JOURNAL OF CLINICAL MICROBIOLOGY, Feb. 2008, p. 740–742 0095-1137/08/$08.00⫹0 doi:10.1128/JCM.01981-07 Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Vol. 46, No. 2
NOTES Cervical Human Papillomavirus (HPV) Infection in South African Women: Implications for HPV Screening and Vaccine Strategies䌤 Bruce Allan,1 Dianne J. Marais,1 Margaret Hoffman,2 Samuel Shapiro,2 and Anna-Lise Williamson1,3* Institute of Infectious Disease and Molecular Medicine and Division of Medical Virology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa1; School of Public Health and Family Medicine, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa2; and National Health Laboratory Service, Groote Schuur Hospital, Observatory, Cape Town, South Africa3 Received 8 October 2007/Accepted 17 October 2007
The prevalence of cervical human papillomavirus (HPV) in South African women (n ⴝ 1,073) increased from 20.4% (173/848) in women with normal cytology to 41.7% (48/115) in women with atypical squamous cells of undetermined significance, 70.2% (40/57) in women with low-grade squamous intraepithelial lesions, and 83% (44/53) in women with high-grade squamous intraepithelial lesions (HSILs). HPV types 16 and 35 were the dominant types in women with HSILs but not in women in the other categories. (16). Thus, the hierarchy of the types of HPV causing infections differs within Africa. In South Africa, where the prevalence of HPV infection and cervical cancer is high (15), there is currently limited knowledge about the individual HPV types associated with cervical disease and a normal cytology. Published accounts of the prevalence of cervical HPV types among small groups of women with cervical neoplasia and cervical cancer (8, 13, 14) found HPV-16 to be predominant. The present analysis constituted the first reported assessment of the HPV types causing cervical infections in a large population (⬎1,000) of women in Southern Africa. Women (n ⫽ 1,491) of mixed-race origins (referred to as colored) and black women were recruited as controls in a case-control study to study the association between hormonal contraceptive use and invasive cervical cancer (12). These women were attending hospitals and community health services in the Western Cape Province of South Africa between January 1998 and December 2001 with primary diagnoses such as trauma or acute infections that were judged to be independent of contraceptive use or cervical cancer risk. The median age of the women was 44 years, and the age range was 21 to 59 years. Cervical specimens for HPV DNA analysis were taken immediately after a Pap smear was taken. Of the 1,491 women examined for cervical HPV, Pap smears were graded normal (no abnormal cervical cells) for 1,264 (84.8%), atypical squamous cells of undetermined significance (ASCUS) for 117 (7.9%), low-grade squamous intraepithelial lesions (LSILs) for 57 (3.8%), and high-grade squamous intraepithelial lesions (HSILs) for 53 (3.6%). Specimens for HPV typing were available from almost all women (n ⫽ 225) with an abnormal cytology and 848 women with a normal cytology. DNA was extracted from the cervical specimen and purified by using a QIAamp DNA blood minikit (Qiagen). The extracts were assayed for 27 HPV types by a
More than 40 known human papillomavirus (HPV) types infect the female genital tract, and 15 to 18 of these are considered oncogenic and are causally implicated in cervical cancer (5, 10). The most important types are HPV type 16 (HPV16) and HPV-18. While commercial vaccines against HPV-16 and HPV-18 are now available, global variations in HPV typespecific prevalence could affect their regional effectiveness (7). The most prevalent type worldwide is HPV-16, and there is less variation in the geographical distribution of HPV-16 than in that of the other types (2, 4). The prevalence of HPV is higher in African women with a normal cervical cytology than in women in other regions of the world. Yet, HPV-16 infections of women with a normal cytology are found more commonly than infections caused by other HPV types in regions of the world apart from sub-Saharan Africa, where infections by other oncogenic types, most significantly, HPV-35, may dominate (3). Indeed, the latter study also showed that HPV-35 was as common in Africa as HPV-16 (in 8% of infections), followed by HPV-31, HPV-45, HPV-56, and HPV-58 (in 6% of infections). In Mozambique it was reported that HPV-35 was the most dominant type among women with no cervical disease and those with cervical dysplasia (1). However, a follow- up study revealed that HPV-16 and HPV-18 were present in 69% of women with cervical cancer (11), although the coexistence of these types with other HPV types was a common occurrence. A study in Senegal found that, in addition to HPV-16, HPV-58 was the most strongly associated with cervical cancer
* Corresponding author. Mailing address: Institute of Infectious Disease and Molecular Medicine and Division of Medical Virology, Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. Phone: 27 21 4066124. Fax: 27 21 4066681. E-mail: anna-lise
[email protected]. 䌤 Published ahead of print on 31 October 2007. 740
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TABLE 1. Frequency of detection of cervical HPV types in women with normal and abnormal (ASCUS, LSIL, HSIL) cervical cytologies as single or multiple isolates Women with normal cytology (n ⫽ 848) HPV group and type
Women with ASCUS (n ⫽ 115)
Women with LSILs (n ⫽ 57)
Women with HSILs (n ⫽ 53)
No. of women with:
No. of women with:
No. of women with:
No. of women with:
Infection Infection with a with Total single multiple type types
Infection Infection with a with Total single multiple type types
Infection Infection with a with Total single multiple type types
Infection Infection with a with Total single multiple type types
Any HPV type
%a
20.4
%
41.7
%
70.2
%
83
Oncogenic HPV types 16 18 31 33 35 39 45 51 52 56 58 59 68 73 82
12 8 2 6 3 1 8 5 11 1 6 7 6 3 4
5 3 2 3 2 4 4 1 5 2 3 2 5 4 0
17 11 4 9 5 5 12 6 16 3 9 9 11 7 4
2.0 1.3 0.5 1.1 0.6 0.6 1.4 0.7 1.9 0.4 1.1 1.1 1.3 0.8 0.5
2 0 1 2 0 1 2 0 7 0 0 2 0 0 0
4 4 2 2 2 7 5 1 7 1 1 1 1 2 1
6 4 3 4 2 8 7 1 14 1 1 3 1 2 1
5.2 3.5 2.6 3.5 1.7 7 6.1 0.9 12.2 0.9 0.9 2.6 0.9 1.7 0.9
3 1 1 0 5 2 1 2 3 0 0 0 0 0 0
4 4 1 4 2 1 2 3 7 2 3 2 0 1 5
7 5 2 4 7 3 3 5 10 2 3 2 0 1 5
12.3 8.8 3.5 7 12.3 5.3 5.3 8.8 17.5 3.5 5.3 3.5 0 1.8 8.8
9 1 4 3 4 0 1 0 2 0 1 1 0 0 1
1 3 2 0 6 1 2 3 4 0 1 0 1 1 0
10 4 6 3 10 1 3 3 6 0 2 1 1 1 1
18.9 7.6 11.3 5.7 18.9 1.9 5.7 5.7 11.3 0 3.8 1.9 1.9 1.9 1.9
Probable oncogenic HPV types 26 53 66 Subtotal
1 12 0 96
1 7 2 55
2 19 2 151
0.2 2.2 0.2
0 1 1 19
0 5 2 48
0 6 3 67
0 5.2 2.6
0 5 2 25
0 4 0 45
0 9 2 70
0 15.8 3.5
1 3 2 33
1 0 1 27
2 3 3 60
3.8 5.7 5.7
Nononcogenic HPV types 6 11 40 42 54 55 57 83 84 Subtotal
2 1 0 2 7 9 0 16 5 42
2 1 0 0 4 3 0 6 4 20
4 2 0 2 11 12 0 22 9 62
0.5 0.2 0 0.2 1.3 1.4 0 2.6 1.1
1 0 0 2 2 0 0 2 1 8
0 0 0 1 0 4 0 2 6 13
1 0 0 3 2 4 0 4 7 21
0.9 0 0 2.6 1.7 3.5 0 3.5 6.1
0 0 1 0 1 0 0 0 0 2
0 0 0 0 2 1 0 4 1 8
0 0 1 0 3 1 0 4 1 10
0 0 1.8 0 5.3 1.8 0 7 1.8
0 0 0 0 2 0 0 0 0 2
1 0 2 0 1 0 0 2 1 7
1 0 2 0 3 0 0 2 1 9
1.9 0 3.8 0 5.7 0 0 3.8 1.9
138
75
213
27
61
88
27
53
80
35
34
69
Total Any oncogenic type (no./total HPV types) a
70.8
70.9
87.5
87
Some women were counted more than once because of infections with multiple HPV types.
reverse line blot assay (Roche). For the purpose of the analysis, 15 HPV types (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) were considered oncogenic (9). Three HPV type (types 26, 53, and 66) were considered probable oncogenic types, and nine HPV types (types 6, 11, 40, 42, 54, 55, 57, 83, and 84) were considered nononcogenic. The prevalence of HPV infection increased from 20.4% (173/848) in women with a normal cytology to 41.7% (48/115) in women with ASCUS, 70.2% (40/57) in women with LSILs, and 83% (44/53) in women with HSILs. Cervical HPV infection was found in 41.8% of women aged ⬍30 years and decreased to a low of 18.6% among women aged 45 to 49 years. The HPV types varied when women were stratified by their cervical cytologies (Table 1). In women with a normal cytology, the most prevalent HPV types were nononcogenic HPV-83 (2.6%), followed by oncogenic HPV-53 (2.2%) and HPV-16
(2.0%). In women with ASCUS, oncogenic HPV-52 predominated (12.2%), followed by HPV-45 (6.1%), nononcogenic HPV-84 (6.1%), and HPV-16 (5.2%). HPV-52 remained prominent in women with LSILs (17.5%), followed by HPV-53 (15.8%) and HPV-16 and HPV-35 (both at 12.3%). In women with HSILs (as in women with LSILs), relatively few nononcogenic types were identified; HPV-16 and HPV-35 emerged most prominently in the hierarchy of types (both at 18.9%), and HPV-18 was found in 7.6% of these women (Table 2). The prevalence of HPV-16 and HPV-18 was 3.3% in women with normal cytology and 16% in women with an abnormal cytology. This is the first study to provide information on the cervical HPV types infecting a large number of South African women. There was a higher prevalence of HPV (20.4%) in women with a normal cytology compared with that reported in studies of
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TABLE 2. Hierarchy of HPV types identified in women according to their cervical cytology Normal cytology
ASCUS
LSILs
HSILs
HPV type(s)
%
HPV type
%
HPV type(s)
%
HPV type(s)
%
83 53 16 52 45/55 18
2.6 2.2 2.0 1.9 1.4 1.3
52 39 84 16 53 18
12.2 7.0 6.1 5.2 5.2 3.5
52 53 16/35 18 51 82
17.5 15.8 12.3 8.8 8.8 8.8
16 35 31/52 18 33/45/51 53/66/54
18.9 18.9 11.3 7.6 5.7 5.7
populations elsewhere in the world. In a comparable study of women on the United States-Mexico border and in Mexico, where rates of cervical cancer as high as those in Africa are recorded (44.4/100,000 women), the overall prevalence of HPV in the present study in women with a normal cytology (20.4%) was higher (compared with prevalences of 12.8% and 8.8% for the United States and Mexico, respectively) (6). In women with cervical disease, the prevalence rates were very comparable to those found in Hispanic women in the United States (6). Whereas in the latter study HPV-16 predominated in all women irrespective of the cervical cytology, the present study showed that HPV-16 predominated only in women with HSILs, in whom HPV-35 was equally prevalent (although in fewer single infections compared to the single infection rate for HPV-16). This confirms the findings of other African studies and the importance of the consideration of HPV-35 in possible vaccine strategies in Africa. In this study, HPV-16 was associated with increasing cervical disease severity, as has been described elsewhere (2, 6). HPV-35 showed a similar association, and HPV-18 also showed a similar association, but to a lesser degree. In conclusion, the present analysis indicates that within a South African population there is a high prevalence of cervical HPV infection, especially oncogenic HPV type infection. According to the study findings, vaccines against oncogenic HPV-16 and HPV-18 would decrease the rate of HPV infection and cervical cancer risk in a significant proportion of women. We are grateful to Janet Kornegay from Roche Molecular Systems Inc., Alameda, CA, for providing the reverse line blot assay for HPV typing.
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