Eficacia, seguridad y recomendaciones de uso de vacunas contra el virus del papiloma humano (VPH) en niños expuestos e infectados por virus de inmunodeficiencia humana (VIH) / Efficacy, security and recommendations for the use of vaccines against human papilloma virus (HPV) in children exposed and infected with human immunodeficiency virus (HIV)

ANTECEDENTES: Las personas infectadas con VIH tienen mayor prevalencia y persistencia de infección por VPH, lo cual produce mayor riesgo de desarrollar enfermedades relacionadas con el VPH, incluyendo cáncer, y adquirir una enfermedad de progresión más rápida. Debido a ello, los programas de inmunización contra VPH son una prioridad de salud pública y una estrategia particularmente importante en la población infantil infectada o expuesta al VIH. OBJETIVO: Describir la evidencia sobre la eficacia, seguridad y recomendaciones de uso de vacunas contra el virus del papiloma humano (VPH) en niños expuestos e infectados con VIH. MÉTODO: Búsqueda electrónica de estudios publicados en español o inglés en PubMed, Cochrane Library, Web of Science y LILACS hasta el 11 de diciembre de 2021. Adicionalmente, se realizó una búsqueda en PubMed y repositorios de organismos elaboradores de Guías de Práctica Clínica. La selección de estudios fue desarrollada por un solo revisor. RESULTADOS: Inmunogenicidad contra VPH-6 El porcentaje de infectados y expuestos pero no infectados con VIH que alcanzó seropositividad fue 84.4% y 92.3% tras una dosis y 82.2% y 100% tras la tercera dosis. En infectados con VIH, la seropositividad después de completar tres dosis varió entre 96.6-100% al primer mes, y 88.5% a los 18 meses. Una cuarta dosis dos años después produjo seropositividad en el 97% a los 2 años, 99% a los 3.5 años y 95% a los 5 años. Inmunogenicidad contra VPH-11: El porcentaje de infectados y expuestos pero no infectados con VIH que alcanzó seropositividad fue 83.1% y 94.5% tras una dosis, y 84.4% y 100% tras la tercera dosis. En infectados con VIH, la seropositividad después de tres dosis varió entre 97.2-100% al primer mes y 84.6% a los 18 meses. Una cuarta dosis produjo seropositividad de 97%, 99% y 98% después de 2, 3.5 y 4-5 años. Inmunogenicidad contra VPH-16: El porcentaje de infectados y expuestos pero no infectados con VIH que alcanzó seropositividad fue 87.7% y 98.9% tras una dosis y 92.2% y 100% tras la tercera dosis. En infectados con VIH, la seropositividad luego de tres dosis varió entre 98.3-100% al primer mes y 100% a los 18 meses. Una cuarta dosis produjo seropositividad de 99% a los 2 a 3.5 años, y de 98% entre los 4 a 5 años. Inmunogenicidad contra VPH-18: La seropositividad en infectados y expuestos pero no infectados con VIH fue 62.3% y 86.8% tras una dosis, y 61.1% y 81.8% tras la tercera dosis. En infectados con VIH, la seropositividad después de tres dosis fue 72.5% a los 6 meses y 72% a los 18 meses. Una cuarta dosis produjo seropositividad en 81% de infectados a los 2 años, 77% a los 3.5 años, y 74% entre los 4 a 5 años. Eventos adversos asociados a la vacunación: Los eventos adversos (EA) fueron reportados en dos estudios y alcanzaron a 49-74.4% de infectados con VIH. Entre un 45.7-64% de los EA correspondieron a molestias en el sitio de inyección. Los EA sistémicos fueron principalmente fatiga y dolor de cabeza (11.4%). En un estudio se reportaron dos EA graves relacionados con la vacunación: nefritis y elevación de alanina aminostransferasa, resueltos sin necesidad de interrumpir el esquema de vacunación. Recomendaciones sobre la vacunación contra VHA en niños con VIH: Todas las GPC recomiendan inmunizar contra VPH. Las GPC de Ecuador, AEPCC, CDC y Colombia recomiendan inmunizar infectados con VIH independientemente de su sexo, mientras que OMS recomienda inmunizar solo a niñas, aunque su recomendación no es explícita para población con VIH. Ecuador y CDC recomiendan aplicar tres dosis y OMS recomienda aplicar dos dosis. En todas las GPC, la edad de inicio recomendada es a los 9 años, aunque Colombia hace la distinción de iniciar a los 11 años en varones. Ecuador, AEPCC y CDC recomiendan inmunizar contra VPH hasta los 26 años. CONCLUSIONES: En niños y adolescentes infectados con VIH, una serie de tres dosis de vacuna contra VPH produjo seropositividad superior a 80% para anticuerpos contra VPH-6, 11 y 16 en todos los periodos de tiempo evaluados, que abarcan un seguimiento de hasta 18 meses posteriores a finalizar la serie. Una dosis de refuerzo a los dos años logró seropositividad cercana al 100% que se mantuvo estable, incluso en periodos de seguimiento de hasta 4-5 años. En relación al genotipo 18 del VPH, la inmunización con tres dosis de vacuna tetravalente contra VPH logró baja seropositividad, entre 62-72%. Una dosis de refuerzo aumentó ligeramente la seropositividad hasta un 74% a los 4-5 años. A pesar de la seropositividad superior al 80% para los genotipos 6, 11 y 16 del VPH, fue consistente observar concentraciones más bajas de anticuerpos en infectados con VIH, en comparación con poblaciones no infectadas. La probabilidad de alcanzar seropositividad o concentraciones más altas de anticuerpos para los diferentes genotipos evaluados se incrementó con una menor edad de inicio de la inmunización, supresión o carga viral de VIH más baja, y niveles más altos de CD4 y CD8. La inmunización contra VPH produjo eventos adversos en 49-74% de participantes, siendo más de la mitad de ellos relacionados con dolor en la zona de punción. Los principales eventos adversos sistémicos fueron dolor de cabeza y fatiga transitorios. Eventos adversos graves asociados a la inmunización fueron muy poco frecuentes y resueltos sin necesidad de interrumpir el esquema de vacunación. Las GPC incluidas recomiendan vacunar contra VPH a la población infantil infectada con VIH independiente del sexo, excepto por OMS que recomienda inmunizar solo a niñas, aunque su recomendación no es explícita para población con VIH. La edad de inicio mayormente suele ser a los 9 años con un esquema de tres dosis.

Human Papillomavirus Vaccination After COVID-19.

The current global novel coronavirus disease 2019 (COVID-19) pandemic threatens to derail the uptake of human papillomavirus (HPV) vaccination in low- and lower-middle income countries with major disruptions to routine immunization and the introduction of new vaccines delayed. This has a major impact on the World Health Organization cervical cancer elimination strategy, where it is dependent on HPV vaccination as well as cervical cancer screening and treatment. We discuss current opportunities and barriers to achieve high uptake of HPV vaccination in low- and lower-middle income countries as well as the impact of COVID-19. Implementation of 4 key recommendations for HPV vaccination in low- and lower-middle income countries is needed: increased global financial investment; improved vaccine supply and accelerated use of a single-dose schedule; education and social marketing; and adoption of universal school-based delivery. With the commitment of the global health community, the adoption of these strategies would underpin the effective elimination of cervical cancer.

Public health impact and cost effectiveness of routine and catch-up vaccination of girls and women with a nine-valent HPV vaccine in Japan: a model-based study.

BACKGROUND: Combined with cancer screening programs, vaccination against human papillomavirus (HPV) can significantly reduce the high health and economic burden of HPV-related disease in Japan. The objective of this study was to assess the health impact and cost effectiveness of routine and catch-up vaccination of girls and women aged 11-26 years with a 4-valent (4vHPV) or 9-valent HPV (9vHPV) vaccine in Japan compared with no vaccination. METHODS: We used a mathematical model adapted to the population and healthcare settings in Japan. We compared no vaccination and routine vaccination of 12-16-year old girls with 1) 4vHPV vaccine, 2) 9vHPV vaccine, and 3) 9vHPV vaccine in addition to a temporary catch-up vaccination of 17-26 years old girls and women with 9vHPV. We estimated the expected number of disease cases and deaths, discounted (at 2% per year) future costs (in 2020 ¥) and discounted quality-adjusted life years (QALY), and incremental cost effectiveness ratios (ICER) of each strategy over a time horizon of 100 years. To test the robustness of the conclusions, we conducted scenario and sensitivity analyses. RESULTS: Over 100 years, compared with no vaccination, 9vHPV vaccination was projected to reduce the incidence of 9vHPV-related cervical cancer by 86% (from 15.24 new cases per 100,000 women in 2021 to 2.02 in 2121). A greater number of cervical cancer cases (484,248) and cancer-related deaths (50,102) were avoided through the described catch-up vaccination program. Routine HPV vaccination with 4vHPV or 9vHPV vaccine prevented 5,521,000 cases of anogenital warts among women and men. Around 23,520 and 21,400 diagnosed non-cervical cancers are prevented by catch-up vaccination among women and men, respectively. Compared with no vaccination, the ICER of 4vHPV vaccination was ¥975,364/QALY. Compared to 4vHPV, 9vHPV + Catch-up had an ICER of ¥1,534,493/QALY. CONCLUSIONS: A vaccination program with a 9-valent vaccine targeting 12 to 16 year-old girls together with a temporary catchup program will avert significant numbers of cases of HPV-related diseases among both men and women. Furthermore, such a program was the most cost effective among the vaccination strategies we considered, with an ICER well below a threshold of ¥5000,000/QALY.

Cost-effectiveness of Interventions to Increase HPV Vaccine Uptake.

OBJECTIVES: We sought to prioritize interventions for increasing human papillomavirus (HPV) vaccination coverage based on cost-effectiveness from a US state perspective to inform decisions by policy makers. METHODS: We developed a dynamic simulation model of HPV transmission and progression scaled to a medium-sized US state (5 million individuals). We modeled outcomes over 50 years comparing no intervention to a one-year implementation of centralized reminder and recall for HPV vaccination, school-located HPV vaccination, or quality improvement (QI) visits to primary care clinics. We used probabilistic sensitivity analysis to assess a range of plausible outcomes associated with each intervention. Cost-effectiveness was evaluated relative to a conservative willingness-to-pay threshold; $50 000 per quality-adjusted life-year (QALY) . RESULTS: All interventions were cost-effective, relative to no intervention. QI visits had the lowest cost and cost per QALY gained ($1538 versus no intervention). Statewide implementation of centralized reminder and recall cost $28 289 per QALY gained versus QI visits. School-located vaccination had the highest cost but was cost-effective at $18 337 per QALY gained versus QI visits. Scaling to the US population, interventions could avert 3000 to 14 000 future HPV cancers. When varying intervention cost and impact over feasible ranges, interventions were typically preferred to no intervention, but cost-effectiveness varied between intervention strategies. CONCLUSIONS: Three interventions for increasing HPV vaccine coverage were cost-effective and offered substantial health benefits. Policy makers seeking to increase HPV vaccination should, at minimum, dedicate additional funding for QI visits, which are consistently effective at low cost and may additionally consider more resource-intensive interventions (reminder and recall or school-located vaccination).

The last strategy for re-dissemination of HPV vaccination in Japan while still under the suspension of the governmental recommendation.

In Japan, the governmental recommnendation of HPV vaccine has been suspended since June 2013, due to media reports of alleged adverse vaccination events. Although evidence of effectiveness and safety of the HPV vaccine has been universally demonstrated, and the medical and academic organizations across Japan have requested the resumption of the government's recommendation, the Japanese government has not changed their official stance towards the HPV vaccine. Under the current suspension of the national government's recommendation, one local government Isumi City started sending a leaflet containing information of cervical cancer and HPV vaccine, but not recommendation for the vaccine, to the tagted girls born in the fiscal year (FY) 2003. The cumulative vaccination rate of them reached 10.07% (14/139), which was significantly higher than that (0.00%) for girls born in FY 2002 who did not receive such a leaflet (p < 0.001). We sincerely ask the national government to change their stance towards the HPV vaccine. We also strongly suggest that, in the meantime, local governments immediately begin to provide an appropriate information of cervical cancer and HPV vaccine to the targeted girls and their parents in a way similar to what Isumi City has now shown to be effective.

Comprehensive Assessment of the Antigenic Impact of Human Papillomavirus Lineage Variation on Recognition by Neutralizing Monoclonal Antibodies Raised against Lineage A Major Capsid Proteins of Vaccine-Related Genotypes.

Human papillomavirus (HPV) is the causative agent of cervical and other epithelial cancers. Naturally occurring variants of HPV have been classified into lineages and sublineages based on their whole-genome sequences, but little is known about the impact of this diversity on the structure and function of viral gene products. The HPV capsid is an icosahedral lattice comprising 72 pentamers of the major capsid protein (L1) and the associated minor capsid protein (L2). We investigated the potential impact of this genome variation on the capsid antigenicity of lineage and sublineage variants of seven vaccine-relevant, oncogenic HPV genotypes by using a large panel of monoclonal antibodies (MAbs) raised against the L1 proteins of lineage A antigens. Each genotype had at least one variant that displayed a ≥4-fold reduced neutralizing antibody sensitivity against at least one MAb, demonstrating that naturally occurring variation can affect one or more functional antigenic determinants on the HPV capsid. For HPV16, HPV18, HPV31, and HPV45, the overall impact was of a low magnitude. For HPV33 (sublineages A2 and A3 and lineages B and C), HPV52 (lineage D), and HPV58 (lineage C), however, variant residues in the indicated lineages and sublineages reduced their sensitivity to neutralization by all MAbs by up to 1,000-fold, suggesting the presence of key antigenic determinants on the surface of these capsids. These determinants were resolved further by site-directed mutagenesis. These data improve our understanding of the impact of naturally occurring variation on the antigenicity of the HPV capsid of vaccine-relevant oncogenic HPV genotypes.IMPORTANCE Human papillomavirus (HPV) is the causative agent of cervical and some other epithelial cancers. HPV vaccines generate functional (neutralizing) antibodies that target the virus particles (or capsids) of the most common HPV cancer-causing genotypes. Each genotype comprises variant forms that have arisen over millennia and which include changes within the capsid proteins. In this study, we explored the potential for these naturally occurring variant capsids to impact recognition by neutralizing monoclonal antibodies. All genotypes included at least one variant form that exhibited reduced recognition by at least one antibody, with some genotypes affected more than others. These data highlight the impact of naturally occurring variation on the structure of the HPV capsid proteins of vaccine-relevant oncogenic HPV genotypes.

Non-invasive Assessment of Vaccine-Induced HPV Antibodies via First-Void Urine.

The potential of first-void (FV) urine as a non-invasive method to monitor human papillomavirus (HPV) vaccination has been reported, mainly focusing on urine as a sample to assess HPV DNA. Besides HPV DNA, vaccine-induced HPV antibodies originating from cervicovaginal secretions were recently shown to be detectable in FV urine as well. This presents a novel opportunity for non-invasive sampling to monitor HPV antibody status in women participating in large epidemiological studies and HPV vaccine trials. The simultaneous assessment of both HPV infection and immunogenicity on a non-invasive, readily obtained sample is particularly attractive.

Geographical disparities in human papillomavirus herd protection.

BACKGROUND: Human papillomavirus (HPV) vaccination has occurred unequally across the United States, potentially contributing to uneven vaccine-type HPV prevalence between regions. We examined whether emerging vaccine-related herd protection exhibits regional differences among unvaccinated girls and women. METHODS: We evaluated the prevalence of vaginal HPV among women 14-59 years of age from 2003 to 2014 using repeated cross-sectional data from the National Health and Nutrition Examination Survey (NHANES). Women who provided an adequate vaginal swab sample were included. Vaginal prevalence of vaccine-type HPV (types 6, 11, 16, 18) were examined in four regions of the United States between 2003 and 2014. We examined vaccine-type HPV prevalence in 2007-2014 in each US census region among younger participants (14-34 years old) stratified by vaccination status to determine whether one or both groups contributed to uneven HPV prevalence. RESULTS: A total of 12 175 participants 14-59 years of age met inclusion criteria. Vaccine-type HPV prevalence decreased in all regions. Vaccine-type HPV varied by region only among unvaccinated 14-34 year olds, with a higher prevalence in the Midwest (13.8%, 95% confidence interval (CI): 10.7-17.0) and South (12.5%, 95% CI: 10.2-14.8) compared to the Northeast (8.9%, 95% CI: 6.5-11.2). No regional variation in vaccine-type HPV prevalence was observed among vaccinated participants. CONCLUSIONS: Higher prevalence of vaccine-type HPV among unvaccinated women in the South and Midwest may contribute to regional disparities in HPV-related cancer incidence, as emerging herd immunity may not be as strong in those regions.

Intralesional immunotherapy with purified protein derivative (PPD) for cryotherapy-resistant warts.

BACKGROUND: Cryotherapy and immunotherapeutic modalities elicit nonspecific immune response against the human papillomavirus. There is a paucity of literature on the effects of a sequential shift to immunotherapy in cryotherapy-resistant warts. AIM: To study the efficacy of intralesional purified protein derivative (PPD) immunotherapy in cryotherapy-resistant warts. METHODS: Patients with cryotherapy-recalcitrant cutaneous warts were given intralesional injections of PPD into the index warts (oldest or largest) at 2-week intervals until complete clearance or up to a maximum of six injections. The response in the treated index and distant warts was defined as complete, partial, and no response (<25%). Complete responders were followed up for another 3 months to check for recurrence. RESULTS: Twenty-eight patients completed the study protocol. Of the eight patients with single warts, four (50%), one (12.5%), and three (37.5%) patients had complete, partial, and no response, respectively. Of the 20 patients with multiple warts, nine (45%) had complete clearance of all warts, two (10%) each had complete and partial response in the index wart, respectively, with no response of the distant warts, and seven (35%) had no response in all warts. Complete response was seen in an average of 3.1 injections (range 1-5). There was no recurrence at the follow-up visit. CONCLUSION: Immunotherapy with PPD has potential in producing regional and remote wart regression even in cryotherapy-resistant warts. It is a safe and economical modality in children, multiple warts, and difficult-to-treat warts.

A roadmap for a comprehensive control of cervical cancer in Poland: integration of available solutions into current practice in primary and secondary prevention.

In Poland, cervical cancer incidence and mortality still remain considerably higher than in Western European countries or North America. Recent data indicate decreasing trends in women younger than 60 years and stable trends in older women. In this article, we identified obstacles in primary and secondary prevention of cervical cancer in Poland. We analysed local legislation, management structure and organization of cervical cancer prevention in Poland and reviewed solutions available and implemented in other European countries. The main weaknesses include: (i) very low coverage of organized screening; concurrent unregistered opportunistic screening with unknown coverage and high test consumption (ii) suboptimal quality assurance in organized screening and no external quality assurance in opportunistic screening (iii) very low coverage of human papillomavirus vaccination that is not centrally reimbursed (iv) absence of pilot evaluation of (a) interventions that may improve population coverage and (b) performance of new preventive strategies. The proposed solutions are multifaceted and involve: (i) legislative and organizational regulation of cervical cancer screening aimed at comprehensive registration of procedures, data access and quality assurance (ii) pilot testing and implementation of new ways to increase coverage of cervical cancer screening, in particular among older women (iii) pilot evaluation with possible introduction of human papillomavirus-based screening and (iv) inclusion of human papillomavirus vaccination into the reimbursed national immunization program.

Billing and payment of commercial and Medicaid health plan adult vaccination claims in Michigan since the Affordable Care Act.

BACKGROUND: Provider concern regarding insurance non-payment for vaccines is a common barrier to provision of adult immunizations. We examined current adult vaccination billing and payment associated with two managed care populations to identify reasons for non-payment of immunization insurance claims. METHODS: We assessed administrative data from 2014 to 2015 from Blue Care Network of Michigan, a nonprofit health maintenance organization, and Blue Cross Complete of Michigan, a Medicaid managed care plan, to determine rates of and reasons for non-payment of adult vaccination claims across patient-care settings, insurance plans, and vaccine types. We compared commercial and Medicaid payment rates to Medicare payment rates and examined patient cost sharing. RESULTS: Pharmacy-submitted claims for adult vaccine doses were almost always paid (commercial 98.5%; Medicaid 100%). As the physician office accounted for the clear majority (79% commercial; 69% Medicaid) of medical (non-pharmacy) vaccination services, we limited further analyses of both commercial and Medicaid medical claims to the physician office setting. In the physician office setting, rates of payment were high with commercial rates of payment (97.9%) greater than Medicaid rates (91.6%). Reasons for non-payment varied, but generally related to the complexity of adult vaccine recommendations (patient diagnosis does not match recommendations) or insurance coverage (complex contracts, multiple insurance payers). Vaccine administration services were also generally paid. Commercial health plan payments were greater for both vaccine dose and vaccine administration than Medicare payments; Medicaid paid a higher amount for the vaccine dose, but less for vaccine administration than Medicare. Patients generally had very low (commercial) or no (Medicaid) cost-sharing for vaccination. CONCLUSIONS: Adult vaccine dose claims were usually paid. Medicaid generally had higher rates of non-payment than commercial insurance.

Determining the HPV vaccine schedule for a HIV-infected population in sub Saharan Africa, a commentary.

BACKGROUND: Epidemiological studies have established human papillomavirus (HPV) infection as the central cause of invasive cervical cancer (ICC) and its precursor lesions. HIV is associated with a higher prevalence and persistence of a broader range of high-risk HPV genotypes, which in turn results in a higher risk of cervical disease. Recent WHO HPV vaccination schedule recommendations, along with the roll out of HAART at an earlier CD4 count within the female HIV-infected population, may have programmatic implications for sub Saharan Africa. This communication identifies research areas, which will need to be addressed for determining a HPV vaccine schedule for this population in sub Saharan Africa. A review of WHO latest recommendations and the evidence concerning one-dose HPV vaccine schedules was undertaken. CONCLUSION: For females ≥15 years at the time of first dose and immunocompromised and/or HIV-infected, a 3-dose schedule (0, 1-2, 6 months) is recommended for all three vaccines. There is some evidence that there is similar protection against HPV 16 and 18 infection from a single vaccination than from two or three doses, however there is no cross protection conferred to other genotypes. There is a need for periodic prevalence studies to determine the vaccination coverage of bivalent, quadrivalent and nonavalent vaccine targeted oncogenic HPV genotypes in women with CIN 3 or ICC at national level. In light of the increasing number of sub Saharan HIV-infected girls initiating HAART at a CD4 count above 350 mm3, there are a number of clinical, virological and public health research gaps to address before a tailored vaccine schedule can be established for this population.

No Vacillation on HPV Vaccination.

Evidence of the safety and protective benefits of human papillomavirus virus (HPV) vaccines as an anti-cancer measure is overwhelming. However, vaccine uptake varies widely across countries and falls short of levels needed to achieve population immunity. We highlight policy measures that would help ensure greater worldwide coverage and save lives.

Expanded strain coverage for a highly successful public health tool: Prophylactic 9-valent human papillomavirus vaccine.

Human papillomavirus is considered the causative factor for cervical cancer, which accounts for approximately 5% of the global cancer burden and more than 600,000 new cases annually that are attributable to HPV infection worldwide. The first-generation prophylactic HPV vaccines, Gardasil® and Cervarix®, were licensed approximately a decade ago. Both vaccines contain the most prevalent high-risk types, HPV16 and 18, which are associated with 70% of cervical cancer. To further increase the type coverage, 5 additional oncogenic HPV types (31, 33, 45, 52 and 58) were added to the existing Gardasil-4 to develop a 9-valent HPV vaccine (9vHPV), Gardasil 9®, increasing the potential level of protection from ∼70% to ∼90%. The efficacy of the vaccine lies primarily in its ability to elicit type-specific and neutralizing antibodies to fend off the viral infection. Therefore, type-specific and neutralizing murine monoclonal antibodies (mAbs) were used to quantitate the antigenicity of the individual vaccine antigens and to measure the antibody levels in the serum samples from vaccinees in a type- and epitope-specific manner in a competitive immunoassay. Assays for 9vHPV are extended from the proven platform used for 4vHPV by developing and adding new mAbs against the additional types. In Phase III clinical trials, comparable safety profile and immunogenicity against the original 4 types were demonstrated for the 9vHPV vaccine, and these were comparable to the 4vHPV vaccine. The efficacy of the 9vHPV vaccine was established in trials with young women. Immunobridging for younger boys and girls was performed, and the results showed higher immunogenicity in the younger age group. In a subsequent clinical trial, the 2-dose regimen of the 9vHPV vaccine used among girls and boys aged 9-14 y showed non-inferior immunogenicity to the regular 3-dose regimen for young women (aged 16-26 years). Overall, the clinical data and cost-effectiveness analysis for the 9vHPV vaccine support its widespread use to maximize the impact of this important, life-saving vaccine.

Health economic analysis of human papillomavirus vaccines in women of Chile: perspective of the health care payer using a Markov model.

BACKGROUND: In Chile, significant reductions in cervical cancer incidence and mortality have been observed due to implementation of a well-organized screening program. However, it has been suggested that the inclusion of human papillomavirus (HPV) vaccination for young adolescent women may be the best prospect to further reduce the burden of cervical cancer. This cost-effectiveness study comparing two available HPV vaccines in Chile was performed to support decision making on the implementation of universal HPV vaccination. METHODS: The present analysis used an existing static Markov model to assess the effect of screening and vaccination. This analysis includes the epidemiology of low-risk HPV types allowing for the comparison between the two vaccines (HPV-16/18 AS04-adjuvanted vaccine and the HPV-6/11/16/18 vaccine), latest cross-protection data on HPV vaccines, treatment costs for cervical cancer, vaccine costs and 6% discounting per the health economic guideline for Chile. RESULTS: Projected incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratio (ICERs) for the HPV-16/18 AS04-adjuvanted vaccine was 116 United States (US) dollars per quality-adjusted life years (QALY) gained or 147 US dollars per life-years (LY) saved, while the projected ICUR/ICER for the HPV-6/11/16/18 vaccine was 541 US dollars per QALY gained or 726 US dollars per LY saved. Introduction of any HPV vaccine to the present cervical cancer prevention program of Chile is estimated to be highly cost-effective (below 1X gross domestic product [GDP] per capita, 14278 US dollars). In Chile, the addition of HPV-16/18 AS04-adjuvanted vaccine to the existing screening program dominated the addition of HPV-6/11/16/18 vaccine. In the probabilistic sensitivity analysis results show that the HPV-16/18 AS04-adjuvanted vaccine is expected to be dominant and cost-saving in 69.3% and 77.6% of the replicates respectively. CONCLUSIONS: The findings indicate that the addition of any HPV vaccine to the current cervical screening program of Chile will be advantageous. However, this cost-effectiveness model shows that the HPV-16/18 AS04-adjuvanted vaccine dominated the HPV-6/11/16/18 vaccine. Beyond the context of Chile, the data from this modelling exercise may support healthcare policy and decision-making pertaining to introduction of HPV vaccination in similar resource settings in the region.

Costs and cost-effectiveness of 9-valent human papillomavirus (HPV) vaccination in two East African countries.

BACKGROUND: Current prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15-30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda). METHODS AND FINDINGS: The analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3% in the base case analysis. We conducted sensitivity analyses to investigate how infection with multiple HPV types, unidentifiable HPV types in cancer cases, and cross-protection against non-vaccine types could affect the potential cost range of the 9-valent vaccine. In the base case analysis in Kenya, we found that vaccination with the 9-valent vaccine was very cost-effective (i.e., had an incremental cost-effectiveness ratio below per-capita GDP), compared to the current vaccines provided the added cost of the 9-valent vaccine did not exceed I$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. CONCLUSIONS: This study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71% and 61% increase over the price offered to the GAVI Alliance ($5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain.

Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study.

BACKGROUND: After the introduction of a quadrivalent human papillomavirus (HPV) vaccination programme in Australia in April, 2007, we measured the prevalence of vaccine-targeted and closely related HPV types with the aim of assessing direct protection, cross-protection, and herd immunity. METHODS: In this repeat cross-sectional study, we recruited women aged 18-24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18-24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012. We compared the crude prevalence of HPV genotypes in cervical specimens between the prevaccine and the postvaccine implementation groups, with vaccination status validated against the National HPV Vaccination Program Register. We estimated adjusted prevalence ratios using log linear regression. We estimated vaccine effectiveness both for vaccine-targeted HPV types (16, 18, 6, and 11) and non-vaccine but related HPV types (31, 33, and 45). FINDINGS: 202 women were recruited into the prevaccine-implementation group, and 1058 were recruited into the postvaccine-implementation group. Crude prevalence of vaccine-targeted HPV genotypes was significantly lower in the postvaccine-implementation sample than in the prevaccine-implementation sample (58 [29%] of 202 vs 69 [7%] of 1058; p<0·0001). Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0·07 (95% CI 0·04-0·14; p<0·0001) in fully vaccinated women and 0·65 (0·43-0·96; p=0·03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes. However, within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71-93), and was 58% (26-76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45). INTERPRETATION: 6 years after the initiation of the Australian HPV vaccination programme, we have detected a substantial fall in vaccine-targeted HPV genotypes in vaccinated women; a lower prevalence of vaccine-targeted types in unvaccinated women, suggesting herd immunity; and a possible indication of cross-protection against HPV types related to the vaccine-targeted types in vaccinated women. FUNDING: Australian National Health and Medical Research Council and Cancer Council Victoria.

Cost-effectiveness analysis of the bivalent and quadrivalent human papillomavirus vaccines from a societal perspective in Colombia.

OBJECTIVE: To compare costs and effectiveness of three strategies used against cervical cancer (CC) and genital warts: (i) Screening for CC; (ii) Bivalent Human Papillomavirus (HPV) 16/18 vaccine added to screening; (iii) Quadrivalent HPV 6/11/16/18 vaccine added to screening. METHODS: A Markov model was designed in order to simulate the natural history of the disease from 12 years of age (vaccination) until death. Transition probabilities were selected or adjusted to match the HPV infection profile in Colombia. A systematic review was undertaken in order to derive efficacy values for the two vaccines as well as for the operational characteristics of the cytology test. The societal perspective was used. Effectiveness was measured in number of averted Disability Adjusted Life Years (DALYS). RESULTS: At commercial prices reported for 2010 the two vaccines were shown to be non-cost-effective alternatives when compared with the existing screening strategy. Sensitivity analyses showed that results are affected by the cost of vaccines and their efficacy values, making it difficult to determine with certainty which of the two vaccines has the best cost-effectiveness profile. To be 'cost-effective' vaccines should cost between 141 and 147 USD (Unite States Dollars) per vaccinated girl at the most. But at lower prices such as those recommended by WHO or the price of other vaccines in Colombia, HPV vaccination could be considered very cost-effective. CONCLUSIONS: HPV vaccination could be a convenient alternative for the prevention of CC in Colombia. However, the price of the vaccine should be lower for this vaccination strategy to be cost-effective. It is also important to take into consideration the willingness to pay, budgetary impact, and program implications, in order to determine the relevance of a vaccination program in this country, as well as which vaccine should be selected for use in the program.

Factors associated with human papillomavirus vaccination among young adult women in the United States.

BACKGROUND: Human papillomavirus (HPV) vaccination is recommended to protect against HPV-related diseases. OBJECTIVE: To estimate HPV vaccine coverage and assess factors associated with vaccine awareness, initiation and receipt of 3 doses among women age 18-30 years. METHODS: Data from the 2010 National Health Interview Survey were analyzed to assess associations of HPV vaccination among women age 18-26 (n=1866) and 27-30 years (n=1028) with previous HPV exposure, cervical cancer screening and selected demographic, health care and behavioral characteristics using bivariate analysis and multivariable logistic regression. RESULTS: Overall, 23.2% of women age 18-26 and 6.7% of women age 27-30 years reported receiving at least 1 dose of HPV vaccine. In multivariable analyses among women age 18-26 years, not being married, having a regular physician, seeing a physician or obstetrician/gynecologist in the past year, influenza vaccination in the past year, and receipt of other recommended vaccines were associated with HPV vaccination. One-third of unvaccinated women age 18-26 years (n=490) were interested in receiving HPV vaccine. Among women who were not interested in receiving HPV vaccine (n=920), the main reasons reported included: not needing the vaccine (41.3%); concerns about safety of the vaccine (12.5%); not knowing enough about the vaccine (11.9%); not being sexually active (8.2%); a doctor not recommending the vaccine (7.6%); and already having HPV (2.7%). Among women with health insurance, 10 or more physician contacts within the past year and no contraindications, 74.5% reported not receiving HPV vaccine. CONCLUSIONS: HPV vaccination coverage among women age 18-26 years remains low. Opportunities to vaccinate are missed. Healthcare providers can play an important role in educating young women about HPV and encouraging vaccination. Successful public health and educational interventions will need to address physician attitudes and practice patterns and other factors that influence vaccination behaviors.