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      Type-specific persistence, clearance and incidence of high-risk HPV among screen-positive Rwandan women living with HIV

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          Abstract

          Background

          Persistent infection with high-risk human papillomavirus (hrHPV) is a critical step in cervical carcinogenesis. We report on type-specific hrHPV persistence, clearance and incidence among screen-positive Rwandan women living with HIV (WLWH).

          Methods

          This was a nested analysis from a large cervical cancer screening study of ~ 5000 Rwandan WLWH. Women who tested positive for hrHPV and/or visual inspection with acetic acid were referred to colposcopy. For a subset of women ( n = 298) who were ≥ 6 months delayed in receiving colposcopy, we tested their screening and colposcopy visit specimens using the AmpFire HPV genotyping assay that tests 14 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) individually.

          Results

          The mean, median (interquartile range [IQR]) and range of time between the screening and colposcopy visits were 644, 650 (490–820.5) and 197–1161 days, respectively. Mean, median (IQR) and range of age at the screening visit were 38, 37 (34–43) and 30–54 years, respectively. Two-hundred eighty-three (95.0%) had CD4 count (cells per mm 3) data available at baseline with mean, median (IQR) and range of 592, 513 (346–717) and 0–7290, respectively. Two-hundred thirty-five WLWH were positive for at least one hrHPV type at the screening visit, of whom 50.2% had at least one HPV type-specific infection persist; 37.2% of all HPV infections detected at the screening visit persisted. Compared to all other HPV types in aggregate, HPV16 (vs. non-HPV16 types) (47.7%, p = 0.03) and HPV33 (vs. non-HPV33 types) (56.7%, p = 0.03) were significantly more likely, and HPV39 (vs. non-HPV39 types) (6.7%, p = 0.01), HPV51 (vs. non-HPV51 types) (15.6%, p < 0.01), and HPV66 (vs. non-HPV66 types (17.9%, p = 0.04) were significantly less likely, to persist. Lower CD4 counts were associated with having any persistent hrHPV infection (p trend = 0.04) and multiple persistent hrHPV infections (p trend = 0.04).

          Conclusion

          There is a significant proportion of WLWH with persistent hrHPV infection, emphasizing the need to vaccinate them against HPV prior to becoming sexually active.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13027-021-00355-6.

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          Most cited references36

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            HPV Vaccination and the Risk of Invasive Cervical Cancer

            The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking.
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              Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices

              Introduction Vaccination against human papillomavirus (HPV) is recommended to prevent new HPV infections and HPV-associated diseases, including some cancers. The Advisory Committee on Immunization Practices (ACIP)* routinely recommends HPV vaccination at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up vaccination has been recommended since 2006 for females through age 26 years, and since 2011 for males through age 21 years and certain special populations through age 26 years. This report updates ACIP catch-up HPV vaccination recommendations and guidance published in 2014, 2015, and 2016 ( 1 – 3 ). Routine recommendations for vaccination of adolescents have not changed. In June 2019, ACIP recommended catch-up HPV vaccination for all persons through age 26 years. ACIP did not recommend catch-up vaccination for all adults aged 27 through 45 years, but recognized that some persons who are not adequately vaccinated might be at risk for new HPV infection and might benefit from vaccination in this age range; therefore, ACIP recommended shared clinical decision-making regarding potential HPV vaccination for these persons. Background HPV is a common sexually transmitted infection, with HPV acquisition generally occurring soon after first sexual activity ( 1 ). Most HPV infections are transient and asymptomatic. Persistent infections with high-risk (oncogenic) HPV types can lead to development of cervical, anal, penile, vaginal, vulvar, and oropharyngeal cancers, usually after several decades ( 1 ). Most new HPV infections occur in adolescents and young adults. Although most sexually active adults have been exposed to HPV ( 4 ), new infections can occur with a new sex partner ( 5 ). Three prophylactic HPV vaccines are licensed for use in the United States: 9-valent (9vHPV, Gardasil 9, Merck), quadrivalent (4vHPV, Gardasil, Merck), and bivalent (2vHPV, Cervarix, GlaxoSmithKline) ( 6 – 8 ). As of late 2016, only 9vHPV is distributed in the United States. The majority of HPV-associated cancers are caused by HPV 16 or 18, types targeted by all three vaccines. In addition, 4vHPV and 9vHPV target HPV 6 and 11, types that cause anogenital warts. 9vHPV also protects against five additional high-risk types: HPV 31, 33, 45, 52, and 58. In October 2018, using results from 4vHPV clinical trials in women aged 24 through 45 years, and bridging immunogenicity and safety data in women and men, the Food and Drug Administration expanded the approved age range for 9vHPV use from 9 through 26 years to 9 through 45 years in women and men ( 6 ). In June 2019, after reviewing evidence related to HPV vaccination of adults, ACIP updated recommendations for catch-up vaccination and for vaccination of adults older than the recommended catch-up age. Methods During April 2018–June 2019, the ACIP HPV Vaccines Work Group held at least monthly conference calls to review and discuss relevant scientific evidence regarding adult HPV vaccination using the Evidence to Recommendations framework. (https://www.cdc.gov/vaccines/acip/recs/grade/downloads/ACIP-evidence-rec-frame-508.pdf). The Work Group evaluated the quality of evidence for efficacy, safety, and effectiveness for HPV vaccination for primary prevention of HPV infection and HPV-related disease using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (https://www.cdc.gov/vaccines/acip/recs/grade/about-grade.html). Scientific literature published during January 1, 2006–October 18, 2018, was searched to identify clinical trials of any licensed HPV vaccine in adults aged 27 through 45 years. Detailed search methods and results for the GRADE tables are available at https://www.cdc.gov/vaccines/acip/recs/grade/HPV-adults.html. Benefits were based on per-protocol analyses of vaccine efficacy; immunogenicity data were also considered. Harms were any vaccine-related serious adverse events. Of 1,388 references identified, 100 were selected for detailed review, and 16 publications were included in GRADE tables presented at the October 2018 ACIP meeting; tables were updated in June 2019 to include new results from a 9vHPV trial. At the June 2019 ACIP meeting, two policy issues were considered: 1) harmonization of catch-up vaccination for all persons through age 26 years, and 2) vaccination of adults aged >26 years. Two Evidence to Recommendations documents were developed (https://www.cdc.gov/vaccines/acip/recs/grade/HPV-harmonization-etr.html ) ( https://www.cdc.gov/vaccines/acip/recs/grade/HPV-adults-etr.html) and presented along with proposed recommendations; after a public comment period, ACIP members voted unanimously to harmonize catch-up vaccination recommendations across genders for all persons through age 26 years. ACIP members also voted 10–4 in favor of shared clinical decision-making for adults aged 27 through 45 years, recognizing that some persons who are not adequately vaccinated might be at risk for new HPV infection and might benefit from vaccination in this age range. Summary of Key Findings Vaccine efficacy and safety. Data were considered from 11 clinical trials of 9vHPV, 4vHPV, and/or 2vHPV in adults aged 27 through 45 years, along with supplemental bridging immunogenicity data. In per-protocol analyses from three trials, 4vHPV and 2vHPV demonstrated significant efficacy against a combined endpoint of persistent vaccine-type HPV infections, anogenital warts, and cervical intraepithelial neoplasia (CIN) grade 1 (low-grade lesions) or worse. In nine trials, seroconversion rates to vaccine-type HPV after 3 doses of any HPV vaccine were 93.6%–100% at 7 months after the first dose. Overall evidence on benefits was GRADE evidence level 2, for moderate-quality evidence. In nine trials, few serious adverse events and no vaccine-related deaths were reported. Overall evidence on harms was also GRADE evidence level 2, for moderate-quality evidence. In the efficacy trial that was the basis for 9vHPV licensure for adults through age 45 years, per-protocol efficacy of 4vHPV among women aged 24 through 45 years was 88.7% (95% confidence interval [CI] = 78.1–94.8), and intention-to-treat efficacy was 47.2% (95% CI = 33.5–58.2) against a combined endpoint of persistent infections, extragenital lesions, and CIN 1+ related to HPV types 6, 11, 16, or 18 ( 9 ). HPV burden of disease and impact of the vaccination program in the United States. Approximately 33,700 cancers are caused by HPV in the United States each year, including 12,900 oropharyngeal cancers among men and women, 10,800 cervical cancers among women, and 6,000 anal cancers among men and women; vaginal, vulvar, and penile cancers are less common ( 10 ). HPV vaccination for adolescents has been routinely recommended for females since 2006 and for males since 2011 ( 1 ). The existing HPV vaccination program for adolescents has the potential to prevent the majority of these cancers. Mean age at acquisition of causal HPV infection for cancers is unknown, but is estimated to be decades before cancer is diagnosed. In 2017, coverage with ≥1 dose of HPV vaccine was 65.5% among adolescents aged 13 through 17 years ( 11 ). Although coverage with the recommended number of doses remains below the Healthy People 2020 target of 80% for adolescents ( 12 ), the U.S. HPV vaccination program has resulted in significant declines in prevalences of vaccine-type HPV infections, anogenital warts, and cervical precancers ( 13 ). For example, prevalences of 4vHPV vaccine-type infection during 2013–2016, compared with those of the prevaccine era, declined from 11.5% to 1.8% among females aged 14 through 19 years and from 18.5% to 5.3% among females aged 20 through 24 years ( 14 ). In addition, declines have been observed among unvaccinated persons, suggesting protective herd effects ( 15 ). Health economic analyses. Five health economic models of HPV vaccination in the United States were reviewed ( 16 ). The cost effectiveness ratio for the current HPV vaccination program ranged from cost-saving to approximately $35,000 per quality-adjusted life year (QALY) gained ( 16 ). In the context of the existing vaccination program, the incremental cost per QALY for expanding male vaccination through age 26 years was $178,000 in a subset of analyses in one of the five models reviewed using more favorable model assumptions for adult vaccination ( 16 ). In the context of the existing program, expanding vaccination to adults through age 45 years would produce relatively small additional health benefits and less favorable cost-effectiveness ratios. The incremental cost per QALY for also vaccinating adults through age 30 or 45 years exceeded $300,000 in four of five models ( 16 ). Variation in results across models was likely due to uncertainties about HPV natural history, such as prevalence of immunity after clearance of natural infections, and level of herd protection from the existing program. Under the existing program, in a subset of analyses in one of the five models reviewed using more favorable model assumptions for adult vaccination, the number needed to vaccinate (NNV) to prevent one case of anogenital warts, CIN grade 2 or worse (high-grade lesions), or cancer would be 9, 22, and 202, respectively. For expanding recommendations for males through age 26 years to harmonize catch-up vaccination across genders, these NNV would be 40, 450, and 3,260, respectively. For expanding recommendations to include adults through age 45 years, these NNV would be 120, 800, and 6,500, respectively ( 16 ). Rationale Adolescents remain the most important focus of the HPV vaccination program in the United States. Recommendations harmonized across genders will simplify the immunization schedule and be more feasible to implement. HPV vaccination is most effective when given before exposure to any HPV, as in early adolescence ( 1 – 3 ). Clinical trials have indicated that HPV vaccines are safe and effective against infection and disease attributable to HPV vaccine types that recipients are not infected with at the time of vaccination. Because HPV acquisition generally occurs soon after first sexual activity, vaccine effectiveness will be lower in older age groups because of prior infections. Some previously exposed adults will have developed natural immunity already. Exposure to HPV decreases among older age groups. Evidence suggests that although HPV vaccination is safe for adults aged 27 through 45 years, population benefit would be minimal; nevertheless, some adults who are not adequately vaccinated might be at risk for new HPV infection and might benefit from vaccination in this age range. Recommendations Children and adults aged 9 through 26 years. HPV vaccination is routinely recommended at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated. † Adults aged >26 years. Catch-up HPV vaccination is not recommended for all adults aged >26 years. Instead, shared clinical decision-making regarding HPV vaccination is recommended for some adults aged 27 through 45 years who are not adequately vaccinated. (Box). HPV vaccines are not licensed for use in adults aged >45 years. BOX Considerations for shared clinical decision-making regarding human papillomavirus (HPV) vaccination of adults aged 27 through 45 years Ideally, HPV vaccination should be given in early adolescence because vaccination is most effective before exposure to HPV through sexual activity. For adults aged 27 through 45 years who are not adequately vaccinated,* clinicians can consider discussing HPV vaccination with persons who are most likely to benefit. HPV vaccination does not need to be discussed with most adults aged >26 years. HPV is a very common sexually transmitted infection. Most HPV infections are transient and asymptomatic and cause no clinical problems. Although new HPV infections are most commonly acquired in adolescence and young adulthood, some adults are at risk for acquiring new HPV infections. At any age, having a new sex partner is a risk factor for acquiring a new HPV infection. Persons who are in a long-term, mutually monogamous sexual partnership are not likely to acquire a new HPV infection. Most sexually active adults have been exposed to some HPV types, although not necessarily all of the HPV types targeted by vaccination. No clinical antibody test can determine whether a person is already immune or still susceptible to any given HPV type. HPV vaccine efficacy is high among persons who have not been exposed to vaccine-type HPV before vaccination. Vaccine effectiveness might be low among persons with risk factors for HPV infection or disease (e.g., adults with multiple lifetime sex partners and likely previous infection with vaccine-type HPV), as well as among persons with certain immunocompromising conditions. HPV vaccines are prophylactic (i.e., they prevent new HPV infections). They do not prevent progression of HPV infection to disease, decrease time to clearance of HPV infection, or treat HPV-related disease. * Dosing schedules, intervals, and definitions of persons considered adequately vaccinated have not changed. Administration. Dosing schedules, intervals, and definitions of persons considered adequately vaccinated have not changed ( 3 ).No prevaccination testing (e.g., Pap or HPV testing) is recommended to establish the appropriateness of HPV vaccination. Cervical cancer screening. Cervical cancer screening guidelines and recommendations should be followed ( 17 ). Special populations and medical conditions. These recommendations for children and adults aged 9 through 26 years and for adults aged >26 years apply to all persons, regardless of behavioral or medical risk factors for HPV infection or disease. § For persons who are pregnant, HPV vaccination should be delayed until after pregnancy; however, pregnancy testing is not needed before vaccination. Persons who are breastfeeding or lactating can receive HPV vaccine. Recommendations regarding HPV vaccination during pregnancy or lactation have not changed ( 1 ). Future Research and Monitoring Priorities CDC continues to monitor safety of HPV vaccines and impact of the vaccination program on HPV-attributable outcomes, including prevalences of HPV infections, anogenital warts, cervical precancers, and cancers. ACIP reviews relevant data as they become available and updates vaccine policy as needed. Summary What is already known about this topic? Vaccination against human papillomavirus (HPV) is routinely recommended at age 11 or 12 years. Catch-up recommendations apply to persons not vaccinated at age 11 or 12 years. What is added by this report? After reviewing new evidence, CDC updated HPV vaccination recommendations for U.S. adults. What are the implications for public health practice? Routine recommendations for HPV vaccination of adolescents have not changed. Catch-up HPV vaccination is now recommended for all persons through age 26 years. For adults aged 27 through 45 years, public health benefit of HPV vaccination in this age range is minimal; shared clinical decision-making is recommended because some persons who are not adequately vaccinated might benefit.
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                Author and article information

                Contributors
                gadcollins@gmail.com
                Journal
                Infect Agent Cancer
                Infect Agent Cancer
                Infectious Agents and Cancer
                BioMed Central (London )
                1750-9378
                19 February 2021
                19 February 2021
                2021
                : 16
                : 16
                Affiliations
                [1 ]GRID grid.490228.5, ISNI 0000 0004 4658 9260, Rwanda Military Hospital, ; Kigali, Rwanda
                [2 ]GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Division of Cancer Prevention, , National Cancer Institute, ; Rockville, MD USA
                [3 ]Research for Development (RD Rwanda), Kigali, Rwanda
                [4 ]GRID grid.10818.30, ISNI 0000 0004 0620 2260, Center for Human Genetics, College of Medicine and Health Sciences, , University of Rwanda, ; Kigali, Rwanda
                [5 ]GRID grid.251993.5, ISNI 0000000121791997, Albert Einstein College of Medicine, ; Bronx, NY USA
                [6 ]GRID grid.48336.3a, ISNI 0000 0004 1936 8075, Division of Cancer Epidemiology and Genetics, , National Cancer Institute, ; Rockville, MD USA
                Author information
                http://orcid.org/0000-0002-5513-5522
                Article
                355
                10.1186/s13027-021-00355-6
                7893720
                33608036
                b1227f58-8ea3-492c-88c3-2530bfadb776
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 7 October 2020
                : 4 February 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: 5U54CA19016304
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                Research Article
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                © The Author(s) 2021

                Oncology & Radiotherapy
                hr-hpv persistence,incidence,hiv,hpv vaccine
                Oncology & Radiotherapy
                hr-hpv persistence, incidence, hiv, hpv vaccine

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