Human papillomavirus (HPV) vaccination is a major strategy for preventing cervical and other ano-genital cancers. Worldwide HPV vaccination introduction and coverage will be facilitated if a single ...dose of vaccine is as effective as two or three doses or demonstrates significant protective effect compared to ‘no vaccination’.
In a multi-centre cluster randomized trial of two vs three doses of quadrivalent HPV vaccination (Gardasil™) in India, suspension of the vaccination due to events unrelated to the study led to per protocol and partial vaccination of unmarried 10–18 year old girls leading to four study groups, two by design and two by default. They were followed up for the primary outcomes of immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity for the vaccine-targeted HPV types and HPV infections. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702.
Of the 17,729 vaccinated girls, 4348 (25%) received three doses on days 1, 60, 180 or later, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses on days 1 and 60, and 4950 (28%) received one dose. One dose recipients demonstrated a robust and sustained immune response against HPV 16 and 18, albeit inferior to that of 3- or 2-doses and the antibody levels were stable over a 4 year period. The frequencies of cumulative incident and persistent HPV 16 and 18 infections up to 7 years of follow-up were similar and uniformly low in all the vaccinated study groups; the frequency of HPV 16 and 18 infections were significantly higher in unvaccinated age-matched control women than among vaccine recipients. The frequency of vaccine non-targeted HPV types was similar in the vaccinated groups but higher in the unvaccinated control women.
Our results indicate that a single dose of quadrivalent HPV vaccine is immunogenic and provides lasting protection against HPV 16 and 18 infections similar to the three- and two-dose vaccine schedules, although the study suffer from some limitations. Data on long term protection beyond 7 years against HPV infection and cervical precancerous lesions are needed before policy guidelines regarding a single dose can be formulated and implemented. Significant and long-lasting protective effect of a single dose can be a strong argument to introduce one dose of the HPV vaccine in many low income countries where the current standard of care for cervical cancer prevention is ‘no intervention’.
Summary Background An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the ...immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. Methods Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10–18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov , number NCT00923702. Findings Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 95% CI 1·02–1·23 and for HPV 18 1·04 0·92–1·19) at 7 months, but was inferior in the two-dose default (0·33 0·29–0·38 for HPV 16 and 0·51 0·43–0·59 for HPV 18) and one-dose default (0·09 0·08–0·11 for HPV 16 and 0·12 0·10–0·14 for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2–5·1). Interpretation Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. Funding Bill & Melinda Gates Foundation.
HPV screening for cervical cancer in rural India Sankaranarayanan, Rengaswamy; Nene, Bhagwan M; Shastri, Surendra S ...
New England journal of medicine/The New England journal of medicine,
04/2009, Letnik:
360, Številka:
14
Journal Article
Recenzirano
Odprti dostop
In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) ...on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India.
In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment.
In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval CI, 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women.
In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.
ObjectivesWe aim to assess the efficacy and safety of therapeutic human papillomavirus (HPV) vaccines to treat cervical intraepithelial neoplasia of grade 2 or 3 (CIN 2/3).DesignSystematic review and ...meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations.Data sourcesPubMed, Embase, Web of Science, Global Index Medicus and CENTRAL Cochrane were searched up to 31 January 2022.Eligibility criteriaPhase II/III randomised controlled trials (RCTs) and single-arm studies reporting the efficacy of therapeutic vaccines to achieve regression of CIN 2/3 lesions were included. Studies evaluating only safety and side effects of the vaccine were excluded.Data extraction and synthesisTwo independent reviewers extracted data and evaluated study quality. A random-effect model was used to pool the proportions of regression and/or HPV clearance.Results12 trials met the inclusion criteria. Out of 734 women (all studies considered) receiving therapeutic HPV vaccine for CIN 2/3, 414 regressed to normal/CIN 1 with an overall proportion of regression of 0.54 (95% CI 0.39 to 0.69) for vaccinated group; 166 women (from five RCTs) receiving placebo only achieving a pooled normal/CIN 1 regression of 0.27 (95% CI 0.20 to 0.34). When including only the five two-arm studies, the regression proportion for the 410 vaccine group participants was higher than that of the 166 control group participants (relative risk (RR) 1.52; 95% CI 1.14 to 2.04). The pooled proportion of high-risk human papillomavirus (hrHPV) clearance was 0.42 (95% CI 0.32 to 0.52) in the vaccine group (six studies with a total of 357 participants) and 0.17 (95% CI 0.11 to 0.26) in the control group (three RCTs with a total of 104 participants). Based on these three RCTs, the hrHPV clearance was significantly higher in the vaccinated group (250 participants) compared with the control group (RR 2.03; 95% CI 1.30 to 3.16). Similar results were found regarding HPV 16/18 clearance. No significant unsolicited adverse events have been consistently reported.ConclusionsThe efficacy of the therapeutic vaccines in the treatment of CIN 2/3 was modest. Implementation issues such as feasibility, acceptability, adoption and cost-effectiveness need to be further studied.PROSPERO registration numberCRD42022307418.
Summary Background Cervical cancer is the most common cancer among women in developing countries. We assessed the effect of screening using visual inspection with 4% acetic acid (VIA) on cervical ...cancer incidence and mortality in a cluster randomised controlled trial in India. Methods Of the 114 study clusters in Dindigul district, India, 57 were randomised to one round of VIA by trained nurses, and 57 to a control group. Healthy women aged 30 to 59 years were eligible for the study. Screen-positive women had colposcopy, directed biopsies, and, where appropriate, cryotherapy by nurses during the screening visit. Those with larger precancerous lesions or invasive cancers were referred for appropriate investigations and treatment. Cervical cancer incidence and mortality in the study groups were analysed and compared using Cox regression taking the cluster design into account, and analysis was by intention to treat. The primary outcome measures were cervical cancer incidence and mortality. Results Of the 49 311 eligible women in the intervention group, 31 343 (63·6%) were screened during 2000–03; 30 958 control women received the standard care. Of the 3088 (9·9%) screened positive, 3052 had colposcopy, and 2539 directed biopsy. Of the 1874 women with precancerous lesions in the intervention group, 72% received treatment. In the intervention group, 274 430 person years, 167 cervical cancer cases, and 83 cervical cancer deaths were accrued compared with 178 781 person-years, 158 cases, and 92 deaths and in the control group during 2000–06 (incidence hazard ratio 0·75 95% CI 0·55–0·95 and mortality hazard ratio 0·65 0·47–0·89). Interpretation VIA screening, in the presence of good training and sustained quality assurance, is an effective method to prevent cervical cancer in developing countries.
Background In Morocco, much progress has been made in breast cancer treatment. However, there is limited information on survival outcomes of breast cancer patients according to their therapeutic ...management. Methods A pattern-of-care study was conducted in Morocco's two main oncology centres: Rabat and Casablanca and has shown that major progress has been made in the quality of care with survival rates comparable to those in developed countries. The present study focuses on the different therapeutic strategies used in breast cancer and their impact on prognosis. Patients were classified into two categories: those considered as appropriately managed and those who were not. Results A total of 1901 women with stage I to III breast cancer were included in this study, the majority (53%) were adequately managed and had better disease-free survival (DFS) rates than those who were not: DFS at 3 years (88% versus 62%) and at 5 years (80% versus 50%). Potential significant determinants of better management were: treatment in Rabat's oncology centre, treatment between 2008 and 2012, being aged younger than 60 years, and early TN stage. Conclusion This study demonstrated the value of proper integrated and coordinated management in a comprehensive cancer centre, to improve breast cancer survival. Keywords: Breast cancer, Management appropriateness, Determinants, Disease-free survival, Morocco
Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9–14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine ...in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial CVT and Institutional Agency for Research on Cancer IARC India trial).
In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9–14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637.
Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years IQR 9–12) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years IQR 9–12) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years 19–23) and 139 one-dose recipients from the IARC India trial (median age 14 years 13–16) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9–26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9–22·5; n=97) for the CVT (GMC ratio 1·30 95% CI 1·00–1·68) and 13·7 IU/mL (11·9–15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5–8·2; n=131) for the IARC India trial (GMC ratio 2·05 1·61–2·61). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5–11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4–10·0; n=97) for the CVT trial (GMC ratio 1·23 95% CI 0·95–1·60) and 5·7 IU/mL (4·9–6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9–2·7; n=129) for the IARC India trial (GMC ratio 2·12 1·59–2·83). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18.
One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine.
UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute.
For the KiSwahili translation of the abstract see Supplementary Materials section.
It is quite well documented that the COVID-19 pandemic disrupted cancer screening services in all countries, irrespective of their resources and healthcare settings. While quantitative estimates on ...reduction in volume of screening tests or diagnostic evaluation are readily available from the high-income countries, very little data are available from the low- and middle-income countries (LMICs). From the CanScreen5 global cancer screening data repository we identified six LMICs through purposive sampling based on the availability of cancer screening data at least for the years 2019 and 2020. These countries represented those in high human development index (HDI) categories (Argentina, Colombia, Sri Lanka, and Thailand) and medium HDI categories (Bangladesh and Morocco). No data were available from low HDI countries to perform similar analysis. The reduction in the volume of tests in 2020 compared to the previous year ranged from 14.1% in Bangladesh to 72.9% in Argentina (regional programme) for cervical screening, from 14.2% in Bangladesh to 49.4% in Morocco for breast cancer screening and 30.7% in Thailand for colorectal cancer screening. Number of colposcopies was reduced in 2020 compared to previous year by 88.9% in Argentina, 38.2% in Colombia, 27.4% in Bangladesh, and 52.2% in Morocco. The reduction in detection rates of CIN 2 or worse lesions ranged from 20.7% in Morocco to 45.4% in Argentina. Reduction of breast cancer detection by 19.1% was reported from Morocco. No association of the impact of pandemic could be seen with HDI categories. Quantifying the impact of service disruptions in screening and diagnostic tests will allow the programmes to strategize how to ramp up services to clear the backlogs in screening and more crucially in further evaluation of screen positives. The data can be used to estimate the impact on stage distribution and avoidable mortality from these common cancers.
Visual inspection after acetic acid application (VIA) and human papillomavirus (HPV) detection tests have been recommended to screen women for cervical cancer in low and middle income countries. A ...demonstration project in rural India screened 39,740 women with both the tests to compare their accuracies in real population setting. The project also evaluated the model of screening women in the existing primary health care facilities, evaluating the screen positive women with colposcopy (and biopsy) in the same setup and recalling the women diagnosed to have disease for treatment at tertiary center. Accuracy of VIA and HPV test used sequentially was also studied. VIA was performed by trained health workers and Hybrid Capture II (HC II) assay was used for oncogenic HPV detection. Test positivity was 7.1% for VIA and 4.7% for HC II. Detection rate of CIN 3+ disease was significantly higher with HC II than VIA. Sensitivities of VIA and HC II to detect 162 histology proved CIN 3+ lesions were 67.9 and 91.2%, respectively after adjusting for verification bias. Specificity for the same disease outcome and verification bias correction was 93.2% for VIA and 96.9% for HC II. Triaging of VIA positive women with HPV test would have considerably improved the positive predictive value (4.0 to 37.5% to detect CIN 3+) without significant drop in sensitivity. All VIA positive women and 74.0% of HC II positive women had colposcopy. There was high compliance to treatment and significant stage‐shift of the screen‐detected cancers towards more early stage.
Whats's new?
Rather than conventional Pap‐smear cytology, visual inspection after acetic acid application, or VIA, and human papillomavirus (HPV) detection tests have been recommended for screening women in low‐ and middle‐income countries for cervical cancer. In this large demonstration project in India, the authors used both techniques, in order to compare their accuracy and to assess triaging scenarios. They found that triaging VIA‐positive women with a hybrid capture II (HC‐II) assay for HPV would considerably improve the positive predictive value, and allow detection of cervical cancers at an earlier, treatable stage.
High variability in the definition and interpretation of organized cancer screening needs to be addressed systematically. Moreover, the relevance of the current practice of categorizing screening ...programmes dichotomously into organized or non-organized needs to be revisited in the context of considerable heterogeneity that exists in the delivery of cancer screening in the real world. We aimed to identify the essential and desirable criteria for organized cancer screening that serve as a charter of best practices in cancer screening.
We first did a systematic review of literature to arrive at an exhaustive list of criteria used by various publications to describe or define organized cancer screening, based on which, a consolidated list of criteria was generated. Next, we used a Delphi process comprising of two rounds of online surveys to seek agreement of experts to categorize each criterion into essential, desirable, or neither. Consensus was considered to have been achieved based on a predetermined criterion of agreement from at least 80% of the experts. The outcomes were presented before the experts in a virtual meeting for feedbacks and clarifications.
A total of 32 consolidated criteria for an organized screening programme were identified and presented to 24 experts from 20 countries to select the essential criteria in the Delphi first round. Total 16 criteria were selected as essential with the topmost criteria (based on the agreement of 96% of experts) being the availability of a protocol/guideline describing at least the target population, screening intervals, screening tests, referral pathway, management of positive cases and a system being in place to identify the eligible populations. In the second round of Delphi, the experts selected eight desirable criteria out of the rest 16. The most agreed upon desirable criterion was existence of a specified organization or a team responsible for programme implementation and/or coordination.
We established an international consensus on essential and desirable criteria, which screening programmes would aspire to fulfil to be better-organized. The harmonized criteria are a ready-to-use guide for programme managers and policymakers to prioritize interventions and resources rather than supporting the dichotomous and simplistic approach of categorizing programmes as organized or non-organized.
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