Human Papillomavirus Type Distribution in Southern China and Taiwan

In 2007, a worldwide analysis was published that assessed the types of HPV infection found in women without cervical disease (1). Of the 291 million women suffered with cervical diseases around the world, it was found that 32% are infected with either HPV16 or HPV18, or both. Data regarding the HPV burden and incidence rates are available on the WHO/ICO Information Centre on HPV and Cervical Cancer Web site (http://www.who.int/ hpvcentre). However, HPV prevalence in different regions of Southern China is not mentioned in this website. Hence the diversity of HPV prevalence and distribution in Taiwan, Hong Kong, and various regions of China is the major focus in this chapter.

The relationship between geography and HPV types is demonstrated in Figure 1, with A~D corresponding to the distribution of HPV 16,18,52, and 58, respectively. Coastal areas in the southeast such as Taiwan and Hong Kong display a higher prevalence than inland cities. HPV prevalence may vary among different regions due to geographical separation, an example of which is Taiwan and Hong Kong. The political separation of Taiwan and Hong Kong most likely caused the HPV types diverse than mainland China. Moreover, the TAR is isolated by mountains from mainland China while Taiwan  be attributed to population conservation. In Taiwan, from 52 HPV types screening, HPV type 52 has the highest frequency (21.48% flowing HPV type 16, 58, 56, 39, 51, 18, 68, 31, 33, 59, 45, and 35(3) among HR-HPV types that is distinguish HPV combination compared to other regions. This also demonstrates the effect of geography despite Taiwan and China essentially being of the same ethnicity only partitioned over 60 years to affect two generations of people including marriage. The more independent, younger generation and their sexual culture are two major factors that cause the variations in HPV types distribution.
Since the prevalence of HPV types in each age group can be linked to sexual behavior, it is reasonable to investigate the multiple HPV infection types that can be found in patients ( Table  2). In Taiwan, the multiple HPV infection rate is over 19%, only slightly lower than Hong Kong's (22.8%) but distinctly higher compared to others. For instance, most of the cities/regions that belong to mainland China, specifically inland cities like Beijng, Shangdong, Shanxi, Shengyang, Shenzhen, and Zhejiang, possess only 4~5% multiple HPV infection rates.
Only Guangdong province has 11.1% between inland and island; however, Guangdong province is closest to Hong Kong and is more well-developed than inland cities. In contrast to Hong Kong and Taiwan, the TAR is isolated from immigration and might have conservative social behaviors, resulting to the lowest fraction of multiple HPV types (1.3%).

Regions\
HPV types (%) 16   Numerous investigations focused on HR-HPV due to its higher relationship to cervical cancer and high-grade squamous intraepithelial lesion. To survey high-risk and low-risk HPV, HR-HPV frequently found in women with ASCUS and CIN3/cervical cancer, and might be at least double frequencies than LR-HPV cases ( Table 2). The average incidence of HR-HPV in population is over 10%, but an extremely high incidence has been found in CIN3/cervical cancer cases (Taiwan reports, Table 2). However, the LR-HPV prevalence might not be estimated correctly due to less LR-HPV types screening. A survey of 52 HPV types reported in Taiwan suggests that the prevalence of LR-HPV (37 types) and HR-HPV (15 types) is 10% and 5%, respectively (3). Other HPV reports listed less than 37 LR-HPV types and focused only on HR-HPV. The same HPV screening type but few LR-HPV screening types caused underestimation for the incidence of LR-HPV that showed in Table  2

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(11.7% and 11.8%) can be observed in the 40-49 and over-60 age groups (7). However, there is no significant difference in HPV rates among age groups in Guangzhou. In Hong Kong, the 20-29 age group has the highest peak in both cancer report and population screening; however, the 40-49 age group had less HPV frequency (7,8) which remains without clear explanation. In other south coast cities, namely, Shanghai and Shenzhen, the 20-29 age group also exhibited the highest HPV infection rate but in Shanghai only; an opposite trend was found in Shenzhen city, where a high infection rate manifested in older people (45-59 age group). Two recent reports related to Shenzhen city have pointed out the discrepancy about HPV prevalence. One demonstrated an increased HPV infection along with elder people and another report mentioned the 25-29 age group is the lowest. However, Shenzhen city has many plants with numerous temporary residents and tertiary sector workers from other counties that might cause residential status being significantly associated with HPV positivity.  Table 3. A list of HPV infection rates among different age groups Zhejiang province provided more interesting data (9) showing a similar low HPV frequency in each age group (Table 3). Although both the 20-24 and 50-54 age groups have slightly higher rates, the highest (14.4%) and lowest (8.4%) frequencies indicated a less diverse range of HPV prevalence than in other cities/regions. For the north coast city of Shenyang, HPV infection rate initially increases with respect to age, starting from 2.7% for women <25 years old to 13% for women 45-54 years old, but then drops to 6.3% for the 55-59 age group. This pattern is unique among coastal cities and is compatible with the flat age-curves that have been described in other countries such as India and Africa (10). A flat age-curve indicates that young women are not infected with new HPV types more frequently than older women (11). The number of sexual partners as well as the husband's extramarital sexual relationships are believed to be explanatory of this flat age-curve. For inland cities, the TAR has consisted of HPV prevalence around 9% in every age group. For Shanxi province, the 35-44 age group has the highest peak of infection distribution (20.5%), followed by age groups 45-54 with 17.0%, 55-59 with 14.3%, 15-24 with 13.3%, and 25-34 with 7.5%. Finally, for Guangzhou, Hong Kong, Shenzhen, and Zhejiang, the age distribution of cervical HPV infection shows a bimodal curve in half of the regions, with a first peak at younger women, a lower prevalence plateau at middle-aged women, and a variable rebound at older ages (≧45 years). One explanation for this is sexual behavior, which is considered an important risk factor for HPV infection. On the other hand, HPV incidence associated with unmarried status along with a high peak of HPV infection suggests that younger, single women may have an increased possibility of encountering complicated sexual relationships (11). However, the lower prevalence plateau at middle-aged women may be caused by less sexual frequency and single sex partners for married Chinese women.

HPV type distribution in invasive cervical cancer and high-grade squamous intraepithelial lesion
Overall HPV prevalence in invasive cervical cancer (ICC) is 87%, ranging from 86% to 94% by region, according to literature. In Jiashan, data for the incidence of invasive cervical cancer (ICC) from 1998 to 2002 has been reported. Incidence rates of cervical cancer ranged from 2.4 per 100,000 women to 4.6 per 100,000 women in Guangzhou (12). Some areas have notably high cervical cancer incidence rates, such as in Yangcheng and Shanxi, where there is an estimated rate of about 81 per 100,000 women between 1998-2002 (12). Incidentally, the incidence rates for cervical cancer in Hong Kong, Singapore, and Taiwan are 9.6, 10.6, and 18.6 per 100,000 women, respectively (13). Between these three regions, the incidence of cervical cancer is highest in Taiwan and is nearly double than Hong Kong's. However, it has declined since 1993 to 2003. Tay et al. (2008) has reported the five most common HPV types in Taiwan to be, in decreasing frequency order: HPV 16, 18, 58, 33, and 52 for women with cervical cancer, and HPV 16, 52, 58, 18, and 51 for women with normal cytology (13). Due to a high HPV prevalence, the Taiwanese National Health Insurance launched a screening program in 1995 for women aged 30 years old and above. This program included quality control monitoring and a training system for medical doctors, public health nurses, cytologists, and medical technicians. By 2001, the screening program has been estimated to reduce cervical cancer incidence by 29% and mortality by 50%, and has been shown to be cost-effective for Taiwanese public health (14). Upon analysis of HPV genotypes present in ICC, HPV 16 was found to be the most common type, rating 52% in Asia and 58% in Europe, while HPV18 was the second most common type which rated from 13% in South/Central America to 22% www.intechopen.com  (13). Other HPV types most commonly related to ICC were HPV 31, 33, 35, 45, and 52. However, the prevalence of both HPV 58 and 52 were notably higher in ICC cases in Asia. For example, the prevalence of HPV 58 and 52 was found to be as important as the prevalence of HPV 16 and 18 in early cervical cancer patients as well as patients with advanced cervical cancer in Taiwan (15). As shown in Table 4, the frequency of HPV in HSIL, ICC, and CIN3 samples is higher than in ASCUS, LSIL, CIN1, and CIN2.
In Beijing, 85.7% of CIN3 patients have been diagnosed with HPV infections similar to 93.3% of HSIL patients (

HPV vaccination in Southern China, Hong Kong, and Taiwan
Based on statistical calculations to determine the link between HPV and cervical cancer, many strategies for the prevention of cervical cancer have been proposed, including vaccination in younger women and improved HPV screening in older women (25). Two  vaccine, Cervarix™ (GlaxoSmithKline, Belgium), has also been approved in both countries. Both vaccines were developed for HPV16 and HPV18, which cause approximately 70% of all reported cervical cancer cases worldwide (26). Thus, the quadrivalent vaccine can be expected to prevent CIN-2 and CIN-3 (CIN-2,3), cervical cancer, as well as genital warts. However, HPV 18 is less common than HPV 52 and 58 in places like China, Hong Kong, and Taiwan (Table 1) where there is no publicly funded vaccination program. Hence vaccination is voluntary and paid by individuals.
HPV vaccination does not increase the clearance of established infections; therefore, young females are ideally targeted before the development of sexual behavior. Initiation of HPV vaccination in younger cohorts combined with HPV screening in older women is a good strategy for HPV prevention. In China and Taiwan, evaluation of HPV vaccination as primary care HPV and assessment of the threshold cost per vaccinated girl (CVG) became potential feasible strategies in public health. Singapore's policy regarding the management of HPV can be a reference for China and Taiwan. In a cervical cancer awareness survey for Singaporean women aged 30-55 years in 2006, 80% have had at least one Pap smear although 25% did not fully understand the significance behind it (13). Furthermore, 80% were unaware of HPV. In Hong Kong, most women have never heard of HPV or its infection by sexual transmission (27). Thus, participants had no knowledge or means of understanding the link between cervical cancer and HPV infection. However, participants agreed to HPV vaccination for both themselves and their teenage daughters if a health department endorsement was provided. Another study demonstrated that 32% of participants accepted HPV vaccination prior to receiving an educational booklet, and that this number increased to 52% after reading the pamphlet (28). About 48% of women remained undecided or disagreed with vaccination after education; 84% were worried about the side effects of vaccination, and 63% of women augmented fear of earlier sexual activity and unsafe sex. In China, a population-based survey related to knowledge concerning HPV vaccination reported that 15.8% of women between the ages of 15-54 have never heard of HPV, of which 49% bewared that HPV was related to cervical cancer. Around 87% of women agreed to be vaccinated with the prophylactic HPV vaccine and, in addition, 88% of women expressed that they would like to have their daughters vaccinated (29). In rural Shanxi, 67% of surveyed women did not believe that they were at risk of HPV infection and cervical cancer, while 65% of women thought there would be no difference whether or not t h e y w e r e v a c c i n a t e d . H o w e v e r , 9 8 % o f the surveyed women preferred to receive information about the HPV vaccine from doctors, nurses, and hospital staff rather than from family members or friends.
To improve the coverage of vaccination programs, a low vaccine price is one important issue to consider, and 83% of the women hoped that health insurance or the government can cover all or part of vaccine-related costs (30). When asked about the vaccine cost, 42% of women said they are willing to pay USD 2.50 or less and 50% agreed to pay USD 2.50-14.00, w h i l e o n l y 8 % c a n a f f o r d t o p a y m o r e t h an USD 15.00 (31). However, according to investigation conducted by Canfell et al. (2011), vaccination combined with once-or twicein-a-lifetime screening is sufficiently cost-effective with a CVG of USD 52. But the maximum vaccine unit cost per dose is USD 9.00-14.00 that is also implied by maximum CVG of $50-54. Therefore, HPV vaccination is potentially feasible for Chinese women at a reasonable price. However, in order to sustain a wide vaccine coverage, vaccine price would be one of the largest barriers for promotion (31).
In terms of HPV vaccine safety, data from pharmaceutical companies responsible for bivalent and quadrivalent vaccines suggest that some patients could be expected to experience mild, transient vaccine-related side effects upon receiving the HPV vaccine (32,33). From reports, pain is the most frequently reported adverse effect, with a prevalence ranging from 83% to 93% in tested vaccine group (34). With the exception of pain, no differences in serious vaccine-related events were prominent between vaccine and placebo groups. Data regarding the long-term safety of these vaccines are not yet available. HPV vaccination tests also did not include pregnant women. Although incidence of spontaneous abortion occurred in 10% of the vaccine group, it also occured in 7% of the placebo group, hence there is no significant difference between the two groups (35). Similarly, results from the quadrivalent vaccine Phase III studies indicated no observable differences in relation to the incidence of spontaneous abortions, late fetal death, or congenital abnormal infants between both groups. Even women who became pregnant more than 30 days after vaccine administration did not contribute any statistical difference whatsoever (35).
Currently, available vaccines contain HPV 16 and 18; however, HPV types 52 and 58 are more prevalent in Southeast Asia, especially in Hong Kong and Taiwan. Although, HPV16 and 18 are major genotypes found in CIN3 and cervical cancer patients, HPV types 52 and 58 also have high prevalence rate in cancer cases. For example, HPV types 52 and 58 have 25% and 12.5% infection rate in Taiwan (15), As shown in Table 1, the prevalence of HPV 52 and HPV 58 in Chengdu, Fujian, Gansu, Guangzhou, Hong Kong, Liaoning, Taiwan, Shandong, Shanxi, Shenyang, Shenzhen, and Zhejiang is higher than HPV 18, 6, and 11. This indicates that bivalent and quadrivalent vaccines are only capable of covering a small part of prospective patients infected with HPV. The emerging question then is, Should women pay for HPV vaccines without understanding their HPV infection types or not? It is safe to say at the present time that a vaccination program, combined with HPV Pap smear screening, is necessary to avoid useless vaccine treatment. The prevalence of HPV 52 and HPV 58 is nearly equal to the frequency of HPV 16 in China, Hong Kong, and Taiwan whether in cervical cancer-related or population-based surveys (Table 1) types may be valuable, especially when indicating the risk in women's sexual behavior which could bring about a high chance of incurring HR-HPV infection in the future. Any HR-HPV/LR-HPV infection is worth to notice the cervical cancer possibility in women even HR-HPV is significant in ICC/CIN3 samples. Although there are little evidences to prove the relationship between LR-HPV and cervical cancer, we would like to point out the importance of LR-HPV screening, which could be useful to get rid of HPV attack, if the cost is reasonable for both HR-HPV and LR-HPV tests. HPV 16,52,and    Cervical cancer is the second most prevalent cancer among women worldwide, and infection with Human

Conclusion
Papilloma Virus (HPV) has been identified as the causal agent for this condition. The natural history of cervical cancer is characterized by slow disease progression, rendering the condition, in essence, preventable and even treatable when diagnosed in early stages. Pap smear and the recently introduced prophylactic vaccines are the most prominent prevention options, but despite the availability of these primary and secondary screening tools, the global burden of disease is unfortunately still very high. This book will focus on epidemiological and fundamental research aspects in the area of HPV, and it will update those working in this fast-progressing field with the latest information.

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