA low pretreatment HPV viral load is an independent prognostic factor for poor prognosis of cervical SCC and is related to other clinicopathological factors. The survival nomogram based on HPV viral load could predict the long-term prognosis.

Clinical Performance of APTIMA Human Papillomavirus (HPV) 16 18/45 mRNA Genotyping Testing for the Detection of Cervical Intraepithelial Neoplasia 3 (CIN3) or Cancer in a Select Group of Chinese Women.

HPV type was evaluated in a select group of Chinese women that were positive with hybrid capture, and correlations were performed between the pathology found, the type of virus and a semiquantitation from the hybrid capture results. Totally 394 referred high-risk-HPV-positive women evaluated by Hybrid Capture 2 (HC-2) assay were enrolled. Before colposcopy, cervical specimens were collected from all participants and suspended into PreservCytcollection medium (Hologic Inc., Marlborough, MA), and tested with the APTIMA HPV16 18/45 mRNA assay. Colposcopy and diagnostic biopsies were done on all participants. Viral load was assessed by HC2 assay. Totally 55 women were diagnosed as CIN 3 plus cancer (≥CIN3), and the prevalence of HPV16/18/45 was 65.5% (95% confidence interval [CI], 52.9-78.0%) among these ≥CIN3 women. Compared with the group with positive HC2 but negative HPV16/18/45, the odds ratio (OR) to identify ≥CIN3 was 6.3 (95% CI, 3.2-12.3) for HPV16 and 3.2 (95% CI, 1.4-7.2) for HPV18/45. When using ≥CIN3 as an endpoint, the sensitivity and specificity was 65.5% (95% CI, 52.9-78.0%) and 72.0% (95% CI, 67.2-76.8%). In the case of HPV16/18/45 negative, no high HPV load had a statistically significant increased risk for the prevalence of ≥CIN3. HPV16, 18 and 45 infection is a major cause for ≥CIN3 in Chinese women. Women with positive HPV16/18/45 should be referred to colposcopy immediately. HPV load was not suitable for the further triaged of the HPV16/18/45 negative cases.

Correction: Synergistic Effect of Viral Load and Alcohol Consumption on the Risk of Persistent High-Risk Human Papillomavirus Infection

Purpose This prospective study aimed to examine the combined effect of viral load and alcohol consumption on the risk of persistent high-risk (HR) human papillomavirus (HPV) infection. Methods Among women undergoing health screening between 2002 and 2011 at the National Cancer Center, 284 and 122 women with HR-HPV infection and cytological findings of low-grade squamous intraepithelial or lower-grade lesions were followed up for 1 and 2 years, respectively. Multivariate logistic regression analysis was performed, and the relative excess risk due to interaction (RERI) and synergy index (S) were calculated. Results Among drinkers, the risks of 1-year (odds ratio [OR] 4.09, 95% confidence interval [CI] 2.05–8.18) and 2-year persistence (OR 8.08, CI 2.36–27.6) were significantly higher for high HPV loads than for low HPV loads; this association was not seen for non-drinkers. The risks for 1-year (OR 4.14, CI 1.89–9.05) and 2-year persistence (OR 6.61, CI 2.09–20.9) were significantly higher in subjects with a high HPV load who were also drinkers than in those who were non-drinkers. A high HPV load together with a longer drinking duration or higher alcohol consumption was associated with increased risks of 1-year (OR 3.07, CI 1.40–6.75 or OR 2.05, CI 0.87–4.83) and 2-year persistence (OR 6.40, CI 1.72–23.8 or OR 4.14, CI 1.18–14.6). The synergistic effect of alcohol consumption and HR-HPV load was stronger on the risk of 2-year persistence (RERI = 3.26, S = 2.38) than on the risk of 1-year persistence (RERI = 1.21, S = 1.63). Conclusions The synergistic effect of HR-HPV load and alcohol consumption was associated with the risk of HR-HPV persistence and was stronger for longer-term HR-HPV infection. Limiting alcohol consumption might be an important measure to prevent the development of cervical cancer in women with a high HR-HPV load.

Synergistic effect of viral load and alcohol consumption on the risk of persistent high-risk human papillomavirus infection.

PurposeThis prospective study aimed to examine the combined effect of viral load and alcohol consumption on the risk of persistent high-risk (HR) human papillomavirus (HPV) infection.MethodsAmong women undergoing health screening between 2002 and 2011 at the National Cancer Center, 284 and 122 women with HR-HPV infection and cytological findings of low-grade squamous intraepithelial or lower-grade lesions were followed up for 1 and 2 years, respectively. Multivariate logistic regression analysis was performed, and the relative excess risk due to interaction (RERI) and synergy index (S) were calculated.ResultsAmong drinkers, the risks of 1-year (odds ratio [OR] 4.09, 95% confidence interval [CI] 2.05–8.18) and 2-year persistence (OR 8.08, CI 2.36–27.6) were significantly higher for high HPV loads than for low HPV loads; this association was not seen for non-drinkers. The risks for 1-year (OR 4.14, CI 1.89–9.05) and 2-year persistence (OR 6.61, CI 2.09–20.9) were significantly higher in subjects with a high HPV load who were also drinkers than in those who were non-drinkers. A high HPV load together with a longer drinking duration or higher alcohol consumption was associated with increased risks of 1-year (OR 3.07, CI 1.40–6.75 or OR 2.05, CI 0.87–4.83) and 2-year persistence (OR 6.40, CI 1.72–23.8 or OR 4.14, CI 1.18–14.6). The synergistic effect of alcohol consumption and HR-HPV load was stronger on the risk of 2-year persistence (RERI = 3.26, S = 2.38) than on the risk of 1-year persistence (RERI = 1.21, S = 1.63).ConclusionsThe synergistic effect of HR-HPV load and alcohol consumption was associated with the risk of HR-HPV persistence and was stronger for longer-term HR-HPV infection. Limiting alcohol consumption might be an important measure to prevent the development of cervical cancer in women with a high HR-HPV load.

HPV E6/E7 mRNA Expression in Oropharyngeal Carcinoma

Objective: Although patients with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OC) respond well to radiation therapy and have good prognosis, HPV integration in OC has not yet been fully analyzed. Therefore, we aimed to clarify the correlation between HPV infection or integration and prognosis of OC in a prospective study setting. Method: From 2006 to 2010, 56 patients with OC participated in the study. All patients were treated with 70 Gy concurrent chemoradiotherapy (CCRT). If OC did not show a partial or complete response at 40-Gy irradiation, radical resection for residual tumor was performed. Results: A total of 26 patients (46.4%) had HPV-positive OC, and 70% of HPV-16-positive OC cases showed integration with the host genome. Control samples obtained from chronic tonsillitis patients showed 1 of 47 specimens as positive for HPV. Patients with high HPV load also showed E6/E7 mRNA expression. Recurrent-free survival at 3 years was 100% in HPV-positive cases and 88.9% in HPV-negative cases. Cases with HPV integration or E6/E7 mRNA expression tended to respond well to CCRT in spite of advanced tumor extensions. Conclusion: Although HPV testing is useful for OC, HPV integration or E6/E7 mRNA expression is a more specific marker for predicting a fair response to CCRT and good prognosis. These findings also indicate that HPV plays a key role in the development and extension of OC.

Absence of dysplasia in the excised cervix by a loop electrosurgical excision procedure in the treatment of cervical intraepithelial neoplasia

Absence of dysplasia in the excised specimen following loop electrosurgical excision procedure (LEEP) for treatment of cervical intraepithelial neoplasia (CIN) 2/3 is an occasional finding of uncertain clinical significance. We evaluated several factors including age, liquid-based Pap (LBP) test, human papillomavirus (HPV) load before treatment, and HPV typing as predictors for absence of dysplasia. Absence of dysplasia in LEEP specimens was analyzed in terms of factors for recurrent disease after LEEP conization In total, 192 women (mean age, 39.3+/-8.4 years; range, 24 to 70 years) with biopsy-proven CIN 2/3 were treated by LEEP conization. Age, LBP test, histological grade, HPV load, and HPV DNA typing were evaluated as possible predictors of the absence of residual dysplasia or recurrent disease. Of the LEEP specimens, 34 (17.7%) showed no dysplasia in preoperative biopsies from patients with proven CIN 2/3. Low HPV load (<100 relative light units [RLU]) was significantly related to the absence of dysplasia in LEEP specimens, using logistic regression. Margin involvement and high HPV load (>/=400 RLU) were significant factors for recurrence. Absence of dysplasia in LEEP specimens occurred in 17.7% of our specimens. Prediction of the absence of dysplasia in LEEP specimens was associated with low HPV load. Residual/recurrent disease after LEEP was associated with a positive resection margin and high viral load, and was not associated with absence of dysplasia in LEEP specimens. Even if there is no dysplasia in conization specimens, close follow-up for residual/recurrent disease is needed.

Genital Human Papillomavirus Prevalence and Human Papillomavirus Concordance in Heterosexual Couples Are Positively Associated with Human Immunodeficiency Virus Coinfection

This study examined the concordance of genital human papillomavirus (HPV) infection in 254 heterosexually active couples and the impact of HIV coinfection. Genital HPV detection was significantly more common among HIV-infected women than among HIV-seronegative women (99 [68%] of 145 women vs. 33 [31%] of 107 women; P < .001); similarly, HPV detection was significantly more common among HIV-infected men than among HIV-seronegative men (67 [72%] of 93 and 65 [43%] of 150 men, respectively; P < .001). HIV-seronegative male partners of HIV-infected women had a significantly greater prevalence of HPV infection than did HIV-seronegative male partners of HIV-seronegative women (38 [58%] of 65 men vs. 27 [32%] of 85 men; P = .001), indicating that HIV coinfection in one partner has a significant impact on the prevalence of HPV genital infection in the other partner. HPV concordance between couples was associated with HIV infection status (P < .001, by Pearson's chi2 test) and was significantly higher among HIV-infected couples than among HIV-seronegative couples. Type-specific sharing of HPV was associated with HIV concordance status (P = .024). HIV-seronegative couples were more likely to share 1 HPV type and were unlikely to share >1 type, whereas HIV-infected or HIV-discordant couples were more likely to share >1 HPV type. Women with a high HPV load frequently shared HPV types with their male partners, suggesting that a high HPV load may play a role in HPV transmission between partners. In conclusion, HIV coinfection in one or both sexually active partners increased HPV prevalence and HPV type-specific concordance.

Link between high human papillomavirus load and invasive cervical cancer

Link between high human papillomavirus load and invasive cervical cancer

Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ.

We have previously shown that high human papillomavirus (HPV) 16 load in Papanicolaou smears negative for dysplasia is strongly associated with risk for carcinoma in situ (CIS) of the cervix. Here we study the amount of HPV DNA for some of the most frequent high-risk HPV types as determinants of progression to cervical CIS. Real-time PCR is used to estimate the normalized viral load of HPV 16, 18, 31, 33, 35, 39, 45, 52, 58 and 67 in 457 cases of cervical CIS and 552 matched population controls. A total of 2,747 archival Pap smears from gynecologic health examinations, collected over a period of up to 26 years, were analyzed to assess viral load during the infection history. Cervical smear samples differ widely in amount of DNA, underscoring the need for normalization of HPV load to number of cells in the sample. The risk of developing cervical CIS increases with higher viral load for most of the HPV types studied. The range of copy numbers per cell does not differ between HPV types but the odds ratio for CIS in the percentile with highest viral load is substantially higher for HPV 16 (OR = 36.9; 95% CI = 8.9-153.2) than for HPV 31 (OR = 3.2; 95% CI = 1.1-9.1) or HPV 18/45 (OR = 2.6; 95% CI = 1.0-6.4). Therefore, HPV viral load may be predictive of future risk of cervical CIS at a stage when smears are negative for squamous abnormalities, but differences between HPV types need closer attention.

Acquisition of high-risk human papillomavirus infections and pap smear abnormalities among women in the New Independent States of the Former Soviet Union.

The rates of acquisition and the times of incident high-risk (HR) human papillomavirus (HPV) infections and Pap smear abnormalities and their predictive factors were analyzed in women participating in a multicenter screening study in three countries of the New Independent States of the former Soviet Union. The 423 patients were prospectively monitored for a mean of 21.6 months. At the baseline, 118 women were HR HPV DNA negative (Hybrid Capture II assay) and Pap smear negative (group 1), 184 were HPV DNA positive and Pap smear negative (group 2), and 121 were HPV DNA negative and Pap smear positive (group 3). The time to the acquisition of an incident abnormal Pap smear (19.4 months) was significantly longer in group 1 than in group 2 (9.2 months) (P = 0.0001). The times of acquisition of incident HR HPV infection were 16.6 and 11.0 months in group 1 and group 3, respectively (P = 0.006). The monthly rates of acquisition of incident HR HPV infections were very similar in group 1 (1.0%) and group 3 (0.8%), whereas the rate of acquisition of an abnormal Pap smear was significantly higher in group 2 (3.1%) than in group 1 (1.5%) (P = 0.0001). The acquisition of HR HPV infection (but not a positive Pap smear result) was significantly (P = 0.0001) age dependent. The only significant independent (P = 0.001) predictor of the incidence of an abnormal Pap smear result was a high HR HPV load of >20 relative light units/control value (CO) (rate ratio, 2.050; 95% confidence interval, 1.343 to 3.129). Independent predictors of incident HR HPV infection were patient category (a sexually transmitted disease) and ever having been pregnant. The time of acquisition of HR HPV infection was 3 months shorter than that of an abnormal Pap smear. At the baseline the high load of a particular HR HPV type is the single most important predictor of an incident Pap smear abnormality, whereas young age and having a sexually transmitted disease predict incident HR HPV infections.

Human papilloma virus testing in patient follow-up post cone biopsy due to high-grade cervical intraepithelial neoplasia

Objectives We evaluated the contribution of the human papilloma virus (HPV) load in planning follow-up and management of women post cone biopsy for high-grade cervical intraepithelial neoplasia (CIN2–3). Methods Ninety-six suitable women were followed-up by Pap smears: two consecutive abnormal smears dictated referral for colposcopy-directed biopsy. Before colposcopy, HPV tests determined high-risk HPV DNA type and load (Hybrid Capture System type I). Patients histologically diagnosed with CIN1 or CIN2–3 underwent repeat conization or hysterectomy for residual disease. HPV load was compared to cytology for the detection of residual disease. Results At follow-up, 20/89 (22.4%) studied women had positive cytology reports of either low- ( n = 11) or high-grade ( n = 9) squamous intraepithelial lesion (SIL). Colposcopic biopsies diagnosed 9 CIN1 and 8 CIN2–3 cases. Residual disease was corroborated in 16/17 (94.1%) women and the status was readjusted based on cone biopsy/hysterectomy: CIN2–3 in 9 and CIN1 in 7. The positive prediction values for CIN2–3 residual disease with high-grade SIL, CIN2–3 on colposcopic punch biopsy, and high HPV load were 89, 100, and 100%, respectively. For CIN1 residual disease with low-grade SIL, CIN1 on colposcopic punch biopsy, and low and borderline HPV load, they were 54.5, 77.7, and 100%. The HPV load was a more accurate predictor for CIN1 or CIN2–3 on the cervical specimen in cases with low-grade SIL or CIN1 on colposcopic biopsy. Conclusions Evaluating HPV loads after a positive cytology report may assist in triaging women post conization biopsy for CIN2–3 to appropriate treatment. Its high positive predictive value, specificity, and sensitivity for CIN1 and CIN2–3 and supplementary information could be especially pertinent for clinical management of low-grade SIL cases.

Increased Risk of Cervical Disease Among Human Immunodeficiency Virus–Infected Women With Severe Immunosuppression and High Human Papillomavirus Load

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

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

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