Human papillomavirus types in 115,789 HPV‐positive women: A meta‐analysis from cervical infection to cancer

Abstract

Genotyping may improve risk stratification of high-risk (HR) human papillomavirus (HPV)-positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta-analysis of cross-sectional HR HPV-type distribution in 115,789 HPV-positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low-grade squamous intraepithelial lesions (LSIL) and 6,616 high-grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR-based studies worldwide. No strong differences in HPV-type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20-28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios 5 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios 5 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV-positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV-based screening programs.

Human papilloma virus genotyping for the cross‐sectional and longitudinal probability of developing cervical intraepithelial neoplasia grade 2 or more

“…HPV33 ranked first based on PPV thus showing strong association with present and future CIN2+ and CIN3+ risk. This result is consistent with other recent reports which found a strong association between HPV33 and high‐grade CIN despite a much weaker association with invasive cancer 8, 24, 25, 26, 27. Conversely, the importance of HPV35 based on PPV was more unexpected even though a previous analysis within the future study28 reported a high probability of transition from HPV35 incident infection to CIN2 and CIN3 lesions after 3 years of follow‐up.…”

“…Genotyping was blind to cytology and histology and its completeness within the areas/phases in which it was done was high and plausibly unselected. On the other hand, despite the large size, the precision of estimates for some less frequent HPV types is low and random variation could explain the differences between our observations and those obtained in other studies 8, 44. Previous screening intensity can account for differences in PPV compared to other studies24 and local variations in type distribution can result in differences in sensitivity and specificity.…”

“…Conversely, the importance of HPV35 based on PPV was more unexpected even though a previous analysis within the future study28 reported a high probability of transition from HPV35 incident infection to CIN2 and CIN3 lesions after 3 years of follow‐up. In other studies, the association between HPV35 and high‐grade CIN varied remarkably between different geographical areas 8, 29. In a recent analysis on viral load and CIN risk,30 HPV35 was one of the four non HPV16/18 types (with HPV31, 52 and 58) whose viral load at baseline was significantly associated with a subsequent increase in CIN2/3 risk.…”

“…In particular, HPV16 has been shown to be strongly associated with both high‐grade CIN and invasive cervical cancer 8, 9, 10. HPV31, 33, 35, 52 and 58 are particularly associated to high‐grade lesions 8.…”

Impacts of human papillomavirus vaccination for different populations: A modeling study

“…The focus is on HPV16, the most frequent and most carcinogenic type,12, 13 which is also the most difficult to control by vaccination8 due to its special propensity to persist. In a previous study,14 using idealized sexual contact structures, we have shown how HPV control through vaccination becomes more challenging in a population transitioning from a traditional to a gender‐equal sexual behavior.…”