Journal of Medical Virology
Meta-Analysis of Type-Specific Human Papillomavirus Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer: Implications For Screening and Vaccination Somayeh Jalilvand,1 Zabihollah Shoja,2 Keramat Nourijelyani,3 Hamid Reza Tohidi,4,5 and Rasool Hamkar1* 1
Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Virology Department, Pasteur Institute of Iran, Tehran, Iran 3 Biostatistics Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 4 Faculty of Health, Gonabad University of Medical Sciences, Gonabad, Iran 5 Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Science Institute, Tehran University of Medical Sciences, Tehran, Iran 2
To predict the impact of current vaccines on cervical cancer and for the improvement of screening programs, regional data on distribution of human papillomavirus (HPV) types in women with or without cervical cancer is crucial. The present meta-analysis intend to comprehensively evaluate the HPV burden in women with invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology, as these data will help decision making in regards with screening programs and HPV vaccination in Iran. To determine the HPV prevalence and type distribution in Iranian women with or without cervical cancer, 20 published studies were included in this meta-analysis. In total, 713, 124, 104, 60, and 2577 women invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal were reviewed, respectively. Overall HPV prevalence in women with invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology were 77.4%, 71.8%, 65.3%, 61.7%, and 8.4%, respectively. The six most common C 2014 WILEY PERIODICALS, INC.
types were HPV 16, 18, 6/11, 31, and 33; among them HPV 16 was the most frequent type in all five different groups. According to this study, it was estimated that HPV vaccines could have a great impact on prevention of cervical cancer in Iran. In conclusion, this meta-analysis highlights the necessity of introducing vaccination program in Iran. J. Med. Virol. # 2014 Wiley Periodicals, Inc.
KEY WORDS:
human papillomavirus; HPV prevalence; HPV types; cervical cancer
INTRODUCTION Cervical cancer is the fourth most frequent cancer among women worldwide. Indeed, just in 2012, an estimated of 528,000 new cases and 266,000 deaths of cervical cancer took place globally [International Agency for Research on Cancer, 2012]. The incidence Grant sponsor: Tehran University of Medical Sciences (TUMS); Grant number: 93-03-27-26731. Conflict of interests: The authors declare that they have no conflict of interests. Correspondence to: Rasool Hamkar, Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14155, Iran. E-mail: [email protected] Accepted 29 July 2014 DOI 10.1002/jmv.24053 Published online in Wiley Online Library (wileyonlinelibrary.com).
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rate of cervical cancer is low in Iranian women, and the mean cervical cancer age-standardized incidence rate (ASR) was reported to be 2.5 per 100,000 women. Regardless of geographical regions, the ASRs were estimated to be below 5 per 100,000, ranging from 4.1 to 0.4 in Fars and Zanjan provinces, respectively. In addition, the mean cervical cancer age-standardized mortality rate was reported 1.04 per 100,000 women. Analysis of age-specific incidence rates revealed that the peak of cervical cancer incidence rate is among women within 55–65 years old [Khorasanizadeh et al., 2013]. The role of human papillomavirus (HPV), as an etiological and essential factor in the development of cervical cancer is well documented. It is known that nearly all cervical cancers and their precursor lesions are associated to cervical infection by 12 highrisk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) [Munoz et al., 2003; Cogliano et al., 2005; Munoz et al., 2006; Bouvard et al., 2009; Doorbar et al., 2012], among which HPV 16 and 18 accounts for 70.1% of cases worldwide [Castellsague´ et al., 2007]. Alongside with high risk types, extra types including 68 and 73 are considered as “possibly” cancer-causing [Munoz et al., 2003; Cogliano et al., 2005; Munoz et al., 2006; Bouvard et al., 2009; Doorbar et al., 2012]. Two prophylactic HPV vaccines are currently available for cervical cancer prevention. Gardasil is a quadrivalent vaccine for the HPV 6, 11, 16, and 18 types whereas cervarix is a bivalent vaccine consisting of HPV 16 and 18 types [Cutts et al., 2007; Schiller et al., 2012]. Regional data on distribution of HPV types in women with or without cervical cancer is crucial not only to predict the impact of current vaccines but also to improve the screening programs. The present meta-analysis intends to comprehensively evaluate the burden of HPV in women with invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal, as these data will help decision making in regards with screening programs and HPV vaccination in Iran. Therefore, published data were retrieved and pooled to determine HPV prevalence and type distribution in women with or without cervical cancer. METHODS Search Strategy A systematic review of the literatures was carried out, up to May 2013, to evaluate the prevalence and type distribution of HPV in Iranian women. To obtain data, the following search engines were used: Medline, PubMed, Current Contents and national databases. To our purpose, we used several terms J. Med. Virol. DOI 10.1002/jmv
including “human papillomavirus (HPV)”, “cervical cancer/cervical neoplasms”, “women/female”, “epidemiology”, “prevalence”, “polymerase chain reaction (PCR)” and “Iran”. Study Selection To focus on the purpose of this study, studies were included only if they had the following criteria: (1) to include at least one group from five different groups (invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal); (2) to split HPV prevalence data for the above categories; (3) to detect HPV DNA using PCR-based assays; (4) to determine at least the HPV 16 and 18 types in positive samples and (5) to stratify HPV type distribution by cervical lesion histology or cytology. As indicated, invasive cervical cancer was further segregated into squamous cell carcinoma and adenocarcinoma. In addition, invasive cervical cancer was considered as unspecific when the prevalence of HPV types was not clear based on histology. Data Extraction The following details were extracted from each study: first author, journal name, year of publication, study period, histology or cytology grade, sample size, age range (if was available), city, the PCR primers, number of HPV-positive, HPV typing methods (direct nucleotide sequencing, PCR with type-specific primers, hybridization, multiplex PCR, others), and type-specific HPV prevalence by histology. In total, 25 papers were assessed, from which 20 articles were included in the present study. Statistical Analysis STATA 12 (Stata Corp, College Station, TX, USA) was used to analyze the data. Binomial distribution formula was used to calculate the variance of HPV prevalence. Heterogeneity among studies was assessed via the X2-based Q test and the P < 0.1 were considered statistically significant. In the absence of heterogeneity between studies, fixed effect model was applied and in the presence of heterogeneity, random effect model was used to estimate the overall prevalence. P < 0.05 was considered statistically significant. To minimize the random variations between point estimates of different studies, all results were adjusted using Bayesian method, and the overall point estimate was used as prior prevalence. RESULTS A total of 3,478 women from 20 studies were included in this meta-analysis review (Fig. 1) [Hamkar et al., 2002; Mortazavi et al., 2002; Farjadian et al., 2003; Ghaffari et al., 2006; Maleknejad
HPV Type Distribution in Iranian Women
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Fig. 1. HPV prevalence and HPV 16/18 prevalence among Iranian women with invasive cervical cancer (ICC), high-grade squamous intraepithelial lesion (HSIL) or (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (LSIL) or (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance (ASCUS) and normal cytology. Each line shows the prevalence of each study and the corresponding 95% confidence interval. Diamond (lozenge) shows the combined weighted prevalence of HPV and HPV 16/18.
J. Med. Virol. DOI 10.1002/jmv
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et al., 2006; Mahmoodi et al., 2007; Omrani et al., 2007; Yarandi et al., 2007; Jamali Zavarei et al., 2008; Esmaeili et al., 2008; Eslami et al., 2008; Zandi et al., 2010; Safaei et al., 2010; Shahsiah et al., 2011; Allameh et al., 2011; Heidarpour et al., 2011; Moradi et al., 2011; Khodakarami et al., 2012; Sharbatdaran et al., 2013]. As indicated in Table I, the crude HPV prevalence and HPV type distribution are shown in invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal groups. Regarding all five histology or cytological grades, no data is available from the Eastern region of Iran. According to the histology or cytology grade, in total, 713, 124, 104, 60, and 2577 women were included invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal groups, respectively (Table I). As indicated in Table II, in total, 98.3%, 76.7%, 62%, 40.3%, and 9.3% of samples of invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous
intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal, respectively, were cytological samples, and the remaining of each group were histological samples (Formalin Fixed Paraffin Embedded Tissues). Stratifying the invasive cervical cancer group, 537, 37, and 139 subjects had squamous cell carcinoma, adenocarcinoma and unspecified histology, respectively (Table III). In most studies, to determine HPV types, PCR using HPV-specific primers were applied followed by either direct nucleotide sequencing or hybridization assays. HPV in Women With Invasive Cervical Cancer Overall, the weighted prevalence of HPV among invasive cervical cancer subjects was estimated to be 80% (Fig. 1). Figure 1 revealed that the most studies were, in fact, detected HPV in more than 77% of cases. Analyzing in particular, following stratification of invasive cervical cancer types, HPV was detected in 75.2%, 80%, and 87% of squamous cell carcinoma, adenocarcinoma and unspecified cases, respectively (Table III). The predominant high-risk HPV types were found to be HPV 16 and 18 at the frequency of 50.1% and 14.4%, respectively, followed by HPV 6/11 (9.4%), 31
TABLE I. Overall HPV and HPV 16/18 Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer Stratified by Geographical Regions Histology or cytology grade Normal
ASCUSa
LSILb or CIN1c
HSILd or CIN 2,3
ICCe
Subregion North Central West South Total North Central West South Total North Central West South Total North Central West South Total North Central West South Total
a
No. of studies
No. of women tested
No. of women HPV positive
HPV prevalence (%) (95% CI)
No. of women HPV16/18 positive
HPV16/18 prevalence (%) (95% CI)
3 4 — 2 9 1 2 — — 3 1 3 2 — 6 — 5 1 — 6 1 9 2 2 14
330 1645 — 602 2577 14 46 — — 60 2 63 39 — 104 — 90 34 — 124 42 438 92 141 713
45 139 — 33 217 9 28 — — 37 1 55 12 — 68 — 61 28 — 89 33 346 57 118 554
13.6 (9.9–17.3) 8.4 (7.1–9.8) — 5.5 (3.7–7.3) 8.4 (7.3–9.5) 64.3 (39.2–89.4) 60.9 (46.8–75) — — 61.7 (49.4–74) 50 (-) 87.3 (79.1–95.5) 30.8 (16.3–45.3) — 65.3 (56.2–74.5) — 67.8 (58.1–77.4) 82.3 (69.5–95.2) — 71.8 (63.9–79.7) 78.6 (66.2–91) 79 (75.2–82.8) 61.9 (52–71.9) 83.7 (77.6–89.8) 77.7 (74.3–80.4)
41 67 — 18 126 5 25 — — 30 1 43 12 — 56 — 57 23 — 80 20 339 56 49 464
12.4 (8.84–15.9) 4.1 (3.1–5) — 3.0 (1.6–4.4) 4.9 (4.1–5.7) 35.7 (10.6–60.8) 54.3 (40–68.7) — — 50 (37.3–62.7) 50 (-) 68.2 (56.8–79.7) 30.8 (16.3–45.3) — 53.8 (44.3–63.4) — 63.3 (53.4–73.3) 67.6 (51.9–83.4) — 64.5 (56.1–72.9) 47.6 (32.5–62.7) 77.4 (73.5–81.3) 60.9 (50.9–70.8) 34.7 (26.9–42.6) 64.5 (61.6–68.6)
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions. CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b c
J. Med. Virol. DOI 10.1002/jmv
HPV Type Distribution in Iranian Women
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TABLE II. Overall HPV Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer Stratified by Pathological Diagnosis Technique and Geographical Regions No. of women tested (%)
No. of women HPV positive (%)
Histology or cytology grade
Subregion
Histology
Cytology
Histology
Cytology
Normal
North Central West South Total North Central West South Total North Central West South Total North Central West South Total North Central West South Total
44 (13.3) 0 (0.0) — 0 (0.0) 44 (1.7) 14 (100) 0 (0.0) — — 14 (23.3) 0 (0.0) 0 (0.0) 39 (100) — 39 (37.5) — 40 (44.5) 34 (100) — 74 (59.7) 42 (100) 372 (84.9) 92 (100) 141 (100) 647 (90.7)
286 (86.7) 1645 (100) — 602 (100) 2533 (98.3) 0 (0.0) 46 (100) — — 46 (76.7) 2 (100) 63 (100) 0 (100) — 65 (62.5) — 50 (55.5) 0 (0.0) — 50 (40.3) 0 (0.0) 66 (15.1) 0 (0.0) 0 (0.0) 66 (9.3)
4 (8.9) 0 (0.0) — 0 (0.0) 4 (1.9) 9 (100) 0 (0.0) — — 9 (24.3) 0 (0.0) 0 (0.0) 12 (100) — 12 (17.7) — 15 (24.6) 28 (100) — 43 (48.3) 33 (100) 282 (83.2) 57 (100) 118 (100) 490 (88.4)
41 (91.1) 139 (100) — 33 (100) 213 (98.1) 0 (0.0) 28 (100) — — 28 (75.7) 1 (100) 55 (100) 0 (0.0) — 56 (82.3) — 46 (75.4) 0 (0.0) — 46 (51.7) 0 (0.0) 64 (16.8) 0 (0.0) 0 (0.0) 64 (11.6)
ASCUSa
LSILb or CIN1c
HSILd or CIN 2,3
ICCe
a
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions or. CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b c
TABLE III. Overall HPV and HPV16/18 Prevalence in Iranian Women With Invasive Cervical Cancer Stratified by Geographic Region and Histology or Cytology Grade Histology or cytology grade Any
SCCa
ADCb
Unspecified
a b
Subregion North Central West South Total North Central West South Total North Central West South Total North Central West South Total
No. of studies
No. of women tested
No. of women HPV positive
1 9 2 2 14 1 7 2 2 12 — 3 2 2 7 — 2 1 1 4
42 438 92 141 713 42 285 82 128 537 — 21 6 10 37 — 132 4 3 139
33 346 57 118 552 33 208 52 111 404 — 19 2 6 27 — 119 1 1 121
HPV prevalence (%) (95% CI) 78.6 79 61.9 83.7 77.4 78.6 73 63.4 86.7 75.2 90.5 33.3 60 80 90.1 25 33.3 87
(66.2–91) (75.2–82.8) (52–71.9) (77.6–89.8) (74.4–80.5) (66.2–91) (67.8–78.1) (53–73.8) (80.8–92.6) (71.6–78.9) — (77.9–100) (0–71.1) (29.6–90.4) (58.7–87.3) — (85.1–95.2) (0–67.4) (0–86.7) (81.5–92.6)
No. of women HPV16/18 positive 20 339 56 49 464 20 202 49 47 318 — 18 2 1 21 — 108 1 1 110
HPV16/18 prevalence (%) (95% CI) 47.6 77.4 60.9 34.7 64.5 47.6 70.9 59.7 36.7 59.2 85.7 33.3 10 56.7 81.8 25 33.3 79.1
(32.5–62.7) (73.5–81.3) (50.9–70.8) (26.9–42.6) (61.6–68.6) (32.5–62.7) (65.6–76.2) (49.1–70.4) (28.4–45.1) (55.1–63.4) — (70.7–100) (0.71.1) (0–28.6) (40.8–72.7) — (75.2–88.4) (0–67.4) (0–86.7) (72.4–85.9)
SCC: squamous cell carcinoma. ADC: adenocarcinoma.
J. Med. Virol. DOI 10.1002/jmv
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Jalilvand et al. TABLE IV. Type-Specific HPV Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer ASCUSa
Normal HPV No. Type cases
HPV þ (%) (95% CI)
No. cases
1 (0.6–1.5) 6/11e 1889 16 2577 3.7 (3–4.4) 18 2577 2.0 (1.5–2.6) 31 1709 0.29 (0.1–0.5) 33 1709 0 45 1632 0.37 (0.1–0.7) 58 1632 0.06 (0–0.2) 59 — — 68 — — 73 — — Any 2577 8.4 (7.3–9.5)
60 60 60 45 — — — — — — 60
LSILb or CIN1c
HPV þ (%) (95% CI)
No. cases
HPV þ (%) (95% CI)
HSILd or CIN 2,3 No. cases
HPV þ (%) (95% CI)
ICCe No. cases
HPV þ (%) (95% CI)
10 (2.4–17.6) 51 11.7 (2.9–20.6) 49 16.3 (6–26.7) 181 9.4 33.3 (21.4–45.3) 104 37.5 (28.2–46.8) 124 47.6 (38.8–56.4) 713 50.1 18.3 (8.5–28.1) 104 16.3 (9.2–23.5) 124 16.9 (10.3–23.5) 713 14.4 0.4 (0–10.5) 28 0 43 23.2 (10.6–35.9) 295 8.1 — 28 0 43 0 314 6.1 — — — — — 221 2.3 — — — — — 132 0.76 — — — — — 146 2.7 — — — — — 219 0.91 — — — — — 132 0.76 61.7 (49.4–74) 104 65.3 (56.2–74.5) 124 71.8 (63.9–79.7) 713 77.4
(5.1–13.6) (46.4–53.7) (11.9–17) (5–11.3) (3.4–8.7) (0.3–4.2) (0–3.6) (0.1–5.4) (0–2.2) (0–2.2) (74.4–80.5)
a
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions or. c CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b
(8.1%), and 33 (6.1%) types. Few extra HPV types (45, 58, 59, 68, and 73) were also reported (Table IV and Fig. S1). The weighted prevalence of HPV 16/18 was 67%, range from 27% to 97% (Fig. 1). Interestingly, HPV 16 was more frequent than HPV 18 in squamous cell carcinoma patients with the frequency of 44.1% and 14%, respectively. However, the difference in the prevalence of HPV 18 (27%) and HPV 16 (29.7%) was not significant in adenocarcinoma (Table V). Although not available for all studies, multiple infections were estimated in 23.9% of invasive cervical cancer group. The most prevalent co-infections were HPV 16/18, followed by HPV 16/31 and 16/58. In these studies, infection with more than two HPV types was found to be rare [Ghaffari et al., 2006; Yarandi et al., 2007; Esmaeili et al., 2008; Shahsiah et al., 2011; Allameh et al., 2011; Khodakarami et al., 2012]. HPV in Women With High and Low-Grade Squamous Intraepithelial Lesions (Cervical Intraepithelial Neoplasia 1-3) Looking at high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and
low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), the overall HPV prevalence was around 79% and 62%, respectively (Fig. 1). As indicated in Figure 1, HPV prevalence for high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) was from 43% to 99%, and for low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) was 22% to 99% in different studies. When data were analyzed based on the HPV types, the majority of cases were found to be positive for HPV 16 and 18, infecting almost the 66% and 47% subjects with high and low-grade squamous intraepithelial lesions, respectively (Fig. 1). Comparing the dominant HPV types between high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and invasive cervical cancer, the difference observed was trivial. In high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) subjects, the most common HPV types were 16 (47.6%) followed by 31 (23.2%), 18 (16.9%), and 6/11 (16.3%). However, for low-grade squamous intraepithelial lesions cases (cervical intraepithelial neoplasia 1), the most common HPV types
TABLE V. Type-Specific Hpv Prevalence Among Iranian Invasive Cervical Cancer Patients Stratified by Histology SCCa
Any HPV Type No. cases 6/11c 16 18 31 33 Any
181 713 713 295 314 713
HPV þ (%) (95%CI) 9.4 50.1 14.4 8.1 6.1 77.4
(5.1–13.6) (46.4–53.7) (11.9–17) (5–11.3) (3.4–8.7) (74.4–80.5)
a
No. cases 136 537 537 149 247 537
HPV þ (%) (95%CI) 14 44.1 13.9 12.7 6.9 59.2
SCC: squamous cell carcinoma. ADC: adencarcinoma. in most studies these two types were mentioned together.
b c
J. Med. Virol. DOI 10.1002/jmv
(8.1–19.8) (39.9–48.3) (11–16.9) (7.4–18.1) (3.7–10) (55.1–63.4)
ADCb
Unspecified
No. cases
HPV þ (%) (95%CI)
No. cases
HPV þ (%) (95%CI)
— 37 37 7 15 37
— 29.7 (15–44.5) 27 (12.7–41.3) 0 6.7 (0–19.3) 56.7 (40.8–72.7)
45 139 139 139 52 139
0 69.1 (61.4–76.7) 10.1 (5.1–15.1) 3.6 (0.5–6.7) 1.9 (0–5.7) 79.1 (72.4–85.9)
HPV Type Distribution in Iranian Women
were HPV 16, 18, and 6/11, detected in 37.5%, 16.3%, and 11.7% of cases, respectively (Table IV and Fig. S1). Regarding multiple infections, 45.6% of high-grade squamous intraepithelial lesion patients were found to be infected by more than one type. The most frequent co-infections were HPV 16/18 followed by HPV 16/31 and 18/31 [Yarandi et al., 2007; Esmaeili et al., 2008; Allameh et al., 2011]. HPV in Women With Atypical Squamous Cells of Undetermined Significance Lesion The weighted HPV prevalence was around 62% in women with atypical squamous cells of undetermined significance lesion (Fig. 1), accounting for 64.3% and 60.9% in the North and the Central parts of Iran, respectively (Table I). The most prevalent HPV type was HPV 16 (33.3%) whereas HPV 18 accounts for 18.3% (Table III and Fig. S1). HPV in Normal Group Among 2,577 women with normal cytology or histology result, HPV was detected in almost 9%, ranging from 2% to 20% (Fig. 1). As shown in Table I, we could not find any data from the West of Iran. The crude age-specific HPV prevalence in Iranian women with normal cytology is shown in Figure 2. As indicated, the prevalence of HPV was decreased with increasing age. The most common types of HPV were HPV 16 (3.7%), 18 (2%), and 6/11 (1%), followed by HPV 45, 31, 58, and 33 (Table IV and Fig. S1).
Fig. 2. Crude age-specific HPV prevalence in Iranian women with normal cytology. Bars indicate the corresponding 95% confidence interval.
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DISCUSSION The present meta-analysis, overviewing the 20 published studies carried out in different geographical regions of Iran, allowed us to make the comprehensive estimation of HPV prevalence and HPV type distribution in Iran. The prevalence of HPV is shown to be around 100% using highly sensitive PCR detection methods [WHO, 2009]; however, the overall prevalence of HPV in Iran seems to be relatively low. Therefore, this lower prevalence are attributable to some factors such as DNA damages due to improper storage of tissue, low sensitivity of methods used to detect HPV DNA, as none of the studies have used nested PCR by GP5 þ /6þ and MY09/11 or PGMY09/11 primers and type of samples (cytological or histological samples). Consistent with the previous reports from other countries [Carozzi et al., 2010; Ciapponi et al., 2011; Seoud, 2012], the overall HPV prevalence in Iranian patients with high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) were 79% and 62%, respectively. Analyzing both groups, the prevalence of HPV was found to be different based on geographic regions in Iran. This variety can result from the small sample size, different methods used to detect HPV DNA and type of samples as HPV more detected among cytological samples than histological samples. Further studies with larger sample size and sensitive detection assays are needed to reliably estimate the prevalence of HPV in Iranian patients with high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1). In this analysis, HPV prevalence was 62% in women with atypical squamous cells of undetermined significance lesion. Data obtained from previous studies indicate the great variability of HPV prevalence, mostly depending on age [Clifford et al., 2006]. In the US, although HPV was detected from 61% of atypical squamous cells of undetermined significance cases, the positivity rate of HPV reduced from 78% in the 18–24-year-old group to 32% in women over 35 years of age [Castle et al., 2005]. Among normal group, HPV was detected in 9% (ranging from 5.5% in the South to 13.6% in the North). This discrepancy may be due to diverse distribution of HPV in different geographical regions, methods with different sensitivity and including the abnormal cytological cases within normal group. In a worldwide meta-analysis carried out on women with normal cervical cytology, overall HPV prevalence was estimated to be 10.4% although it was different according to the geographical regions. Indeed, the prevalence of HPV was estimated 22.1% in Africa, 20.4% in central America and Mexico, 11.3% in J. Med. Virol. DOI 10.1002/jmv
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northern America, 8.1% in Europe, and 8% in Asia [Castellsague´ et al., 2007; de Sanjose et al., 2007]. Regarding the age-specific HPV prevalence in the world, the highest HPV prevalence was reported in women younger than 35 years of age [de Sanjose et al., 2003; de Sanjose et al., 2007; Forman et al., 2012; Monsonego et al., 2012]. The six most frequent HPV types were HPV 16, 18, 6/11, 31, and 33 in invasive cervical cancer highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), and atypical squamous cells of undetermined significance cases. However, they were slightly different in women with normal group as HPV 16, 18, 6/ 11, 31, and 45 were the six most frequent types. The most frequent HPV type was HPV 16 followed by HPV 18 in all five different groups. These data are compatible with the worldwide reports showing around 70% of invasive cervical cancer are caused by HPV 16 or 18 [Castellsague´ et al., 2007; Giorgi et al., 2012]. The type distribution pattern of HPVs in Iran is more similar to those of Africa, America and Europe than to most Asian countries [Castellsague´ et al., 2007; Tornesello et al., 2011; Demir et al., 2012]. HPV 16 was more frequent than HPV 18 in squamous cell carcinoma cases. However, in adenocarcinoma, HPV 18 was as important as HPV 16 which was consistent with the previous findings [Clifford et al., 2003; Clifford et al., 2006; Li et al., 2011]. In this study, the prevalence ratio of HPV 16 in invasive cervical cancer/high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and invasive cervical cancer/low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) were higher than one, representing that HPV 16 is probably more progressive than the other HPV types to cause cervical cancer from lowgrade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion; almost consistent to previous studies [Bao et al., 2008; Chen et al., 2009; Ciapponi et al., 2011]. Looking at multiple HPV infections, 23.9% of invasive cervical cancer and 45.6% of high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) patients were found to be infected with more than one type. Infection with multiple HPV types appears to act synergistically in progression to cervical cancer [Trottier et al., 2006]. The potential impact of prophylactic vaccines for the future protection against cervical cancer can be expected from the fraction of HPV types in women with cervical cancer. Regarding to the present study, it is estimated that two current vaccines (Cervarix and Gardasil) will provide around 64.5% and 73.9% prevention of cervical cancer in Iran, respectively. These findings present an exhaustive report of overall and type-specific HPV prevalence in Iran, J. Med. Virol. DOI 10.1002/jmv
Jalilvand et al.
stratified by geographic region. However, we consider that HPV 16 and 18 to be more prevalent than obtained in the present study, because most studies did not use highly sensitive assays. Therefore, we assume that our estimation on the percentage of HPV 16 and HPV 18 positive invasive cervical cancer cases could be elevated if highly sensitive techniques had been applied to detect HPV DNA in HPV negative invasive cervical cancer samples. In conclusion, this meta-analysis highlights the necessity of introducing vaccination program in Iran. In addition, future investigations from different areas of Iran, particularly regions with lack of eligible data, is needed in order to determine the HPV prevalence and type distribution in women with invasive cervical cancer, high-grade squamous intraepithelial lesion, low-grade squamous intraepithelial lesion and atypical squamous cells of undetermined significance and normal cytology. This will surely assist policy makers to decide if HPV vaccine is needed in all regions of Iran or not. REFERENCES Allameh T, Moghim S, sadi-Zeidabadi M. 2011. A survey on the prevalence of high-risk subtypes of human papilloma virus among women with cervical neoplasia in Isfahan University of Medical Science. Arch Gynecol Obstet 284:1509–1513. Bao YP, Li N, Smith JS, Qiao YL. 2008. Human papillomavirus type distribution in women from Asia: A meta-analysis. Int J Gynecol Cancer 18:71–79. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El GF, brahimTallaa L, Guha N, Freeman C, Galichet L, Cogliano V. 2009. A review of human carcinogens–Part B: Biological agents. Lancet Oncol 10:321–322. Carozzi FM, Tornesello ML, Burroni E, Loquercio G, Carillo G, Angeloni C, Scalisi A, Macis R, Chini F, Buonaguro FM, Giorgi RP. 2010. Prevalence of human papillomavirus types in high-grade cervical intraepithelial neoplasia and cancer in Italy. Cancer Epidemiol Biomarkers Prev 19:2389–2400. Castellsague´ X, de Sanjose´ S, Aguado T, Louie KS, Bruni L, Mu~ noz J, Diaz M, Irwin K, Gacic M, Beauvais O, Albero G, Ferrer E, Byrne S, Bosch FX. 2007. HPV and cervical cancer in the World 2007 report. Vaccine 25:C1–C230. Castle PE, Solomon D, Schiffman M, Wheeler CM. 2005. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 97:1066–1071. Chen W, Zhang X, Molijn A, Jenkins D, Shi JF, Quint W, Schmidt JE, Wang P, Liu YL, Li LK, Shi H, Liu JH, Xie X, Niyazi M, Yang P, Wei LH, Li LY, Li J, Liu JF, Zhou Q., et al. 2009. Human papillomavirus type-distribution in cervical cancer in China: the importance of HPV 16 and 18. Cancer Causes Control 20:1705–1713. Ciapponi A, Bardach A, Glujovsky D, Gibbons L, Picconi MA. 2011. Type-specific HPV prevalence in cervical cancer and high-grade lesions in Latin America and the Caribbean: Systematic review and meta-analysis. PLoS One 6:e25493. Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL. 2006. Chapter 3: HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine 24:S3/26-S3/34. Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. 2003. Human papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer 88:63–73. Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El GF. 2005. Carcinogenicity of human papillomaviruses. Lancet Oncol 6:204. Cutts FT, Franceschi S, Goldie S, Castellsague X, de SS, Garnett G, Edmunds WJ, Claeys P, Goldenthal KL, Harper DM, Markowitz L. 2007. Human papillomavirus and HPV vaccines: A review. Bull World Health Organ 85:719–726.
HPV Type Distribution in Iranian Women de Sanjose S, Almirall R, Lloveras B, Font R, Diaz M, Munoz N, Catala I, Meijer CJ, Snijders PJ, Herrero R, Bosch FX. 2003. Cervical human papillomavirus infection in the female population in Barcelona, Spain. Sex Transm Dis 30:788–793. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, Bosch FX. 2007. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: A meta-analysis. Lancet Infect Dis 7:453–459. Demir ET, Ceyhan M, Simsek M, Gunduz T, Arlier S, Aytac R, Aycan AE, Gurbuz V. 2012. The prevalence of different HPV types in Turkish women with a normal Pap smear. J Med Virol 84:1242–1247. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, Stanley MA. 2012. The biology and life-cycle of human papillomaviruses. Vaccine 30:F55–F70. Eslami G, Golshani M, Rakhshan M, Fallah F, Goudarzi H, Taghavi A. 2008. PCR detection and high risk typing of human papillomavirus DNA in cervical cancer in Iranian women. Cancer Therapy 6:361–366. Esmaeili M, Bonyadi M, Dastranj A, Alizadeh M, Melli MS, Shobeiri MJ. 2008. HPV typing in women with cervical precancerous and cancerous lesions in northwestern Iran. Gynecol Obstet Invest 66:68–72. Farjadian S, Asadi E, Doroudchi M, Dehaghani AS, Tabei SZ, Kumar VP, Ghaderi A. 2003. High risk HPV types in southern Iranian patients with cervical cancer. Pathol Oncol Res 9:121– 125. Forman D, de MC, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, Vignat J, Ferlay J, Bray F, Plummer M, Franceschi S. 2012. Global burden of human papillomavirus and related diseases. Vaccine 30:F12–F23. Ghaffari SR, Sabokbar T, Mollahajian H, Dastan J, Ramezanzadeh F, Ensani F, Yarandi F, Mousavi-Jarrahi A, Mohagheghi MA, Moradi A. 2006. Prevalence of human papillomavirus genotypes in women with normal and abnormal cervical cytology in Iran. Asian Pac J Cancer Prev 7:529–532. Giorgi RP, Sideri M, Carozzi FM, Vocaturo A, Buonaguro FM, Tornesello ML, Burroni E, Mariani L, Boveri S, Zaffina LM, Chini F. 2012. HPV type distribution in invasive cervical cancers in Italy: Pooled analysis of three large studies. Infect Agent Cancer 7:26. Hamkar R, Azad TM, Mahmoodi M, Seyedirashti S, Severini A, Nategh R. 2002. Prevalence of human papillomavirus in Mazandaran Province, Islamic Republic of Iran. East Mediterr Health J 8:805–811. Heidarpour M, Salehi R, Kamali Z, yaraghi H. 2011. The frequency of high risk sub-types of Human Papillomavirus in the samples with varying degrees of cervical neoplasia. Journal of Isfahan Medical School 28: International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012. Ref Type: Report. Jamali Zavarei M, Hamkar R, Ghobadi Dana V, Delforoosh M, Shojamoradi MH, Modarresi Gilani M. 2008. Prevalence of HPV infection and its association with cytological abnormalities of Pap smears in Tehran. Iranian J Publ Health 37:101–106. Khodakarami N, Clifford GM, Yavari P, Farzaneh F, Salehpour S, Broutet N, Bathija H, Heideman DA, van Kemenade FJ, Meijer CJ, Hosseini SJ, Franceschi S. 2012. Human papillomavirus infection in women with and without cervical cancer in Tehran, Iran. Int J Cancer 131:E156–E161. Khorasanizadeh F, Hassanloo J, Khaksar N, Mohammad TS, Marzaban M, Rashidi H, Akbari SA, Zendehdel K. 2013. Epidemiology of cervical cancer and human papilloma virus infection among Iranian women—analyses of national data and systematic review of the literature. Gynecol Oncol 128:277–281. Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. 2011. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer 128:927– 935. Mahmoodi MM, Hamkar R, Akhavan-Tafti M, Eslamifar A, Adibi L, Sadrdabadi SA, Nategh R. 2007. HPV genotyping in cervical cancer in Yazd province. Iranian Journal of Infectious Diseases 12:19–24.
9 Maleknejad P, Rakhshan M, Kazemi B, Farokh F, Shahsavan S. 2006. Detection of Human Papilomavirus types 16 and 18 in pathologic samples from patients with cervical cancer by PCR and RFLP methods. Daru 14:78–81. Monsonego J, Zerat L, Syrjanen K, Zerat JC, Smith JS, Halfon P. 2012. Prevalence of type-specific human papillomavirus infection among women in France: Implications for screening, vaccination, and a future generation of multivalent HPV vaccines. Vaccine 30:5215–5221. Moradi A, Bakhshandeh Nosrat S, Besharat S. 2011. Molecular epidemiology of high-risk types of Human Papillomaviruses (16, 18) in Pap-smear, the North East of Iran. Iran J Cancer Prev 3:135–140. Mortazavi S, Zali M, Raoufi M, Nadji M, Kowsarian P, Nowroozi A. 2002. The prevalence of Human Papillomavirus in cervical cancer in Iran. Asian Pac J Cancer Prev 3:69–72. Munoz N, Bosch FX, de SS, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ. 2003. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348:518–527. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. 2006. Chapter 1: HPV in the etiology of human cancer. Vaccine 24:S3– 1-S310. Omrani M, Saleh S, Lotfinejad S, Bagheri M, Lotfelai-Haghi L, Alavi E. 2007. Prevalence of HPV16 and 18 in cervical cancer by PCR in Western Azarbaijan. Urmia Medical Journal 18:414–421. Safaei A, Khanlari M, Momtahen M, Monabati A, Robati M, Amooei S, Valibeigi B, Azarpira N. 2010. Prevalence of high-risk human papillomavirus types 16 and 18 in healthy women with cytologically negative pap smear in Iran. Indian J Pathol Microbiol 53:681–685. Schiller JT, Castellsague X, Garland SM. 2012. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 30:F123–F138. Seoud M. 2012. Burden of human papillomavirus-related cervical disease in the extended middle East and north Africa—A comprehensive literature review. J Low Genit Tract Dis 16:106– 120. Shahsiah R, Khademalhosseini M, Mehrdad N, Ramezani F, Nadji SA. 2011. Human papillomavirus genotypes in Iranian patients with cervical cancer. Pathol Res Pract 207:754–757. Sharbatdaran M, Siadati S, Zeinalzadeh M, Shafaei S, Basirat Z, Esmi A. 2013. The frequency of HPV 16 and 18 in cervical discharge by PCR in women with abnormal pap smear or biopsy. Iranian Journal of Pathology 8:17–20. Tornesello ML, Losito S, Benincasa G, Fulciniti F, Botti G, Greggi S, Buonaguro L, Buonaguro FM. 2011. Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix. Gynecol Oncol 121:32–42. Trottier H, Mahmud S, Costa MC, Sobrinho JP, Duarte-Franco E, Rohan TE, Ferenczy A, Villa LL, Franco EL. 2006. Human papillomavirus infections with multiple types and risk of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 15:1274– 1280. WHO. Human papillomavirus laboratory manual. 2009. Yarandi F, Izadi Mood N, Eftekhar Z, Niakan R, Tajziachi S. 2007. HPV infection among patients with high grade cervical intraepithelial neoplasia and squamous cell carcinoma of cervix. Tehran University Medical Journal 65:5–11. Zandi K, Eghbali SS, Hamkar R, Ahmadi S, Ramedani E, Deilami I, Nejad HA, Farshadpour F, Rastian Z. 2010. Prevalence of various human papillomavirus (HPV) genotypes among women who subjected to routine Pap smear test in Bushehr city (south west of Iran) 2008–2009. Virol J 7:65.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publishers web-site.
J. Med. Virol. DOI 10.1002/jmv
Meta-Analysis of Type-Specific Human Papillomavirus Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer: Implications For Screening and Vaccination Somayeh Jalilvand,1 Zabihollah Shoja,2 Keramat Nourijelyani,3 Hamid Reza Tohidi,4,5 and Rasool Hamkar1* 1
Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran Virology Department, Pasteur Institute of Iran, Tehran, Iran 3 Biostatistics Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 4 Faculty of Health, Gonabad University of Medical Sciences, Gonabad, Iran 5 Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Science Institute, Tehran University of Medical Sciences, Tehran, Iran 2
To predict the impact of current vaccines on cervical cancer and for the improvement of screening programs, regional data on distribution of human papillomavirus (HPV) types in women with or without cervical cancer is crucial. The present meta-analysis intend to comprehensively evaluate the HPV burden in women with invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology, as these data will help decision making in regards with screening programs and HPV vaccination in Iran. To determine the HPV prevalence and type distribution in Iranian women with or without cervical cancer, 20 published studies were included in this meta-analysis. In total, 713, 124, 104, 60, and 2577 women invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal were reviewed, respectively. Overall HPV prevalence in women with invasive cervical cancer, highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology were 77.4%, 71.8%, 65.3%, 61.7%, and 8.4%, respectively. The six most common C 2014 WILEY PERIODICALS, INC.
types were HPV 16, 18, 6/11, 31, and 33; among them HPV 16 was the most frequent type in all five different groups. According to this study, it was estimated that HPV vaccines could have a great impact on prevention of cervical cancer in Iran. In conclusion, this meta-analysis highlights the necessity of introducing vaccination program in Iran. J. Med. Virol. # 2014 Wiley Periodicals, Inc.
KEY WORDS:
human papillomavirus; HPV prevalence; HPV types; cervical cancer
INTRODUCTION Cervical cancer is the fourth most frequent cancer among women worldwide. Indeed, just in 2012, an estimated of 528,000 new cases and 266,000 deaths of cervical cancer took place globally [International Agency for Research on Cancer, 2012]. The incidence Grant sponsor: Tehran University of Medical Sciences (TUMS); Grant number: 93-03-27-26731. Conflict of interests: The authors declare that they have no conflict of interests. Correspondence to: Rasool Hamkar, Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran 14155, Iran. E-mail: [email protected] Accepted 29 July 2014 DOI 10.1002/jmv.24053 Published online in Wiley Online Library (wileyonlinelibrary.com).
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rate of cervical cancer is low in Iranian women, and the mean cervical cancer age-standardized incidence rate (ASR) was reported to be 2.5 per 100,000 women. Regardless of geographical regions, the ASRs were estimated to be below 5 per 100,000, ranging from 4.1 to 0.4 in Fars and Zanjan provinces, respectively. In addition, the mean cervical cancer age-standardized mortality rate was reported 1.04 per 100,000 women. Analysis of age-specific incidence rates revealed that the peak of cervical cancer incidence rate is among women within 55–65 years old [Khorasanizadeh et al., 2013]. The role of human papillomavirus (HPV), as an etiological and essential factor in the development of cervical cancer is well documented. It is known that nearly all cervical cancers and their precursor lesions are associated to cervical infection by 12 highrisk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) [Munoz et al., 2003; Cogliano et al., 2005; Munoz et al., 2006; Bouvard et al., 2009; Doorbar et al., 2012], among which HPV 16 and 18 accounts for 70.1% of cases worldwide [Castellsague´ et al., 2007]. Alongside with high risk types, extra types including 68 and 73 are considered as “possibly” cancer-causing [Munoz et al., 2003; Cogliano et al., 2005; Munoz et al., 2006; Bouvard et al., 2009; Doorbar et al., 2012]. Two prophylactic HPV vaccines are currently available for cervical cancer prevention. Gardasil is a quadrivalent vaccine for the HPV 6, 11, 16, and 18 types whereas cervarix is a bivalent vaccine consisting of HPV 16 and 18 types [Cutts et al., 2007; Schiller et al., 2012]. Regional data on distribution of HPV types in women with or without cervical cancer is crucial not only to predict the impact of current vaccines but also to improve the screening programs. The present meta-analysis intends to comprehensively evaluate the burden of HPV in women with invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal, as these data will help decision making in regards with screening programs and HPV vaccination in Iran. Therefore, published data were retrieved and pooled to determine HPV prevalence and type distribution in women with or without cervical cancer. METHODS Search Strategy A systematic review of the literatures was carried out, up to May 2013, to evaluate the prevalence and type distribution of HPV in Iranian women. To obtain data, the following search engines were used: Medline, PubMed, Current Contents and national databases. To our purpose, we used several terms J. Med. Virol. DOI 10.1002/jmv
including “human papillomavirus (HPV)”, “cervical cancer/cervical neoplasms”, “women/female”, “epidemiology”, “prevalence”, “polymerase chain reaction (PCR)” and “Iran”. Study Selection To focus on the purpose of this study, studies were included only if they had the following criteria: (1) to include at least one group from five different groups (invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal); (2) to split HPV prevalence data for the above categories; (3) to detect HPV DNA using PCR-based assays; (4) to determine at least the HPV 16 and 18 types in positive samples and (5) to stratify HPV type distribution by cervical lesion histology or cytology. As indicated, invasive cervical cancer was further segregated into squamous cell carcinoma and adenocarcinoma. In addition, invasive cervical cancer was considered as unspecific when the prevalence of HPV types was not clear based on histology. Data Extraction The following details were extracted from each study: first author, journal name, year of publication, study period, histology or cytology grade, sample size, age range (if was available), city, the PCR primers, number of HPV-positive, HPV typing methods (direct nucleotide sequencing, PCR with type-specific primers, hybridization, multiplex PCR, others), and type-specific HPV prevalence by histology. In total, 25 papers were assessed, from which 20 articles were included in the present study. Statistical Analysis STATA 12 (Stata Corp, College Station, TX, USA) was used to analyze the data. Binomial distribution formula was used to calculate the variance of HPV prevalence. Heterogeneity among studies was assessed via the X2-based Q test and the P < 0.1 were considered statistically significant. In the absence of heterogeneity between studies, fixed effect model was applied and in the presence of heterogeneity, random effect model was used to estimate the overall prevalence. P < 0.05 was considered statistically significant. To minimize the random variations between point estimates of different studies, all results were adjusted using Bayesian method, and the overall point estimate was used as prior prevalence. RESULTS A total of 3,478 women from 20 studies were included in this meta-analysis review (Fig. 1) [Hamkar et al., 2002; Mortazavi et al., 2002; Farjadian et al., 2003; Ghaffari et al., 2006; Maleknejad
HPV Type Distribution in Iranian Women
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Fig. 1. HPV prevalence and HPV 16/18 prevalence among Iranian women with invasive cervical cancer (ICC), high-grade squamous intraepithelial lesion (HSIL) or (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (LSIL) or (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance (ASCUS) and normal cytology. Each line shows the prevalence of each study and the corresponding 95% confidence interval. Diamond (lozenge) shows the combined weighted prevalence of HPV and HPV 16/18.
J. Med. Virol. DOI 10.1002/jmv
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et al., 2006; Mahmoodi et al., 2007; Omrani et al., 2007; Yarandi et al., 2007; Jamali Zavarei et al., 2008; Esmaeili et al., 2008; Eslami et al., 2008; Zandi et al., 2010; Safaei et al., 2010; Shahsiah et al., 2011; Allameh et al., 2011; Heidarpour et al., 2011; Moradi et al., 2011; Khodakarami et al., 2012; Sharbatdaran et al., 2013]. As indicated in Table I, the crude HPV prevalence and HPV type distribution are shown in invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal groups. Regarding all five histology or cytological grades, no data is available from the Eastern region of Iran. According to the histology or cytology grade, in total, 713, 124, 104, 60, and 2577 women were included invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal groups, respectively (Table I). As indicated in Table II, in total, 98.3%, 76.7%, 62%, 40.3%, and 9.3% of samples of invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous
intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal, respectively, were cytological samples, and the remaining of each group were histological samples (Formalin Fixed Paraffin Embedded Tissues). Stratifying the invasive cervical cancer group, 537, 37, and 139 subjects had squamous cell carcinoma, adenocarcinoma and unspecified histology, respectively (Table III). In most studies, to determine HPV types, PCR using HPV-specific primers were applied followed by either direct nucleotide sequencing or hybridization assays. HPV in Women With Invasive Cervical Cancer Overall, the weighted prevalence of HPV among invasive cervical cancer subjects was estimated to be 80% (Fig. 1). Figure 1 revealed that the most studies were, in fact, detected HPV in more than 77% of cases. Analyzing in particular, following stratification of invasive cervical cancer types, HPV was detected in 75.2%, 80%, and 87% of squamous cell carcinoma, adenocarcinoma and unspecified cases, respectively (Table III). The predominant high-risk HPV types were found to be HPV 16 and 18 at the frequency of 50.1% and 14.4%, respectively, followed by HPV 6/11 (9.4%), 31
TABLE I. Overall HPV and HPV 16/18 Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer Stratified by Geographical Regions Histology or cytology grade Normal
ASCUSa
LSILb or CIN1c
HSILd or CIN 2,3
ICCe
Subregion North Central West South Total North Central West South Total North Central West South Total North Central West South Total North Central West South Total
a
No. of studies
No. of women tested
No. of women HPV positive
HPV prevalence (%) (95% CI)
No. of women HPV16/18 positive
HPV16/18 prevalence (%) (95% CI)
3 4 — 2 9 1 2 — — 3 1 3 2 — 6 — 5 1 — 6 1 9 2 2 14
330 1645 — 602 2577 14 46 — — 60 2 63 39 — 104 — 90 34 — 124 42 438 92 141 713
45 139 — 33 217 9 28 — — 37 1 55 12 — 68 — 61 28 — 89 33 346 57 118 554
13.6 (9.9–17.3) 8.4 (7.1–9.8) — 5.5 (3.7–7.3) 8.4 (7.3–9.5) 64.3 (39.2–89.4) 60.9 (46.8–75) — — 61.7 (49.4–74) 50 (-) 87.3 (79.1–95.5) 30.8 (16.3–45.3) — 65.3 (56.2–74.5) — 67.8 (58.1–77.4) 82.3 (69.5–95.2) — 71.8 (63.9–79.7) 78.6 (66.2–91) 79 (75.2–82.8) 61.9 (52–71.9) 83.7 (77.6–89.8) 77.7 (74.3–80.4)
41 67 — 18 126 5 25 — — 30 1 43 12 — 56 — 57 23 — 80 20 339 56 49 464
12.4 (8.84–15.9) 4.1 (3.1–5) — 3.0 (1.6–4.4) 4.9 (4.1–5.7) 35.7 (10.6–60.8) 54.3 (40–68.7) — — 50 (37.3–62.7) 50 (-) 68.2 (56.8–79.7) 30.8 (16.3–45.3) — 53.8 (44.3–63.4) — 63.3 (53.4–73.3) 67.6 (51.9–83.4) — 64.5 (56.1–72.9) 47.6 (32.5–62.7) 77.4 (73.5–81.3) 60.9 (50.9–70.8) 34.7 (26.9–42.6) 64.5 (61.6–68.6)
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions. CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b c
J. Med. Virol. DOI 10.1002/jmv
HPV Type Distribution in Iranian Women
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TABLE II. Overall HPV Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer Stratified by Pathological Diagnosis Technique and Geographical Regions No. of women tested (%)
No. of women HPV positive (%)
Histology or cytology grade
Subregion
Histology
Cytology
Histology
Cytology
Normal
North Central West South Total North Central West South Total North Central West South Total North Central West South Total North Central West South Total
44 (13.3) 0 (0.0) — 0 (0.0) 44 (1.7) 14 (100) 0 (0.0) — — 14 (23.3) 0 (0.0) 0 (0.0) 39 (100) — 39 (37.5) — 40 (44.5) 34 (100) — 74 (59.7) 42 (100) 372 (84.9) 92 (100) 141 (100) 647 (90.7)
286 (86.7) 1645 (100) — 602 (100) 2533 (98.3) 0 (0.0) 46 (100) — — 46 (76.7) 2 (100) 63 (100) 0 (100) — 65 (62.5) — 50 (55.5) 0 (0.0) — 50 (40.3) 0 (0.0) 66 (15.1) 0 (0.0) 0 (0.0) 66 (9.3)
4 (8.9) 0 (0.0) — 0 (0.0) 4 (1.9) 9 (100) 0 (0.0) — — 9 (24.3) 0 (0.0) 0 (0.0) 12 (100) — 12 (17.7) — 15 (24.6) 28 (100) — 43 (48.3) 33 (100) 282 (83.2) 57 (100) 118 (100) 490 (88.4)
41 (91.1) 139 (100) — 33 (100) 213 (98.1) 0 (0.0) 28 (100) — — 28 (75.7) 1 (100) 55 (100) 0 (0.0) — 56 (82.3) — 46 (75.4) 0 (0.0) — 46 (51.7) 0 (0.0) 64 (16.8) 0 (0.0) 0 (0.0) 64 (11.6)
ASCUSa
LSILb or CIN1c
HSILd or CIN 2,3
ICCe
a
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions or. CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b c
TABLE III. Overall HPV and HPV16/18 Prevalence in Iranian Women With Invasive Cervical Cancer Stratified by Geographic Region and Histology or Cytology Grade Histology or cytology grade Any
SCCa
ADCb
Unspecified
a b
Subregion North Central West South Total North Central West South Total North Central West South Total North Central West South Total
No. of studies
No. of women tested
No. of women HPV positive
1 9 2 2 14 1 7 2 2 12 — 3 2 2 7 — 2 1 1 4
42 438 92 141 713 42 285 82 128 537 — 21 6 10 37 — 132 4 3 139
33 346 57 118 552 33 208 52 111 404 — 19 2 6 27 — 119 1 1 121
HPV prevalence (%) (95% CI) 78.6 79 61.9 83.7 77.4 78.6 73 63.4 86.7 75.2 90.5 33.3 60 80 90.1 25 33.3 87
(66.2–91) (75.2–82.8) (52–71.9) (77.6–89.8) (74.4–80.5) (66.2–91) (67.8–78.1) (53–73.8) (80.8–92.6) (71.6–78.9) — (77.9–100) (0–71.1) (29.6–90.4) (58.7–87.3) — (85.1–95.2) (0–67.4) (0–86.7) (81.5–92.6)
No. of women HPV16/18 positive 20 339 56 49 464 20 202 49 47 318 — 18 2 1 21 — 108 1 1 110
HPV16/18 prevalence (%) (95% CI) 47.6 77.4 60.9 34.7 64.5 47.6 70.9 59.7 36.7 59.2 85.7 33.3 10 56.7 81.8 25 33.3 79.1
(32.5–62.7) (73.5–81.3) (50.9–70.8) (26.9–42.6) (61.6–68.6) (32.5–62.7) (65.6–76.2) (49.1–70.4) (28.4–45.1) (55.1–63.4) — (70.7–100) (0.71.1) (0–28.6) (40.8–72.7) — (75.2–88.4) (0–67.4) (0–86.7) (72.4–85.9)
SCC: squamous cell carcinoma. ADC: adenocarcinoma.
J. Med. Virol. DOI 10.1002/jmv
6
Jalilvand et al. TABLE IV. Type-Specific HPV Prevalence in Iranian Women With Normal Cytology, Precancerous Cervical Lesions and Invasive Cervical Cancer ASCUSa
Normal HPV No. Type cases
HPV þ (%) (95% CI)
No. cases
1 (0.6–1.5) 6/11e 1889 16 2577 3.7 (3–4.4) 18 2577 2.0 (1.5–2.6) 31 1709 0.29 (0.1–0.5) 33 1709 0 45 1632 0.37 (0.1–0.7) 58 1632 0.06 (0–0.2) 59 — — 68 — — 73 — — Any 2577 8.4 (7.3–9.5)
60 60 60 45 — — — — — — 60
LSILb or CIN1c
HPV þ (%) (95% CI)
No. cases
HPV þ (%) (95% CI)
HSILd or CIN 2,3 No. cases
HPV þ (%) (95% CI)
ICCe No. cases
HPV þ (%) (95% CI)
10 (2.4–17.6) 51 11.7 (2.9–20.6) 49 16.3 (6–26.7) 181 9.4 33.3 (21.4–45.3) 104 37.5 (28.2–46.8) 124 47.6 (38.8–56.4) 713 50.1 18.3 (8.5–28.1) 104 16.3 (9.2–23.5) 124 16.9 (10.3–23.5) 713 14.4 0.4 (0–10.5) 28 0 43 23.2 (10.6–35.9) 295 8.1 — 28 0 43 0 314 6.1 — — — — — 221 2.3 — — — — — 132 0.76 — — — — — 146 2.7 — — — — — 219 0.91 — — — — — 132 0.76 61.7 (49.4–74) 104 65.3 (56.2–74.5) 124 71.8 (63.9–79.7) 713 77.4
(5.1–13.6) (46.4–53.7) (11.9–17) (5–11.3) (3.4–8.7) (0.3–4.2) (0–3.6) (0.1–5.4) (0–2.2) (0–2.2) (74.4–80.5)
a
ASCUS: atypical squamous cells of undetermined significance. LSIL: low-grade squamous intraepithelial lesions or. c CIN: cervical intraepithelial neoplasia. d HSIL: high-grade squamous intraepithelial lesions. e ICC: invasive cervical cancer. b
(8.1%), and 33 (6.1%) types. Few extra HPV types (45, 58, 59, 68, and 73) were also reported (Table IV and Fig. S1). The weighted prevalence of HPV 16/18 was 67%, range from 27% to 97% (Fig. 1). Interestingly, HPV 16 was more frequent than HPV 18 in squamous cell carcinoma patients with the frequency of 44.1% and 14%, respectively. However, the difference in the prevalence of HPV 18 (27%) and HPV 16 (29.7%) was not significant in adenocarcinoma (Table V). Although not available for all studies, multiple infections were estimated in 23.9% of invasive cervical cancer group. The most prevalent co-infections were HPV 16/18, followed by HPV 16/31 and 16/58. In these studies, infection with more than two HPV types was found to be rare [Ghaffari et al., 2006; Yarandi et al., 2007; Esmaeili et al., 2008; Shahsiah et al., 2011; Allameh et al., 2011; Khodakarami et al., 2012]. HPV in Women With High and Low-Grade Squamous Intraepithelial Lesions (Cervical Intraepithelial Neoplasia 1-3) Looking at high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and
low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), the overall HPV prevalence was around 79% and 62%, respectively (Fig. 1). As indicated in Figure 1, HPV prevalence for high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) was from 43% to 99%, and for low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) was 22% to 99% in different studies. When data were analyzed based on the HPV types, the majority of cases were found to be positive for HPV 16 and 18, infecting almost the 66% and 47% subjects with high and low-grade squamous intraepithelial lesions, respectively (Fig. 1). Comparing the dominant HPV types between high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and invasive cervical cancer, the difference observed was trivial. In high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) subjects, the most common HPV types were 16 (47.6%) followed by 31 (23.2%), 18 (16.9%), and 6/11 (16.3%). However, for low-grade squamous intraepithelial lesions cases (cervical intraepithelial neoplasia 1), the most common HPV types
TABLE V. Type-Specific Hpv Prevalence Among Iranian Invasive Cervical Cancer Patients Stratified by Histology SCCa
Any HPV Type No. cases 6/11c 16 18 31 33 Any
181 713 713 295 314 713
HPV þ (%) (95%CI) 9.4 50.1 14.4 8.1 6.1 77.4
(5.1–13.6) (46.4–53.7) (11.9–17) (5–11.3) (3.4–8.7) (74.4–80.5)
a
No. cases 136 537 537 149 247 537
HPV þ (%) (95%CI) 14 44.1 13.9 12.7 6.9 59.2
SCC: squamous cell carcinoma. ADC: adencarcinoma. in most studies these two types were mentioned together.
b c
J. Med. Virol. DOI 10.1002/jmv
(8.1–19.8) (39.9–48.3) (11–16.9) (7.4–18.1) (3.7–10) (55.1–63.4)
ADCb
Unspecified
No. cases
HPV þ (%) (95%CI)
No. cases
HPV þ (%) (95%CI)
— 37 37 7 15 37
— 29.7 (15–44.5) 27 (12.7–41.3) 0 6.7 (0–19.3) 56.7 (40.8–72.7)
45 139 139 139 52 139
0 69.1 (61.4–76.7) 10.1 (5.1–15.1) 3.6 (0.5–6.7) 1.9 (0–5.7) 79.1 (72.4–85.9)
HPV Type Distribution in Iranian Women
were HPV 16, 18, and 6/11, detected in 37.5%, 16.3%, and 11.7% of cases, respectively (Table IV and Fig. S1). Regarding multiple infections, 45.6% of high-grade squamous intraepithelial lesion patients were found to be infected by more than one type. The most frequent co-infections were HPV 16/18 followed by HPV 16/31 and 18/31 [Yarandi et al., 2007; Esmaeili et al., 2008; Allameh et al., 2011]. HPV in Women With Atypical Squamous Cells of Undetermined Significance Lesion The weighted HPV prevalence was around 62% in women with atypical squamous cells of undetermined significance lesion (Fig. 1), accounting for 64.3% and 60.9% in the North and the Central parts of Iran, respectively (Table I). The most prevalent HPV type was HPV 16 (33.3%) whereas HPV 18 accounts for 18.3% (Table III and Fig. S1). HPV in Normal Group Among 2,577 women with normal cytology or histology result, HPV was detected in almost 9%, ranging from 2% to 20% (Fig. 1). As shown in Table I, we could not find any data from the West of Iran. The crude age-specific HPV prevalence in Iranian women with normal cytology is shown in Figure 2. As indicated, the prevalence of HPV was decreased with increasing age. The most common types of HPV were HPV 16 (3.7%), 18 (2%), and 6/11 (1%), followed by HPV 45, 31, 58, and 33 (Table IV and Fig. S1).
Fig. 2. Crude age-specific HPV prevalence in Iranian women with normal cytology. Bars indicate the corresponding 95% confidence interval.
7
DISCUSSION The present meta-analysis, overviewing the 20 published studies carried out in different geographical regions of Iran, allowed us to make the comprehensive estimation of HPV prevalence and HPV type distribution in Iran. The prevalence of HPV is shown to be around 100% using highly sensitive PCR detection methods [WHO, 2009]; however, the overall prevalence of HPV in Iran seems to be relatively low. Therefore, this lower prevalence are attributable to some factors such as DNA damages due to improper storage of tissue, low sensitivity of methods used to detect HPV DNA, as none of the studies have used nested PCR by GP5 þ /6þ and MY09/11 or PGMY09/11 primers and type of samples (cytological or histological samples). Consistent with the previous reports from other countries [Carozzi et al., 2010; Ciapponi et al., 2011; Seoud, 2012], the overall HPV prevalence in Iranian patients with high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) were 79% and 62%, respectively. Analyzing both groups, the prevalence of HPV was found to be different based on geographic regions in Iran. This variety can result from the small sample size, different methods used to detect HPV DNA and type of samples as HPV more detected among cytological samples than histological samples. Further studies with larger sample size and sensitive detection assays are needed to reliably estimate the prevalence of HPV in Iranian patients with high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1). In this analysis, HPV prevalence was 62% in women with atypical squamous cells of undetermined significance lesion. Data obtained from previous studies indicate the great variability of HPV prevalence, mostly depending on age [Clifford et al., 2006]. In the US, although HPV was detected from 61% of atypical squamous cells of undetermined significance cases, the positivity rate of HPV reduced from 78% in the 18–24-year-old group to 32% in women over 35 years of age [Castle et al., 2005]. Among normal group, HPV was detected in 9% (ranging from 5.5% in the South to 13.6% in the North). This discrepancy may be due to diverse distribution of HPV in different geographical regions, methods with different sensitivity and including the abnormal cytological cases within normal group. In a worldwide meta-analysis carried out on women with normal cervical cytology, overall HPV prevalence was estimated to be 10.4% although it was different according to the geographical regions. Indeed, the prevalence of HPV was estimated 22.1% in Africa, 20.4% in central America and Mexico, 11.3% in J. Med. Virol. DOI 10.1002/jmv
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northern America, 8.1% in Europe, and 8% in Asia [Castellsague´ et al., 2007; de Sanjose et al., 2007]. Regarding the age-specific HPV prevalence in the world, the highest HPV prevalence was reported in women younger than 35 years of age [de Sanjose et al., 2003; de Sanjose et al., 2007; Forman et al., 2012; Monsonego et al., 2012]. The six most frequent HPV types were HPV 16, 18, 6/11, 31, and 33 in invasive cervical cancer highgrade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), and atypical squamous cells of undetermined significance cases. However, they were slightly different in women with normal group as HPV 16, 18, 6/ 11, 31, and 45 were the six most frequent types. The most frequent HPV type was HPV 16 followed by HPV 18 in all five different groups. These data are compatible with the worldwide reports showing around 70% of invasive cervical cancer are caused by HPV 16 or 18 [Castellsague´ et al., 2007; Giorgi et al., 2012]. The type distribution pattern of HPVs in Iran is more similar to those of Africa, America and Europe than to most Asian countries [Castellsague´ et al., 2007; Tornesello et al., 2011; Demir et al., 2012]. HPV 16 was more frequent than HPV 18 in squamous cell carcinoma cases. However, in adenocarcinoma, HPV 18 was as important as HPV 16 which was consistent with the previous findings [Clifford et al., 2003; Clifford et al., 2006; Li et al., 2011]. In this study, the prevalence ratio of HPV 16 in invasive cervical cancer/high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) and invasive cervical cancer/low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1) were higher than one, representing that HPV 16 is probably more progressive than the other HPV types to cause cervical cancer from lowgrade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion; almost consistent to previous studies [Bao et al., 2008; Chen et al., 2009; Ciapponi et al., 2011]. Looking at multiple HPV infections, 23.9% of invasive cervical cancer and 45.6% of high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3) patients were found to be infected with more than one type. Infection with multiple HPV types appears to act synergistically in progression to cervical cancer [Trottier et al., 2006]. The potential impact of prophylactic vaccines for the future protection against cervical cancer can be expected from the fraction of HPV types in women with cervical cancer. Regarding to the present study, it is estimated that two current vaccines (Cervarix and Gardasil) will provide around 64.5% and 73.9% prevention of cervical cancer in Iran, respectively. These findings present an exhaustive report of overall and type-specific HPV prevalence in Iran, J. Med. Virol. DOI 10.1002/jmv
Jalilvand et al.
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J. Med. Virol. DOI 10.1002/jmv
