Wendy C. S. Ho

Distribution of human papillomavirus types in cervical cancers in Hong Kong: Current situation and changes over the last decades

Human papillomavirus (HPV) type distribution among cervical cancers and its possible changes over time are key issues that determine the cost‐effectiveness of HPV vaccines. Cervical cancers diagnosed during 3 periods (1997–2007, N = 280; 1984–1986, N = 74; 1972–1973, N = 81) in Hong Kong were examined for HPV type distribution using sensitive broad‐catching methods. The results showed a variation in HPV distribution between histological groups. Among cervical squamous cell carcinoma (SCC) cases diagnosed over the past 10 years, HPV16 was most commonly found (61.2%), followed by HPV18 (17.7%), HPV52 (14.7%) and HPV58 (9.9%), whereas adeno/adenosquamous cell carcinoma was dominated by HPV18 (56.3%) and HPV16 (50.0%). The proportion of HPV16‐positive SCC showed a significant linear trend of increase with time (45.2% for 1972–1973, 58.8% for 1984–1986, 61.2% for 1997–2007; pTrend = 0.023), whereas HPV52‐positive SCC decreased with time (30.1% for 1972–1973; 29.4% for 1984–1986, 14.7% for 1997–2007; pTrend = 0.001). Vaccines comprising HPV16/18 cover 62.6% of SCC and 93.8% of adeno/adenosquamous carcinoma in Hong Kong, and inclusion of HPV52 and HPV58 can increase the coverage by 18.4% for SCC and 4.1% for adeno/adenosquamous cell carcinoma. HPV type distribution may change over time. Further investigations to reveal the determinants for such changes and continuous monitoring for possible type replacement as a result of widespread long‐term use of HPV vaccines are warranted. Multiple infections are commonly revealed by sensitive broad‐catching methods such as those used in this study. However, their implication on vaccine efficacy and cost‐effective analyses should be taken cautiously.

Attribution of human papillomavirus types to cervical intraepithelial neoplasia and invasive cancers in Southern China

The attribution of individual human papillomavirus (HPV) types to cervical neoplasia, especially intraepithelial lesions, varies ethnogeographically. Population‐specific data are required for vaccine cost‐effectiveness assessment and type replacement monitoring. HPV was detected from 2,790 Chinese women (444 invasive cervical cancers [ICC], 772 cervical intraepithelial neoplasia [CIN] grade 3, 805 CIN2 and 769 CIN1. The attribution of each HPV type found in multiple‐type infections was approximated by the fractional contribution approach. Multiple‐type infection was common and correlated inversely with lesion severity (54.7% for CIN1, 48.7% for CIN2, 46.2% for CIN3, 27.5% for ICC). Vaccine‐covered high‐risk types (HPV16/18) attributed to 59.5% of squamous cell carcinoma, 78.6% of adenocarcinoma, 35.9% of CIN3, 18.4% of CIN2 and 7.4% of CIN1. Distinct features compared to worldwide were a higher attribution of HPV52 and HPV58, and a much lower attribution of HPV45. Inclusion of HPV52 and HPV58 in future vaccines would provide the highest marginal increase in coverage with 11.7% for squamous cell carcinoma, 14.4% for CIN3, 22.6% for CIN2 and 17.7% for CIN1. The attribution of HPV types in southern China is different from elsewhere, which should be considered in prioritizing HPV types for vaccine and screening assay development.

Epidemiologic Risk Profile of Infection With Different Groups of Human Papillomaviruses

This study identified the age‐specific prevalence and epidemiologic risk profile for infection with different groups and species of human papillomaviruses (HPV). Structured interview and HPV testing were conducted for 2,604 Chinese women self‐referred for cervical screening. Independent risk factors for infection were identified by multiple logistic regressions. Overall, a major peak of HPV infection was observed at women aged 26–30 years, and a minor peak at 46–55 years. This pattern was observed for high‐risk, low‐risk, and alpha‐5/7/9 HPVs; but alpha‐3/6 HPVs showed peaks of similar magnitudes in young and older women. Independent risk factors for HPV infection (all types combined) included younger age (OR [95% CI] for >55 vs. ≤30 years = 0.22 [0.09–0.55]; 31‐45 vs. ≤ 30 years = 0.57 [0.33–0.99]), having ≥4 lifetime sexual partners (2.28 [1.06–4.88]), and smoking (2.24 [1.22–4.10]). Young age and smoking were the most consistent independent risk factors observed across different HPV groups. The risk profile for high‐risk HPV was similar to alpha‐5/7/9. Single‐type infection was associated with having more sexual partners, higher education level and oral contraception; whereas multiple‐type infection was associated with smoking. In conclusion, a U‐shaped age‐specific prevalence curve was observed for HPV infection overall, but with a different pattern for different HPV species. Different HPV groups showed variations in their risk profiles. These data are useful for formulating preventative strategy for HPV‐related diseases. Catch‐up vaccination program in Hong Kong should cover a wider age group as the first peak of infection occurred relatively late. J. Med. Virol. 81:1635–1644, 2009.

Meta-Analysis on Prevalence and Attribution of Human Papillomavirus Types 52 and 58 in Cervical Neoplasia Worldwide

Objective To estimate the prevalence and attribution of two non-vaccine-covered HPV types (HPV52 and HPV58) across the world. Methods Meta-analysis on studies reported in English and Chinese between 1994 and 2012. Results The pooled prevalence and attribution rates of HPV52 and HPV58 in invasive cervical cancers were significantly higher in Eastern Asia compared to other regions (HPV52 prevalence: 5.7% vs. 1.8–3.6%, P<0.001; HPV52 attribution: 3.7% vs. 0.2–2.0%; HPV58 prevalence: 9.8% vs. 1.1–2.5%, P<0.001; HPV58 attribution: 6.4% vs. 0.7–2.2%, P<0.001). Oceania has an insufficient number of studies to ascertain the prevalence of HPV52. Within Eastern Asia, the attribution of HPV58 to invasive cervical cancer was 1.8-fold higher than that of HPV52. Similarly, HPV52 and HPV58 shared a higher prevalence and attribution among cervical intraepithelial neoplasia in Eastern Asia. In contrast to the classical high-risk type, HPV16, the prevalence and attribution of HPV52 and HPV58 decreased with increasing lesion severity. Thus, HPV52 and HPV58 behave as an “intermediate-risk” type. Conclusion The attribution of HPV52 and HPV58 to cervical intraepithelial neoplasia and invasive cancer in Eastern Asia were respectively 2.5–2.8 and 3.7–4.9 folds higher than elsewhere. Changes in the attributed disease fraction can serve as a surrogate marker for cross-protection or type replacement following widespread use of HPV16/18-based vaccines. This unique epidemiology should be considered when designing HPV screening assays and vaccines for Eastern Asia.

A pilot randomized study to assess immunogenicity, reactogenicity, safety and tolerability of two human papillomavirus vaccines administered intramuscularly and intradermally to females aged 18-26 years.

Intradermal administration of human papillomavirus (HPV) vaccines could be dose-sparing and cost-saving. This pilot randomized study assessed Cervarix(®) and Gardasil(®) administered either intramuscularly or intradermally, in different doses (full-dose or reduced to 20%) by different methods (needle and syringe or PharmaJet needle-free jet injection device). Following an initial reactogenicity study of 10 male subjects, sexually naïve women aged 18-26 years were randomized to the eight study groups to receive vaccine at 0, 2 and 6 months. 42 female subjects were enrolled and complete data were available for 40 subjects. Intradermal administration of either vaccine raised no safety concerns but was more reactogenic than intramuscular administration, although still tolerable. All subjects demonstrated a seroconversion (titre≥1:320) by Day 95. Further evaluation of intradermal HPV vaccination and its potential for cost reduction in resource poor settings is warranted.

Hospitalization Incidence, Mortality, and Seasonality of Common Respiratory Viruses Over a Period of 15 Years in a Developed Subtropical City.

AbstractInformation on respiratory viruses in subtropical region is limited.Incidence, mortality, and seasonality of influenza (Flu) A/B, respiratory syncytial virus (RSV), adenovirus (ADV), and parainfluenza viruses (PIV) 1/2/3 in hospitalized patients were assessed over a 15-year period (1998–2012) in Hong Kong.Male predominance and laterally transversed J-shaped distribution in age-specific incidence was observed. Incidence of Flu A, RSV, and PIV decreased sharply from infants to toddlers; whereas Flu B and ADV increased slowly. RSV conferred higher fatality than Flu, and was the second killer among hospitalized elderly. ADV and PIV were uncommon, but had the highest fatality. RSV, PIV 2/3 admissions increased over the 15 years, whereas ADV had decreased significantly. A “high season,” mainly contributed by Flu, was observed in late-winter/early-spring (February–March). The “medium season” in spring/summer (April–August) was due to Flu and RSV. The “low season” in late autumn/winter (October–December) was due to PIV and ADV. Seasonality varied between viruses, but predictable distinctive pattern for each virus existed, and temperature was the most important associating meteorological variable.Respiratory viruses exhibit strong sex- and age-predilection, and with predictable seasonality allowing strategic preparedness planning. Hospital-based surveillance is crucial for real-time assessment on severity of new variants.

The role of human papillomavirus in head and neck squamous cell carcinoma: A case control study on a southern Chinese population

HPV plays a role in the development of a portion of head and neck squamous cell carcinoma (HNSCC), but only limited information on its role in southern Chinese population is available. A multicenter case‐control study was conducted. HPV type, viral integration, E6/7 mRNA expression status, and TP53 mutation were determined. A total of 228 HNSCC were recruited including 137 (60.1%) oral SCC, 34 (14.9%) oropharyngeal SCC, 31 (13.6%) laryngeal SCC, 21 (9.2%) hypopharyngeal SCC, and 5 (2.2%) lip and paranasal sinus SCC. High‐risk HPV infection was found in 7.5% (17/228) of HNSCC, but only a small proportion of samples had evidence of viral integration (5.3%, 12/228) or E6/7 mRNA expression (4.4%, 10/228). HPV infection with oncogenic phenotype (integration and E6/7 mRNA expression) was significantly more common in oropharyngeal SCC than controls (9/34, 26.5% vs. 0/42, 0.0%, P < 0.001). Smoking showed a significant association with HNSCC, oropharyngeal SCC, and laryngeal SCC. TP53 mutation was associated with HNSCC (P < 0.001). Older age, TP53 mutation, and HPV16 infection with oncogenic phenotypes were independently associated factors for HNSCC with odds ratios of 1.03 (1.02–1.05), 3.38 (1.71–6.66), and 9.19 (1.13–74.68), respectively. High‐risk HPV infection of head and neck mucosa is not uncommon in the Hong Kong population. This study found that 26–30% of oropharyngeal carcinoma was associated with HPV infection, mostly HPV16, and that smoking which predisposes to TP53 mutations was another important risk factor. J. Med. Virol. 88:877–887, 2016.

Distribution of human papillomavirus genotypes among cervical intraepithelial neoplasia and invasive cancers in Macao.

Macao is a densely populated city situated in East Asia where a relatively high prevalence of human papillomavirus (HPV) types 52 and 58 has been reported in women with invasive cervical cancer. To provide data for a population‐specific estimation on the impact of HPV vaccines, paraffin‐embedded tissues collected from women with invasive cervical cancer or cervical intrapeitheilal neoplasia grade 2 or 3 confirmed histologically were examined for HPV using the INNO‐LiPa kit. Of the 35 HPV‐positive patients with invasive cancer, one HPV type was detected in 68.6%, and 31.4% were co‐infected with more than one HPV type. Overall, HPV 16, HPV 18, HPV 52, and HPV 54 were the most common types found respectively in 57.1%, 17%, 11.4%, and 8.5% of patients with invasive cervical cancer. Among the 59 HPV‐positive patients with cervical intraepithelial neoplasia grade 2/3, 55.9% hardbored one HPV type, and 44.1% had co‐infections. The common HPV types found included HPV 16 (52.5%), HPV 52 (23.7%), HPV 58 (18.7%), and HPV 33 (17%). Although HPV 11 (a low‐risk type) was also found commonly in invasive cervical cancers (14.3%) and cervical intraepithelial neoplasia grade 2/3 (15.3%), the fact that they all existed as co‐infections with another high‐risk type suggested HPV 11 was not the cause of the lesion. The current vaccines targeting HPV 16/18 are expected to cover 62.9–74.3% of invasive cervical cancers and 32.2–55.9% of cervical intraepithelial neoplasia 2/3 in Macao. Widespread HPV vaccination is expected to reduce substantially the disease burden associated with cervical neoplasia in Macao. J. Med. Virol. 82:1600–1605, 2010.

Ancient evolution and dispersion of human papillomavirus 58 variants

ABSTRACT Human papillomavirus 58 (HPV58) is found in 10 to 18% of cervical cancers in East Asia but is rather uncommon elsewhere. The distribution and oncogenic potential of HPV58 variants appear to be heterogeneous, since the E7 T20I/G63S variant is more prevalent in East Asia and confers a 7- to 9-fold-higher risk of cervical precancer and cancer. However, the underlying genomic mechanisms that explain the geographic and carcinogenic diversity of HPV58 variants are still poorly understood. In this study, we used a combination of phylogenetic analyses and bioinformatics to investigate the deep evolutionary history of HPV58 complete genome variants. The initial splitting of HPV58 variants was estimated to occur 478,600 years ago (95% highest posterior density [HPD], 391,000 to 569,600 years ago). This divergence time is well within the era of speciation between Homo sapiens and Neanderthals/Denisovans and around three times longer than the modern Homo sapiens divergence times. The expansion of present-day variants in Eurasia could be the consequence of viral transmission from Neanderthals/Denisovans to non-African modern human populations through gene flow. A whole-genome sequence signature analysis identified 3 amino acid changes, 16 synonymous nucleotide changes, and a 12-bp insertion strongly associated with the E7 T20I/G63S variant that represents the A3 sublineage and carries higher carcinogenetic potential. Compared with the capsid proteins, the oncogenes E7 and E6 had increased substitution rates indicative of higher selection pressure. These data provide a comprehensive evolutionary history and genomic basis of HPV58 variants to assist further investigation of carcinogenic association and the development of diagnostic and therapeutic strategies. IMPORTANCE Papillomaviruses (PVs) are an ancient and heterogeneous group of double-stranded DNA viruses that preferentially infect the cutaneous and mucocutaneous epithelia of vertebrates. Persistent infection by specific oncogenic human papillomaviruses (HPVs), including HPV58, has been established as the primary cause of cervical cancer. In this work, we reveal the complex evolutionary history of HPV58 variants that explains the heterogeneity of oncogenic potential and geographic distribution. Our data suggest that HPV58 variants may have coevolved with archaic hominins and dispersed across the planet through host interbreeding and gene flow. Certain genes and codons of HPV58 variants representing higher carcinogenic potential and/or that are under positive selection may have important implications for viral host specificity, pathogenesis, and disease prevention.

Prognostic Implication of Human Papillomavirus Types and Species in Cervical Cancer Patients Undergoing Primary Treatment

High-risk human papillomavirus (HPV) types are associated with cervical cancer. It is well established that individual HPV types vary in oncogenicity, but current data on their prognostic implication remain controversial. We examined the association between HPV types/species and the survival of 236 Chinese women aged 26–87 (mean 54.4) years after receiving primary treatment for cervical cancer. Overall, 45.8% were of FIGO stage I, 41.9% stage II, and 12.3% stage III. The four most prevalent types found were HPV-16 (60.2%), HPV-18 (21.6%), HPV-52 (11.9%), and HPV-58 (9.3%). Overall, 19.5% of patients had multiple-type infections, 78.4% harboured one or more alpha-9 species, and 28.8% harboured one or more alpha-7 species. After a median follow-up of 8.0 years, 156 (66.1%) patients survived. The 3-year overall survival rate was 75.5%. Factors independently associated with a poorer 3-year overall survival were age >60 years, tumour size >4 cm, lymph node involvement and treatment with radiotherapy+/-chemotherapy. Univariate analysis showed HPV-16 single-type infection was associated with a marginally poorer disease-specific survival (71.6% vs. 87.0%, HR: 1.71, 95% CI = 1.01–2.90), whereas non-HPV-16 alpha-9 species was associated with a better disease-specific survival (90.0% vs. 76.2%, HR: 0.36, 95% CI = 0.16–0.79). However, on multivariate analysis, HPV infection status irrespective of different grouping methods, including individual types, species, single-type or co-infection, did not carry any significant prognostic significance. In conclusion, we did not observe any association between infection with a particular HPV type/species and survival. An HPV type-based stratification in treatment and follow-up plan could not be recommended.