Clearance Of High-risk Human Papillomavirus Infection Research Articles

AHCC® Supplementation to Support Immune Function to Clear Persistent Human Papillomavirus Infections.

ObjectiveTo determine the efficacy, safety, and durability of the use of AHCC supplementation for 6 months to support the host immune system to clear high-risk human papillomavirus (HPV) infections. The AHCC supplement is a proprietary, standardized extract of cultured lentinula edodes mycelia (AHCC®, Amino Up, Ltd., Sapporo, Japan) that has been shown to have unique immune modulatory benefits.Study DesignThis was a randomized, double-blind, placebo-controlled study (CTN: NCT02405533) in 50 women over 30 years of age with confirmed persistent high-risk HPV infections for greater than 2 years. Patients were randomized to placebo once daily for 12 months (N = 25) or AHCC 3-g supplementation by mouth once daily on empty stomach for 6 months followed by 6 months of placebo (N = 25). Every 3 months, patients were evaluated with HPV DNA and HPV RNA testing as well as a blood sample collected to evaluate a panel of immune markers including interferon-alpha, interferon-beta (IFN-β), interferon-gamma (IFN-γ), IgG1, T lymphocytes, and natural killer (NK) cell levels. At the completion of the 12-month study period, patients on the placebo arm were given the option to continue on the study to receive AHCC supplementation unblinded for 6 months with the same follow-up appointments and testing as the intervention arm.ResultsFifty women with high-risk HPV were enrolled, and 41 completed the study. Fourteen (63.6%) of the 22 patients in the AHCC supplementation arm were HPV RNA/HPV DNA negative after 6 months, with 64.3% (9/14) achieving a durable response defined as being HPV RNA/HPV DNA negative 6 months off supplementation. On the placebo arm, two (10.5%) of 19 patients were HPV negative at 12 months. In the twelve placebo arm patients who elected to continue on the unblinded study, 50% (n = 6) were HPV RNA/HPV DNA negative after 6 months of AHCC supplementation. At the time of completion of the study, there were a total of 34 patients (22 blinded and 12 unblinded) who had received AHCC supplementation with an overall response rate of 58.8% that cleared HPV persistent infections. At the time of enrollment, the mean IFN-β level was 60.5 ± 37.6 pg/ml in women with confirmed persistent HPV infections. Suppression of IFN-β to less than 20 pg/ml correlated with an increase in T lymphocytes and IFN-γ and durable clearance of HPV infections in women who received AHCC supplementation.ConclusionResults from this phase II study demonstrated that AHCC 3 g once daily was effective to support the host immune system to eliminate persistent HPV infections and was well tolerated with no significant adverse side effects reported. The duration of AHCC supplementation required beyond the first negative result needs more evaluation to optimize success for durable outcomes. The suppression of the IFN-β level to less than 20 pg/ml correlated with clearance of HPV infections and merits further evaluation as a clinical tool for monitoring patients with HPV infections.Clinical Trial Registrationclinicaltrials.gov/ct2/, identifier NCT02405533

Interferon lambda4 polymorphism is not associated with human papillomavirus infection outcome.

Interferon (IFN) lambdas are important specific components of the mucosal innate immune response. The IFN lambda 4 (IFNL4) dinucleotide polymorphism (ΔG/TT) determines the IFN lambdas and related Interferon-stimulated genes activation, in HCV and other chronic infections. Our group first reported that IFN Lambda response was impaired in high-risk Human Papillomavirus (HPV) cervical infections and in precancerous lesions. Accordingly, we sought to evaluate the possible role of the IFNL4 polymorphism in determining HPV infection outcome. The ΔG/TT alleles were not differently distributed in 221 women with high- or low-risk HPV infection, with HPV infection clearance or persistence, and with abnormal cytology.

High-risk human papillomavirus infection clearance following conization among patients with cervical intraepithelial neoplasm grade 3 aged at least 45years.

To investigate high-risk human papillomavirus (HPV) infection clearance rates following successful cold knife conization and factors predictive of HPV clearance among patients with cervical intraepithelial neoplasm grade 3. The present retrospective study analyzed clinical data from patients aged at least 45years with cervical intraepithelial neoplasm grade 3 who had undergone successful cold knife conization and attended regular follow-up at Peking Union Medical College Hospital, China, between January 1, 2002 and December 31, 2012. HPV clearance rates and potential indicators for HPV clearance were analyzed. Data from 156 patients were included; persistent high-risk HPV infection was recorded in 78 (50.0%), 45 (28.8%), 35 (22.4%), 24 (15.4%), and 21 (13.5%) patients at 4, 8, 12, 18, and 24months after conization, respectively. Clearance rates were significantly lower among patients aged at least 55years compared with younger patients, with increased odds of persistent HPV infection at 8months (odds ratio [OR] 4.038; 95% confidence interval [CI] 1.766-10.839), 12months (OR 5.923; 95% CI 2.450-16.604), 18months (OR 5.957; 95% CI 2.031-17.469), and 24months (OR 5.327; 95% CI 1.909-17.971) compared with patients aged 45-49years. Age was a prognostic factor for post-operative high-risk HPV infection clearance. Lower clearance rates were observed among patients aged at least 55years.

Methylation pattern of CDH1 promoter and its association with CDH1 gene expression in cytological cervical specimens.

Cervical cancer is the fourth leading cause of cancer mortality in females worldwide. Infection with high-risk human papillomavirus (HPV) is essential but insufficient to cause cervical cancer, and the clearance of HPV infection is mediated by the immune system. The deficit of molecules responsible for adhesion may play a role in the development of cervical cancer. E-cadherin is encoded by the cadherin 1 (CDH1) gene, and is involved in cell adhesion by forming adherens junctions. The aim of present study was to investigate the methylation pattern of the CDH1 promoter and to identify the association between CDH1 promoter hypermethylation, CDH1 gene expression and HPV infection in cervical specimens obtained from 93 patients with low-grade squamous intraepithelial lesions (SILs), high-grade SILs or squamous cell carcinomas, and from 47 patients with normal cervical cytology (HPV-negative). The methylation pattern of the CDH1 promoter was investigated by methylation-specific polymerase chain reaction and quantitative pyrosequencing. CDH1 gene expression was measured by relative quantification. CDH1 methylation was significantly higher in both types of lesions and in cervical cancer than in normal samples, and CDH1 gene expression was significantly reduced during SIL progression (P=0.0162). However, the influence of HPV infection or HPV E6 expression on the methylation pattern of the CDH1 gene or its gene expression levels could not be confirmed. The present results support that the methylation of the CDH1 gene is age-related in patients with cervical lesions (P=0.01085), and therefore, older patients could be more susceptible to cancer than younger patients. The important methylation of the CDH1 promoter occurred near the transcription factor binding sites on nucleotides −13 and +103, which are close to the translational start codon. These results suggest that methylation at these sites may be an important event in the transcriptional regulation of E-cadherin, and in patients harboring these methylated cytosines, this event may facilitate HPV-driven carcinogenesis.

Cervical cytokines and clearance of incident human papillomavirus infection: Hawaii HPV cohort study

Mechanisms for the control and resolution of human papillomavirus (HPV) infection of the cervix include the local production of cytokines, which control recruitment and function of cells integral to pathogen control. We established a cohort of women for long-term follow-up to examine the mucosal expression of antiviral (IFN-α2), Type-1 (IFN-γ, IL-12), regulatory (IL-10), and proinflammatory (IL-1α, IL-1β, IL-6, IL-8, MIP-1α, and TNF) cytokines in association with the clearance of incident cervical HPV infection. Interviews and specimens for HPV DNA analysis and cytokine protein measurement were obtained at baseline and at 4-month intervals. A Cox proportional hazards model was used to study the relationship between clearance of 107 high-risk and 111 low-risk incident HPV infections and cytokine levels among 154 women. Positive changes from baseline levels of IL-10, IL-12, MIP-1α, and TNF were associated with significantly longer times to type-specific HPV clearance. Inverse trends in the hazard ratios associated with clearance of high-risk HPV infections were monotonic and significant for IL-12 (ptrend = 0.02) and TNF (ptrend = 0.02); the likelihood of high-risk HPV clearance was reduced by 65% and 67%, respectively, among women in the highest as compared with the lowest quartile of change from baseline. Our results suggest that in women with a nontransient cervical HPV infection, proinflammatory, Type-1, and regulatory cytokines are elevated, underscoring the long-term commitment of local immune mediators to viral eradication.

Association Between Serum Cytokine Profiles and Clearance or Persistence of High-Risk Human Papillomavirus Infection: A Prospective Study

The cytokines that may be associated with the clearance or persistence of high-risk human papillomavirus (HPV) infection in patients with mild dysplasia or less of the uterine cervix were determined. A prospective study of 160 patients who harbored high-risk HPV with histologically confirmed mild dysplasia or less between January 2006 and August 2008 was performed. All patients were followed up at every 4 months during the first year. Human papillomavirus DNA tests by the Hybrid Capture 2 method (Digene, Gaithersburg, Md) were performed at every visit on all patients. Blood sampling was performed in all patients at their initial visit, and an enzyme-linked immunosorbent assay was used to measure the serum levels of interferon gamma, tumor necrosis factor alpha, and interleukins 6 and 10. Of the 160 patients, 107 (66.9%) had clearance of HPV infection after 12 months of follow-up. The median age of patients in the persistence group was significantly higher than that of patients in the clearance group (47 vs 38 years, respectively; range, 21-77 vs 21-71 years, respectively; P = 0.0009). In univariate analysis, the number of patients with serum negative for tumor necrosis factor alpha was significantly higher in the clearance group than the persistence group (P = 0.0363). However, in multivariate logistic regression analysis, all 4 cytokines failed to show any significant association with the clearance or persistence of HPV infection. The baseline serum cytokine levels were not associated with the clearance or persistence of HPV infection. Systemic immunity may not influence the natural history of HPV infection.

Circumcision of HIV‐Infected Men: Effects on High‐Risk Human Papillomavirus Infections in a Randomized Trial in Rakai, Uganda

In Rakai, Uganda, human immunodeficiency virus (HIV)-positive men were randomized to undergo either immediate circumcision (intervention arm) or delayed circumcision (control arm). Penile swab samples were assayed for high-risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and at 24 months (intervention arm, 103 subjects; control arm, 107 subjects). Rate ratios (RRs) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was found in 57 (55.3%) of 103 subjects in the intervention arm and in 77 (71.7%) of 107 subjects in the control arm (RR, 0.77; 95% confidence interval [CI], 0.62-0.97). Multiple HR-HPV infections were found in 19 (22.4%) of 85 subjects in the intervention arm and in 45 (42.5%) of 106 subjects in the control arm (RR, 0.53; 95% CI, 0.33-0.83). New HR-HPV genotypes were acquired by 34 (42.0%) of 81 subjects in the intervention arm and by 53 (57.0%) 85 subjects in the control arm (RR, 0.74; 95% CI, 0.54-1.01; P = .06). Multiple new HR-HPV genotypes were acquired by 8 (9.9%) of 81 subjects in the intervention arm and by 23 (24.7%) of 93 subjects in the control arm (RR, 0.40; 95% CI, 0.19-0.84; P = .01). Circumcision did not affect the acquisition of single HR-HPV infections (RR, 1.00; 95% CI 0.65-1.53) or clearance of HR-HPV infections (RR, 1.09; 95% CI 0.94-1.27). Circumcision of HIV-positive men reduced the prevalence and incidence of multiple HR-HPV infections. ClinicalTrials.gov identifier: NCT00124878 .

Natural history of persistent high-risk human papillomavirus infections in Korean women

ObjectiveThis prospective study was performed to evaluate the clearance of high-risk human papillomavirus (HPV) infection and incidence of cytologic abnormality and cervical intraepithelial neoplasia (CIN) during the follow-up of persistent infection in Korean women. MethodsA total of 4170 women who were screened for cervical cancer, were aged 30 years or older, had no abnormal last Pap smear results for 3 years, had no history of treatment for cervical neoplastic disease, and were not pregnant were analyzed for high-risk HPV prevalence using the Hybrid capture (HC) II assay. The 224 women with normal cytology but positive for high-risk HPV DNA using the HC-II assay were analyzed for their clearance of HPV infection. ResultsThe median time to clearance in women with initially normal cytology was 7.5 months from initial detection (95% CI, 5.2–9.8 months). There were significant differences in the median time to clearance (4.5 vs. 14.5 months, p <0.001) of high-risk HPV infection between women with the initial relative light unit/ cutoff (RLU/CO) ratio values <10.0 and ≥10.0, as determined by the HC-II assay. In Kaplan–Meier analysis, probability of development of cytologic abnormalities, CIN and high-grade CIN was 38.2%, 21.7% and 8.5% respectively at 24 months of persistent high-risk HPV infection. ConclusionThe prevalence and clearance of high-risk infection in Korean women was similar to that in Western countries. Persistent high-risk HPV infection was associated with high viral load.

Time to clearance of human papillomavirus infection by type and human immunodeficiency virus serostatus

Persistent infection with high-risk human papillomavirus (HPV) is central to cervical carcinogenesis. Certain high-risk types, such as HPV16, may be more persistent than other HPV types, and type-specific HPV persistence may differ by HIV serostatus. This study evaluated the association between HPV type and clearance of HPV infections in 522 HIV-seropositive and 279 HIV-seronegative participants in the HIV Epidemiology Research Study (HERS, United States, 1993-2000). Type-specific HPV infections were detected using MY09/MY11/HMB01-based PCR and 26 HPV type-specific probes. The estimated duration of type-specific infections was measured from the first HPV-positive visit to the first of two consecutive negative visits. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HPV clearance were calculated using Cox models adjusted for study site and risk behavior (sexual or injection drugs). A total of 1,800 HPV infections were detected in 801 women with 4.4 years median follow-up. HRs for clearance of HPV16 and related types versus low-risk HPV types were 0.79 (95% CI: 0.64-0.97) in HIV-positive women and 0.86 (95% CI: 0.59-1.27) in HIV-negative women. HRs for HPV18 versus low-risk types were 0.80 (95% CI: 0.56-1.16) and 0.57 (95% CI: 0.22-1.45) for HIV-positive and -negative women, respectively. HPV types within the high-risk category had low estimated clearance rates relative to low-risk types, but HRs were not substantially modified by HIV serostatus.

High-Risk Human Papillomavirus and Cervical Intraepithelial Neoplasia at Time of Atypical Squamous Cells of Undetermined Significance Cytologic Results in a Population with Human Immunodeficiency Virus

Little information exists regarding high-risk human papillomavirus (HPV) subtypes in human immunodeficiency virus (HIV) patients with atypical squamous cells of undetermined significance (ASCUS) cytologic results. This study aimed to characterize further HPV prevalence and high-grade cervical intraepithelial neoplasia (CIN) in this sub-population of patients. This is a secondary analysis of a prospective HPV natural history study involving 200 HIV-sero-positive patients. We analyzed 102 patients from this cohort with a cervical cytologic diagnosis of ASCUS for high-risk and low-risk HPV prevalence, clearance of HPV infection, progression or regression of cervical cytologic abnormality, and prevalence of CIN 2 or worse at the time of indicated colposcopy. Pap smears were slide-based and HPV testing was performed using nested polymerase chain reaction. Overall prevalence of ASCUS in the HIV population was 20% (40 of 200 patients). Despite a high prevalence of all HPV subtypes (74 of 102 subtypes; 73%), high-risk subtypes were present in only 32% of patients (33 of 102 patients) with ASCUS cytologic results. In 5 of 42 patients (12%) undergoing colposcopy within 6 months of ASCUS cytologic results, CIN 2 or worse was found. Sensitivity, specificity, positive predictive value, and negative predictive value of a high-risk or intermediate-risk HPV test for CIN 2,3 were 100%, 70%, 31%, and 100%, respectively. Progression to high-grade intraepithelial lesion cytologic results after ASCUS was rare (5/64 evaluable patients; 8%) but persistence of low-grade cytologic results (ASCUS or low-grade intraepithelial lesion) was common (43/64 evaluable patients; 67%). Despite a high rate of HPV infection in the HIV population with ASCUS Pap results, high-risk HPV subtypes represent a minority of patients and are significantly associated with presence of high-grade CIN at colposcopy. High-risk HPV testing should be investigated further in the HIV population.