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Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV. This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R. At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+. This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+. ClinicalTrials.gov NCT00128661.

Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed. The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening. In this randomised trial, women aged 29–56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002. Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken. At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment. The primary endpoint was the number of CIN grade 3 or worse detected. Analysis was done by intention to screen. The trial is now finished and is registered, number ISRCTN20781131. 22 420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20 106 in the control group were eligible for analysis at the first screen. At the second screen, 19 579 women in the intervention group and 19 731 in the control group were eligible, of whom 16 750 and 16 743, respectively, attended the second screen. In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19 731 in the control group; relative risk 0·73, 95% CI 0·55–0·96; p=0·023). Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19 731; 0·29, 0·10–0·87; p=0·031). In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20 106; 1·15, 0·92–1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19 286 vs 12 of 19 373; 2·85, 1·47–5·49; p=0·001). Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20 106; 1·25, 1·05–1·50; p=0·015). In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27–0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57–1·72; p=1·00). The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20 106; 0·96, 0·81–1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20 106; 1·08, 0·94–1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29–33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74–1·27; CIN grade 2 or worse in women aged 29–33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81–1·26; CIN grade 3 or worse in women aged 34–56 years: 157 of 16 860 vs 167 of 16 978; 0·95, 0·76–1·18; CIN grade 2 or worse in women aged 34–56 years: 274 of 16 860 vs 248 of 16 978; 1·11, 0·94–1·32). Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer. Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit. Our results lend support to the use of HPV DNA testing for all women aged 29 years and older. Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development).

ObjectiveDue to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+).MethodsWe report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials’ end.ResultsDuring the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88).ConclusionsTen years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects.Trial registration numberNCT01393470.

Standard adjuvant chemoradiotherapy (60–66 Gy) following surgery for HPV-associated oropharyngeal squamous cell carcinoma has excellent oncological control but high treatment morbidity. We aimed to compare toxicity of a 30–36 Gy regimen of de-escalated adjuvant radiotherapy and standard of care treatment. We did this phase 3, open-label, randomised controlled trial in two academic sites in the USA. Eligible participants were adults aged 18 years or older, with American Joint Committee on Cancer 7th edition pathological stage III–IV HPV-associated oropharyngeal squamous cell carcinoma and had more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and at least one intermediate pathological risk factor. Patients were stratified by the presence of extranodal extension and smoking status (<10 packs per year vs ≥10 packs per year) Eligible patients were randomly assigned (2:1) using a minimisation method with a random element to receive de-escalated adjuvant radiotherapy (30–36 Gy in 1·5–1·8 Gy fractions twice per day over 2 weeks plus intravenous docetaxel 15 mg/m2 on days 1 and 8 of treatment) or standard of care (60 Gy in 2 Gy fractions once daily over 6 weeks plus intravenous cisplatin 40 mg/m2 once a week). The primary endpoint was cumulative, chronic grade 3 or higher toxicity rate 3–24 months after radiotherapy. Primary analysis was done in patients who received treatment and had no missing data. This trial is registered with ClinicalTrials.gov, NCT02908477, and is complete. Between Oct 11, 2016, and Aug 20, 2020, 254 patients with newly diagnosed oropharyngeal squamous cell carcinoma were assessed for inclusion. Nine did not meet inclusion criteria and 17 declined to participate. 228 patients were enrolled, with 194 proceeding to protocol treatment and analysis (130 in the de-escalated adjuvant radiotherapy group and 64 in the standard of care group). Median patient age was 59·4 years (range 37·9–81·6). 173 (89%) of 194 patients were male and 21 (11%) were female. 183 (95%) of 194 patients were White, four (2%) were Hispanic, three (2%) were Asian, and one (1%) was Native American. Median follow-up was 37·3 months (IQR 27·6–49·2). Seven patients were excluded from analysis of the primary late toxicity endpoint (five patients in the de-escalated adjuvant radiotherapy group and two patients in the standard of care group). The cumulative chronic grade 3 or higher toxicity rate at 3–24 months was 3% (four of 125 patients) in the de-escalated adjuvant radiotherapy group and 11% (seven of 62 patients) in the standard of care group (p=0·042) with a cumulative chronic percutaneous endoscopic gastric (PEG) tube rate of 2% (two of 125 patients) in the de-escalated adjuvant radiotherapy group and 8% (five of 62 patients) in the standard of care group (p=0·039). The most common grade 3 or higher toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (two [2%] of 125 patients), oesophagitis (one patient [1%]) and hearing impairment (one patient [1%]). The most common grade 3 or higher toxic effects in the standard of care group were dysphagia (five [8%] of 61 patients), oesophagitis (one patient [2%]), fatigue (one patient [2%]), pain (one patient [2%]), and osteonecrosis of the jaw (one patient [2%]). De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care. Further clinical trials exploring indications for the DART regimen are warranted. The Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund.

Background Human papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes. Methods/Design The study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint. Discussion PATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment. Trial registration This study is registered with ClinicalTrials.gov identifier NCT02215265 .

The efficacy of the quadrivalent Human Papillomavirus (HPV) vaccine is thought to be mediated by humoral immunity. We evaluated the correlation between quadrivalent HPV vaccine-induced serum anti-HPV responses and efficacy. 17,622 women were vaccinated at day 1, and months 2 and 6. At day 1 and at 6–12 months intervals for up to 48 months, subjects underwent Papanicolaou and genital HPV testing. No immune correlate of protection could be found due to low number of cases. Although 40% of vaccine subjects were anti-HPV 18 seronegative at end-of-study, efficacy against HPV 18-related disease remained high (98.4%; 95% CI: 90.5–100.0) despite high attack rates in the placebo group. These results suggest vaccine-induced protection via immune memory, or lower than detectable HPV 18 antibody titers.

The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Testing for human papillomavirus (HPV) DNA is reportedly more sensitive than cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN). The effectiveness of HPV testing in primary cervical screening was assessed in the ARTISTIC trial, which was done over two screening rounds approximately 3 years apart (2001–03 and 2004–07) by comparing liquid-based cytology (LBC) combined with HPV testing against LBC alone. Women aged 20–64 years who were undergoing routine screening as part of the English National Health Service Cervical Screening Programme in Greater Manchester were randomly assigned (between July, 2001, and September, 2003) in a ratio of 3:1 to either combined LBC and HPV testing in which the results were revealed and acted on, or to combined LBC and HPV testing where the HPV result was concealed from the patient and investigator. The primary outcome was the detection rate of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in the second screening round, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number ISRCTN25417821. There were 24 510 eligible women at entry (18 386 in the revealed group, 6124 in the concealed group). In the first round of screening 233 women (1·27%) in the revealed group had CIN3+, compared with 80 (1·31%) women in the concealed group (odds ratio [OR] 0·97, 95% CI 0·75–1·25; p>0·2). There was an unexpectedly large drop in the proportion of women with CIN3+ between the first and second rounds of screening in both groups, at 0·25% (29 of 11 676) in the revealed group and 0·47% (18 of 3866 women) in the concealed group (OR 0·53, 95% CI 0·30–0·96; p=0·042). For both rounds combined, the proportion of women with CIN3+ were 1·51% (revealed) and 1·77% (concealed) (OR 0·85, 95% CI 0·67–1·08; p>0·2). LBC combined with HPV testing resulted in a significantly lower detection rate of CIN3+ in the second round of screening compared with LBC screening alone, but the effect was small. Over the two screening rounds combined, co-testing did not detect a higher rate of CIN3+ or CIN2+ than LBC alone. Potential changes in screening methodology should be assessed over at least two screening rounds. National Institute of Health Research Health Technology Assessment Programme.

Background Cytological samples are genotyped to inform clinical management of HPV-infected women due to their accessibility. Conversely, HPV genotypes identified in biopsies are deemed directly associated with cervical lesions. Thus, investigating genotyping agreement between these two sample types and potential influence of lesion severity and vaccination status on their degree of concordance is essential for understanding their diagnostic reliability. Methods Paired cervical cytological samples and formalin-fixed paraffin-embedded (FFPE) biopsies from 392 cervical intraepithelial neoplasia or cancer (CIN+) cases (187 CIN1, 111 CIN2, 94 CIN3+; 262 unvaccinated, 130 vaccinated) were genotyped using SPF 10 -DEIA-LiPA 25 detection system. Strength of agreement was measured by kappa, with thresholds indicating varying levels of agreement. Results Overall, most HPV genotypes were more frequently detected in cytological samples, with seven genotypes showing statistical differences between sample types (HPV39, 51, 52, 53, 56, 58, 68/73). Multi-type infection was more prevalent in cytological samples (147 versus 76, P McNemar’s test <0.001), whereas single-type infection was more common in FFPE biopsies (233 versus 296, P McNemar’s test <0.001). Proportions of observed agreement for all genotypes detected exceeded 95% and Prevalence-And-Bias-Adjusted kappa values (range: 0.832 to 0.990) indicated “Strong” (threshold: 0.80 to 0.90) to “Almost Perfect” (threshold: above 0.90) agreement. Lesion severity and vaccination status had negligible impacts on genotyping agreement. Conclusions In conclusion, HPV genotyping by cytological samples and FFPE biopsies performed equally well regardless of lesion severity and vaccination status, directly supporting reliable utility of cytological HPV genotyping for clinical decisions. However, impact of sample type needs to be considered when interpretating and utilizing multi-type and/or single-type infection for scientific research. Trial registration ClinicalTrials.gov (NCT00779766). Registered on the 23th of October 2008.

Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC-ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. ISRCTN Registry 48776874.