Human Papillomavirus and Vaccination

Maximizing the Potential Public Health Impact of HPV Vaccines: A Focus on Parents

INTRODUCTION Cervical cancer (CC) is the fourth most common malignancy in women, with a global estimate of 570,000 new cases and 311,000 deaths in 2018.[1] Approximately 27,000 anal, 27,000 vulvar, 13,000 vaginal and 22,000 penile cancer cases are diagnosed worldwide annually.[2] Human papillomavirus (HPV) infection is the leading cause of CC and has been identified as a human carcinogen for vulvar, vaginal, penile and head and neck cancers, thus accounting for a significant proportion of the global cancer burden.[2-4] Most HPV-related diseases occur in underdeveloped or developing countries, with the incidence rates being higher in Central and South America, Sub-Saharan Africa and South Asia.[5,6] In Malaysia, CC is the third most common female cancer, with around 1,682 new cases and 944 deaths occurring annually.[1] The age-standardised incidence of HPV-related female CC in Malaysia is 10.5 per 100,000 women per year versus 17.2 per 100,000 women per year in Southeast Asia and 13.1 per 100,000 women per year worldwide.[1,3] Crude incidence rates for female anal, vulvar and vaginal cancers in Malaysia range from 0.2 to 0.7 per 100,000 women per year,[3] and rates of male anal and penile cancers are 0.0–0.3 and 0.1–0.7 per 100,000 men per year, respectively.[3] More than 200 HPV types have been identified; of these, 85 have been characterised.[7] HPV types 16/18/31/33/45/52/58 are high risk and oncogenic,[7] whereas HPV types 6/11 have been associated with genital warts. In Malaysia, high-risk HPV types account for 93% of all HPV infections in women aged 18–60 years[8] and oncogenic HPV types 16/18/52/58 account for 52.8%/35.9%/10.7%/8.9% of CC cases, 41.1%/8.2%/20.5%/8.2% of high-grade cervical lesions and 26.1%/4.3%/17.4%/(no data available for HPV 58) of low-grade cervical lesions.[3] In addition, HPV types 52 and 58 are the second and third most prevalent types detected from the cervicovaginal swabs of healthy adults in Malaysia, with detection rates of 12.8% and 8.1%, respectively.[8] These Malaysian estimates are higher than the global percentages of HPV 52/58-attributable CC, high-grade cervical lesions and low-grade cervical lesions (7.4%, 19.1% and 15.6%, respectively).[2] Globally, HPV types 16/18 account for approximately 70% of all CCs;[9] they are also the most common HPV types detected in patients with HPV-related anal (84.3%), vaginal (63.7%), penile (70.2%) and head and neck (85.2%) cancers.[9] Furthermore, HPV 16/18/31/33/45/52/58 together account for most of the HPV-related cervical (89.3%), anal (95.3%), vaginal (85.3%), penile (84.4%) and head and neck (90.0%) cancers.[9] Low-risk HPV types 6/11 have been linked to most genital wart cases worldwide, with an estimated global annual incidence of 1.60–2.89 cases per 1,000 people.[10] In Singapore, an analysis of data from the National Skin Centre estimated the annual genital warts incidence to be 0.28 cases per 1,000 people in 2008.[11] Although there is a dearth of data on local genital wart incidence, an earlier study conducted in Malaysia estimated that only 30% of genital wart cases (approximately 2,304 treated cases per year) in women received treatment annually.[12] The relative HPV disease burden attributed to various HPV types can be seen in Table S1 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[3,5,13-15] Currently, three HPV vaccines are available: a bivalent vaccine (2vHPV) targeting HPV 16/18, a quadrivalent vaccine (4vHPV) targeting HPV 6/11/16/18 and a nonavalent vaccine (9vHPV) targeting HPV 6/11/16/18/31/33/45/52/58.[16] As of 15 July 2020, 106 countries have introduced HPV immunisation programmes, including 15 out of 27 (56%) countries in the Western Pacific and 6 out of 11 (55%) countries in the Southeast Asian region (including Malaysia).[17] In countries where an HPV vaccination programme has been implemented, reduction in vaccine-type HPV infections, genital warts and cervical precancers has already been observed.[18] Currently, the CC cytology screening programme in Malaysia recommends women aged 20–65 years to be screened every 3 years; however, screening uptake is low at 22% and there is no active invitation to the programme.[3] In 2010, in an effort to prevent HPV-related diseases, Malaysia introduced routine HPV vaccination with either the 2vHPV or 4vHPV vaccine available in a three-dose schedule through schools and community health centres as part of its free national immunisation programme (NIP) for 13-year-old girls, which achieved 94% coverage in the target group by 2013.[19,20] the NIP converted the HPV vaccination to a two-dose schedule in 2014.[3] The Malaysian government also implemented catch-up vaccination for girls aged 18 years, which achieved an 87% coverage rate.[20] Neither the 2vHPV nor the 4vHPV vaccine protects against HPV 52/58-related infections, which are among the most prevalent types detected in women with invasive CC in Malaysia.[3] Because the 9vHPV vaccine provides broader coverage, including prevention against HPV 52/58-related infections, it is necessary to assess the potential impact of introducing 9vHPV as part of the Malaysian NIP. A large randomised clinical trial showed that the 9vHPV vaccine prevented HPV 31/33/45/52/58-related infections and diseases in a susceptible population and generated an antibody response to HPV 6/11/16/18 that was non-inferior to that generated by the 4vHPV vaccine.[21] In a subanalysis of an international phase 2b/3 study, the 9vHPV vaccine prevented HPV 31/33/45/52/58-related persistent (≥6 months) infections in Asian participants aged 16–26 years at sites in Hong Kong, Taiwan, Japan, South Korea and Thailand, with an efficacy of 95.8% (95% confidence interval [CI] 87.8–98.9).[22] Furthermore, the per-protocol efficacy population of this study demonstrated that 9vHPV reduced the incidence of HPV 52- and 58-related persistent infection by 91.3% (95% CI 74.5–97.7) and 100.0% (95% CI 86.3–100.0), respectively.[22] The objective of this study was to compare the public health and economic impact of implementing a routine vaccination programme with two-dose 9vHPV vaccination compared to two-dose 2vHPV or 4vHPV vaccination in 13-year-old girls in Malaysia. Results from this model will assist the Malaysian healthcare policymakers in identifying a cost-effective programme to avert HPV-related diseases. METHODS Model design A previously validated HPV-type transmission dynamic model simulating the natural history of HPV infections and estimating the cost associated with HPV-related diseases[23] was adapted to the Malaysia setting to evaluate the public health and economic impact of vaccinating 13-year-old girls with the 9vHPV versus the 2vHPV or 4vHPV vaccines. HPV infection and disease state transitions, lifetime duration of infection-derived immunity and unvaccinated compartments of the current model have been previously described in detail.[23] The population impact was estimated for the entire Malaysian population. Model compartments The age-structured mathematical population model incorporates epidemiology of HPV infection, disease and economics into a single dynamic model to capture both the direct and indirect herd immunity benefits and costs of HPV vaccination for the population over time in a transparent and reproducible manner. The model structure and assumptions have been previously described in detail [see Supplemental Digital Appendix 1 https://links.lww.com/SGMJ/A49].[23] The model comprises three connected modules: (1) a demographic variables model describing how individuals enter, age and exit the model (modelling of birth, ageing and death, and a behavioural model describing sexual activity);(2) an epidemiological model simulating the transmission of HPV 6/11/16/18/31/33/45/52/58, occurrence of genital warts, precancers such as cervical intraepithelial neoplasia (CIN) 1/2/3 and vaccine type-related CC; and (3) a disease variables model describing the rates of screening, HPV infection and HPV-related disease transmission.[23] Epidemiological model parameters Epidemiological model inputs comprising demographic details, sexual behaviour, disease and treatment patterns, and CC screening were taken from publicly available sources and unpublished data (provided by Prof Woo YL; available upon request) and are described in detail in Supplemental Digitial Appendix 1 https://links.lww.com/SGMJ/A49 and Table S2 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[3,10-13,16,18,24,25] Local Malaysia-specific data were utilised whenever available. The prophylactic efficacy of all three vaccines was assumed to be equivalent against HPV 6/11 (4vHPV and 9vHPV) and against HPV 16/18 (2vHPV, 4vHPV and 9vHPV) based on clinical trial data, as shown in Table S3 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50].[21,26-30] The model assumed lifelong duration of protection against HPV types 6/11/16/18/31/33/45/52/58 and herd immunity. Economic model parameters The economic model allowed us to estimate total costs, survival (life-years gained), quality-adjusted survival (quality-adjusted life-years [QALYs]) and incremental cost-effectiveness ratio (ICER). Inputs for the economic model included vaccine strategy and cost parameters. All costs were from a healthcare provider perspective and were reported in 2018 Malaysian ringgit (RM). A discount rate of 3% for costs and QALYs was applied to the model.[31] The base cases analyses were conducted according to two different scenarios: two-dose vaccination strategy of 9vHPV versus 4vHPV in 13-year-old girls and two-dose vaccination strategy of 9vHPV versus 2vHPV in 13-year-old girls. Both scenarios were assessed at a vaccine coverage rate (VCR) of 90%. Cost parameters used in the model included cost per episode of care, cost of vaccination and cost of screening tests, as shown in Table S4 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50]. Outcome parameters The following health outcome parameters were estimated using the model: the cumulative incidence and number of prevented cases of CIN (1/2/3), CC and genital warts, and the cumulative reduction of premature CC deaths. The model also estimated the following economic outcome parameters: cumulative HPV-related disease healthcare costs, QALYs of the model population, and the ICER, which was estimated as the ratio of incremental vaccination costs and incremental QALYs. Cost-effectiveness was assumed at a ceiling threshold of RM 43,378, or USD 10,252, which corresponded to 1 gross domestic product (GDP) per capita in Malaysia in 2020 and reflected the maximum willingness of decision-makers to pay for an additional QALY.[31,32] Health outcomes and costs were assessed over a 100-year time horizon because a long period of time is required before the benefit of HPV vaccination on clinical outcomes and costs become apparent.[33-35] All model equations and inputs were programmed in Mathematica (Wolfram Research, Champaign, IL, USA) version 5.2, and the NDSolve subroutine in Mathematica was used to generate numerical solutions for the differential equations making up the model. Model calibration Calibration of the current model is described in Supplemental Digital Appendix 1 https://links.lww.com/SGMJ/A49 and Tables S1 & S2 [see Supplemental Digital Appendix 2 https://links.lww.com/SGMJ/A50]. Sensitivity analyses Deterministic one-way sensitivity analyses were conducted to assess the sensitivity of ICER values to variables that may have an impact on cost-effectiveness. These included VCR for both males and females, which was assessed at different levels (VCR 80% and 95%), and discount rate of costs and QALYs (0% and 5%). RESULTS HPV-related disease incidence Over a 100-year period, greater overall reduction in estimated cumulative HPV-related disease incidence was observed for the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine [Table 1]. The predicted cumulative reduction in CC incidence over 100 years with the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine was 41,079 CC cases avoided (35.8% reduction), as shown in Table 1 and Figure S1A [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51], whereas the predicted cumulative reductions in HPV 16/18-related CIN 1 and CIN 2/3 incidence with the 9vHPV versus the 2vHPV or 4vHPV vaccine were 143,455 (51.0% reduction) and 294,142 (48.9%) cases, respectively, as shown in Table 1 and Figures S1B & S1C [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. The model also predicted cumulative reduction of 10,873 CC deaths (30.5%) when vaccinating with the 9vHPV vaccine versus the 2vHPV or 4vHPV vaccine, as shown in Table 1 and Figure S1D [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. The 9vHPV vaccine also resulted in reduction of approximately 1.32 million and 1.15 million cases of genital warts (78.9% and 65.8% reduction, respectively) among females and males, respectively, versus 2vHPV [Table 1]. Reduction in the incidence of genital warts and HPV 6/11-related CIN 1 was projected to be observed as early as during the first 5 years after implementation of routine immunisation in females with the 9vHPV vaccine versus the 2vHPV vaccine, as shown in Table 1 and Figures S1E–S1G [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51].Table 1: Cumulative reductions in incidence of HPV-related diseasea and deaths upon vaccination with the 9vHPV vs. 2vHPV & 4vHPV vaccines over a 100-year period.Cost-effectiveness analyses Cumulative disease-related costs were estimated to decrease by RM 1,262,728,192 and RM 94,913,034, with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines, respectively [Table 2]. Cost reduction with the 9vHPV vaccine versus the 2vHPV vaccine was predicted to be attributable mainly to savings in HPV 6/11-related treatment, as shown in Figure S2A [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51], together with cost savings related to HPV 31/33/45/52/58-related outcomes, whereas cost savings versus the 4vHPV vaccine were predicted to be attributable to savings in HPV 31/33/45/52/58-related treatment, as shown in Figure S2B [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. When avoided HPV 6/11/16/18/31/33/45/52/58-related disease costs were applied to vaccination costs, net vaccination costs were RM 1,604,230,042 and RM 2,271,267,004 for 9vHPV versus 2vHPV and 4vHPV, respectively. Implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines led to increases of 0.00402 and 0.00286 QALYs per person, respectively. As a result, the overall ICERs of implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines were RM 12,593/QALY and RM 25,011/QALY, respectively [Table 3].Table 2: Estimated reductions in cumulative HPV-related disease costs with the 9vHPV vs. 2vHPV & 4vHPV vaccines over a 100-year period.Table 3: Cost–effectiveness analysis of HPV vaccination strategies.Sensitivity analyses When a sensitivity analysis was conducted for which VCR was adjusted, reducing the VCR to 80% was found to decrease ICERs of implementing a routine vaccination programme in females with the 9vHPV vaccine versus the 2vHPV and 4vHPV vaccines to RM 11,756/QALY and RM 23,321/QALY, respectively , as shown in Figure S3 [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. In contrast, increasing the VCR to 95% was found to increase ICERs for the 9vHPV versus the 2vHPV and 4vHPV vaccines to RM 13,009/QALY and RM 25,865/QALY, respectively. Adjustment of discount rate of costs and QALYs had the largest impact on cost-effectiveness, as shown in Figure S3 [see Supplemental Digital Appendix 3 https://links.lww.com/SGMJ/A51]. When costs and QALYs were not discounted (0% discount rate), ICERs for the 9vHPV versus the 2vHPV and 4vHPV vaccines were found to be decreased to RM 3,791/QALY and RM 9,823/QALY, respectively. In contrast, increasing the discount rate of costs and QALYs to 5% was found to increase ICERs to RM 25,976/QALY and RM 50,535/QALY, respectively. DISCUSSION This analysis predicted the impact of replacing the 2vHPV and 4vHPV vaccines used in the current HPV NIP in Malaysia with the 9vHPV vaccine on HPV-related disease incidence and HPV-related healthcare costs. The model estimated that switching to the 9vHPV vaccine would lead to substantial reduction in CC and cervical lesions over the course of 100 years. As both the 4vHPV and 9vHPV vaccines protect against infection from HPV 6/11, estimated reductions in genital warts were deemed equivalent; similarly, as both the 2vHPV and 4vHPv vaccines protect against HPV 16/18, the 9vHPV vaccine demonstrated equivalent reduction in HPV 16/18-related CCs when compared to both of them. Previously, implementation of a school-based 2vHPV vaccination programme for 12-year-old girls in Singapore was shown to be cost-effective versus screening only and dominant over 4vHPV vaccination.[36] However, the study used a static lifetime Markov model, which is not the preferred model for HPV infection given that the force of infection can change over time following vaccination.[37] Furthermore, health disutility and the economic impact of genital warts were not considered in the base case analysis. Subsequently, a similar transmission dynamic model demonstrated that school-based 9vHPV vaccination of 11- to 12-year-old girls in Singapore would provide incremental benefit with the additional coverage of HPV 31/33/45/52/58-related precancerous lesions and CC, thus making 9vHPV vaccination a cost-effective strategy relative to either 2vHPV or 4vHPV.[38] It should be noted that the distribution of oncogenic HPV genotypes contributing to CC differs between Southeast Asia (i.e. Malaysia and Singapore) and Western countries (i.e. the USA and the United Kingdom), with HPV 52/58 being more prevalent in Southeast Asia.[39-42] Therefore, the benefit of 9vHPV vaccination in Malaysia would be similar to that in Singapore. Previous analyses showed that implementing national HPV vaccination programmes had overall positive clinical and economic impact. In Australia, implementation of the programme with the 4vHPV vaccine led to reduced incidence of genital warts in males and females,[43,44] and an analysis of surveillance data through June 2014 demonstrated that genital warts have become rare among young Australian women and heterosexual men.[45] In a systematic review of 10 years of experience in the real-world setting, prophylactic 4vHPV vaccination resulted in maximal reductions in low- and high-grade cervical abnormalities of 45% and 85%, respectively.[46] For example, within 5 years of implementing Australia's 4vHPV vaccination programme in females aged 12–26 years in Victoria, the overall reductions in low- and high-grade cervical cytological abnormalities were found to be 34% and 47%, respectively.[46,47] Similarly, other countries (Denmark and Colombia) have also reported the long-term effectiveness of the 4vHPV vaccine in terms of reduction in cervical cytological abnormalities after 6 years of follow-up.[48,49] Taken together, ensuring broad coverage against HPV infections may provide additional public health benefits and lessen the HPV-related burden on the national health system. A large community-based survey of healthy women in Malaysia reported that three of the top five most prevalent HPV types were the high-risk types 16/52/58 targeted by the 9vHPV vaccine.[8] Given the high prevalence of CC and the current low cervical screening uptake (uptake rate of 22%[3]) in Malaysia, expanding HPV vaccine coverage to include protection against five additional high-risk types with the 9vHPV vaccine is likely to be beneficial in the long term to overall CC and HPV-related cancer rates. When assessing disease costs, the estimated reduction in healthcare costs over 100 years after applying a 3% discount rate for the 9vHPV vaccine was 43.0% versus the 2vHPV vaccine and 5.4% versus the 4vHPV vaccine. The large reduction in costs when switching to the 9vHPV vaccine versus the 2vHPV vaccine is largely due to reduction in treating genital warts and HPV 31/33/45/52/58-associated cervical lesions and cancers. The 2vHPV and 4vHPV vaccines do not provide protection against HPV types 52/58, which are highly prevalent in Malaysia.[8] We did not assume any cross protection for 2vHPV. Previous studies evaluating the 2vHPV vaccine have demonstrated cross-protective efficacy against infection from HPV 31/33/45; however, cross protection was not consistent across studies and may have been confounded by differences in study design and co-infections with HPV 16/18.[50-53] In addition, there was little to no evidence of cross protection against HPV 52/58.[16] The cost-per-QALY gained of vaccination with the 9vHPV vaccine in 13-year-old girls in Malaysia was RM 12,593 versus the 2vHPV vaccine and RM 25,011 versus the 4vHPV vaccine, assuming equal vaccine efficacy, lifelong protection and no cross protection, which are well below the established threshold of RM 43,378 (1 GDP per capita in Malaysia in 2020).[31,32] Furthermore, sensitivity analyses demonstrated that vaccination with the 9vHPV vaccine remained cost-effective at VCRs of 80% and 95%. Although vaccination with the 9vHPV vaccine also remained cost-effective at a cost and QALYs discount rate of 0% (less than RM 10,000/QALY), cost-effectiveness at a 5% discount rate increased substantially for the 9vHPV versus the 2vHPV vaccines (RM 25,976/QALY) and exceeded the established threshold of RM 43,378 for the 9vHPV versus the 4vHPV vaccines (RM 50,535/QALY). This can be explained by the fact that the benefits of vaccinating girls aged 11–12 years in the prevention of CC and other HPV-related cancers are only realised at a late stage of the time horizon. Therefore, applying a high discount rate to future health outcomes will be less valuable, resulting in less-favourable outcomes from the economical evaluation. A limitation of this study is that our model is based on lifelong protection; however, the duration of protection for all HPV vaccines is not known. Another limitation of the study was that protection from the additional five HPV types targeted by the 9vHPv vaccine (31/33/45/52/58) was assumed only for CC; the impact of protection against HPV 31/33/45/52/58 on the incidence of vulvar, vaginal, anal, penile, and head and neck cancers was not estimated. This assumption provides a conservative estimate of the public health benefit associated with the 9vHPV vaccine. A further limitation is that cost-effectiveness was determined at a ceiling threshold of RM 43,378 or USD 10,252, which reflected the maximum willingness of decision-makers to pay for an additional QALY.[31,32] In addition, the model does not take into account improvements in cervical screening methods over the course of the 100 years, which could further reduce HPV-related healthcare costs. In conclusion, this analysis demonstrated that use of the 9vHPV vaccine in the national vaccination programme in Malaysia is projected to lead to greater reduction in HPV-related disease and to be highly cost-effective in comparison to either the 2vHPV or 4vHPV vaccine. Acknowledgement We thank Woo Yin Ling, MD, PhD, for her contributions to the development of this manuscript. Financial support and sponsorship This study was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Medical writing assistance was provided by Max Chang, BSc (Hons), and Lei Bai, PhD, of ApotheCom (New York, NY, USA), and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Conflicts of interest Hsu T-Y was an employee of MSD, Singapore, Pte Ltd when the study was conducted. Saxena K, Walia A and Prabhu VS are employees of and own stock in Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pavelyev A is a paid consultant for Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and is working under contract with HCL America, Inc., Sunnyvale, CA, USA.

Human Papillomavirus (Cervical Cancer) Vaccine Update

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

HPV vaccines in Brazil and the world

Correlation of high-risk human papilloma viruses but not of herpes viruses or Chlamydia trachomatis with endometriosis lesions

Human Papillomavirus: Current Prevalence and Future Protection

An Update on Childhood and Adolescent Vaccines

Despite many years of rigorous evaluation of a variety of interventions, HIV incidence rates in parts of Africa remain unacceptably high. A recent review identified 37 randomized controlled trials testing interventions to reduce HIV incidence.1 Except for 3 randomized controlled trials of male circumcision2‐4 and 1 trial of syndromic treatment of sexually transmitted diseases,5 and, recently, 1 trial of a vaginal microbicide,6 no significant reductions in HIV incidence were observed. In some trials of vaginal microbicides, trial participants in the active treatment arm actually had increased HIV incidence rates.7 Trials with candidate vaccines have been equally disappointing.8 A recently completed trial of a prime-boost strategy conducted in Thailand showed statistically significant, but limited, protection against HIV.9 Nevertheless, even vaccine optimists think that a preventive HIV vaccine is many years away. Sexually transmitted infections (STIs) were identified as important cofactors for HIV transmission early in the epidemic.10,11 Many prospective observational studies showed that the presence of ulcerative and nonulcerative STIs increased the likelihood of HIV transmission.10,11 Several interventions were based on this observation including mass treatment with antibiotics,12 improved syndromic management of STIs,5,13 and herpes simplex virus (HSV)-2 suppressive treatment.14 Null findings of these interventions should be interpreted with caution. Failure to show an effect does not necessarily mean that the STI is not causally associated with HIV. As Barnabas and Wasserheit highlight,15 the stage of the HIV epidemic in which an intervention trial is conducted may significantly influence observed efficacy. Another possible reason for the failure of these trials to demonstrate efficacy is that the intervention may not have adequately controlled the STI or its biologic effects.

Oral squamous cell carcinoma positive for p16/human papilloma virus in post allogeneic stem cell transplantation: 2 cases and review of the literature

These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of a quadrivalent human papillomavirus (HPV) vaccine licensed by the U.S. Food and Drug Administration on June 8, 2006. This report summarizes the epidemiology of HPV and associated diseases, describes the licensed HPV vaccine, and provides recommendations for its use for vaccination among females aged 9-26 years in the United States. Genital HPV is the most common sexually transmitted infection in the United States; an estimated 6.2 million persons are newly infected every year. Although the majority of infections cause no clinical symptoms and are self-limited, persistent infection with oncogenic types can cause cervical cancer in women. HPV infection also is the cause of genital warts and is associated with other anogenital cancers. Cervical cancer rates have decreased in the United States because of widespread use of Papanicolaou testing, which can detect precancerous lesions of the cervix before they develop into cancer; nevertheless, during 2007, an estimated 11,100 new cases will be diagnosed and approximately 3,700 women will die from cervical cancer. In certain countries where cervical cancer screening is not routine, cervical cancer is a common cancer in women. The licensed HPV vaccine is composed of the HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein in yeast using recombinant DNA technology produces noninfectious virus-like particles (VLP) that resemble HPV virions. The quadrivalent HPV vaccine is a mixture of four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant. Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among females who have not already been infected with the respective HPV type. No evidence exists of protection against disease caused by HPV types with which females are infected at the time of vaccination. However, females infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types. The vaccine is administered by intramuscular injection, and the recommended schedule is a 3-dose series with the second and third doses administered 2 and 6 months after the first dose. The recommended age for vaccination of females is 11-12 years. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 13--26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.

HPV vaccination in women aged 24–45 years

Racial Disparity in the Prevalence of Cervical Cancer

Understanding and preventing human papillomavirus infection during adolescence and young adulthood

Impact of the human papillomavirus vaccine in low-resource settings