Cervical intraepithelial neoplasia grade 1 (CIN1) is a precancerous lesion closely related to cervical cancer and characterized by a shorter and less observable clinical course. There is no consensus for intervention and treatment of CIN1, and there are currently no clear markers to predict disease progression and regression [
A systematic search was conducted using the Cochrane Library, Excerpta Medica database (EMBASE), PubMed, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and the Wan fang Data. The literature search was performed on April 20, 2016. The PICOS items were identified (see Appendix
We systematically reviewed published studies according to the following inclusion criteria: studies examining the impact of HPV infection on the natural history of CIN1 disease; studies including at least HPV-negative and HPV-positive; results at the start and end of follow-up including cervical histology or cytology, a diagnosis consistent with the CIN classification system or atypical hyperplasia (dysplasia) and the carcinoma in situ (CIS) classification system; patients diagnosed with CIN1 who did not undergo interventions including cryosurgery, electrocoagulation therapy, laser therapy, microwave therapy, cold knife conization, loop electrosurgical excision procedure, and trachelectomy; follow-up observation for at least 6 months; complete information so that each document contained sufficient information to calculate statistical indicators of relative risk (RR) or 95% confidence intervals (CIs). The exclusion criteria were as follows: studies that did not meet the inclusion criteria, literature reviews, the absence of a control group, and duplicate publications. We also excluded papers with incomplete initial data.
The Newcastle-Ottawa scale (NOS), recognized as a good study quality assessment tool, was used to assess the quality of the studies identified in our literature search (see Appendix
Two authors (Mingzhu Liu and Xiaolong Yan) independently extracted data and crosschecked their data after aggregating the results. Disagreements were resolved by discussion with Professor Mingxia Jing. Data were collected at the start of the study, including basic information, background and characteristics of the research object, and disease diagnosis and evolution. This information is presented in Table
Basic characteristics and quality assessment of included studies.
Study | Design | Age |
Region |
HPV type | HPV infection time | Indexes | Follow-up time (months) | Quality rating |
---|---|---|---|---|---|---|---|---|
Sagasta et al. (2016) [ |
Prospective |
|
Spain (Europe) | HR-HPV | NR | ①②③ | 28 | 8 |
Veijalainen et al. (2015) [ |
Retrospective | 40.4 | Finland (Europe) | HR-HPV | NR | ① | 96 | 8 |
He et al. (2015) [ |
Retrospective |
|
China (Asia) | HR-HPV | NR | ①②③ | 15 (8–24) | 9 |
Zhou et al. (2015) [ |
Prospective |
|
China (Asia) | HR-HPV | NR | ③ | 24 | 7 |
Mou et al. (2014) [ |
Retrospective |
|
China (Asia) | NR | NR | ①②③ | 36 | 7 |
Siriaunkgul et al. (2014) [ |
Prospective | 46.6 | Thailand (Asia) | NR | NR | ①②③ | 24 | 8 |
Hu et al. (2014) [ |
Prospective | 30–59 | China (Asia) | HR-HPV | Transient | ①②③ | 24 | 9 |
Persistent | ①②③ | |||||||
Jiang (2013) [ |
Retrospective |
|
China (Asia) | HR-HPV | NR | ①②③ | 24 | 8 |
Waldstrøm et al. (2013) [ |
Prospective | 32.3 | Denmark (Europe) | NR | NR | ①②③ | 60 | 8 |
Katki et al. (2013) [ |
Prospective | 30–64 | United States (America) | NR | NR | ①②③ | 60 | 8 |
Byun et al. (2013) [ |
Prospective | 46 | Korea (Asia) | HR-HPV | NR | ① | 8 | 8 |
Liao et al. (2013) [ |
Prospective | 30–49 | China (Asia) | HR-HPV | NR | ① | 36 | 8 |
Li et al. (2013) [ |
Prospective | 38 | China (Asia) | HR-HPV | NR | ③ | 6 | 8 |
Wang et al. (2012) [ |
Retrospective | 35.4 (20–53) | China (Asia) | HR-HPV | Persistent | ① | 18.6 (8–24) | 9 |
Huang et al. (2012) [ |
Retrospective | 30 (22–70) | China (Asia) | HR-HPV | NR | ① | 24 | 7 |
Bowring et al. (2012) [ |
Prospective |
|
Britain (Europe) | HR-HPV | NR | ①②③ | 12 | 8 |
Jakobsson et al. (2012) [ |
Retrospective | 34 | Finland (Europe) | HR-HPV | NR | ① | 6 | 8 |
Ozaki et al. (2011) [ |
Prospective | 39 | Japan (Asia) | NR | NR | ① | 17 | 7 |
Li and Yang (2011) [ |
Prospective |
|
China (Asia) | HR-HPV | NR | ①②③ | 6 | 8 |
LR-HPV | ②③ | |||||||
Gonzalez-Bosquet et al. (2010) [ |
Prospective | 32.25 | Germany (Europe) | HR-HPV | NR | ① | 25 | 7 |
Waldstrøm and Ømskov (2010) [ |
Retrospective | 32 | Denmark (Europe) | NR | NR | ①②③ | 36 | 8 |
Heider et al. (2010) [ |
Retrospective | 33 | United States (America) | HR-HPV | NR | ①②③ | 34 | 9 |
Cotton et al. (2010) [ |
Prospective | 20–59 | Britain (Europe) | HR-HPV | NR | ① | 36 | 8 |
Thrall et al. (2009) [ |
Prospective | ≥30 | United States (America) | HR-HPV | NR | ①②③ | 24 | 9 |
Liao (2008) [ |
Prospective | 30–49 | China (Asia) | HR-HPV | NR | ③ | 24 | 7 |
Gong (2007) [ |
Prospective |
|
China (Asia) | HR-HPV | Transient | ①②③ | 24 | 7 |
Persistent | ①②③ | |||||||
Luis Ferreira Santos et al. (2006) [ |
Prospective | 31 (16–63) | United States (America) | NR | NR | ①②③ | 12 | 8 |
Tarkkanen et al. (2006) [ |
Prospective | 35 (20–60) | Finland (Europe) | NR | NR | ① | 6 | 7 |
Song et al. (2006) [ |
Retrospective | 38 | Korea (Asia) | NR | NR | ①②③ | 24 | 8 |
Clavel et al. (2005) [ |
Retrospective | 30 | France (Europe) | HR-HPV | NR | ①②③ | 24 | 8 |
Massad et al. (2004) [ |
Prospective | 37.4 | United States (America) | HR-HPV | NR | ①②③ | 90 | 8 |
LR-HPV | NR | ①②③ | ||||||
Sastre-Garau et al. (2004) [ |
Retrospective | 31 | France (Europe) | HR-HPV | NR | ①③ | 24 | 8 |
Alameda et al. (2004) [ |
Retrospective | 25–45 | Spain (Europe) | HPV | NR | ②③ | 24 | 7 |
Schlecht et al. (2003) [ |
Retrospective | 16–65 | Brazil (America) | HR-HPV | NR | ① | 53.3 | 8 |
LR-HPV | NR | ① | ||||||
Denise Zielinski et al. (2001) [ |
Retrospective | 40.5 (20–76) | Holland (Europe) | HR-HPV | NR | ①②③ | 16.8 (0–54) | 8 |
Matsuura et al. (1997) [ |
Prospective | NR | United States (America) | NR | NR | ①②③ |
|
8 |
Kaufman et al. (1997) [ |
Retrospective | NR | United States (America) | HR-HPV | NR | ①③ | 6 | 7 |
Campion et al. (1986) [ |
Prospective | <30 | Britain (Europe) | NR | NR | ①②③ | 22.4 (19–30) | 7 |
Thirty-eight articles were analyzed using RevMan 5.0 (Cochrane systems IMS) and Stata 12.0 (Stata Corp, College Station, Texas, TX, USA). To assess the heterogeneity among studies, we calculated the
Figure
Flowchart of identifying and including studies.
The basic features of the 38 studies included in this meta-analysis are listed in Table
A total of 38 studies were included in this study, and of these, 34 estimated the impact of HPV infection on the progression of CIN1 lesions; pooled analysis showed that the risk of CIN1 disease progression was 3.04-fold higher in the HPV-positive group than in the HPV-negative group (95% CI: 2.41–3.83;
Forest plot of HPV-positive patients and CIN1 disease outcomes. HPV positivity in the exposed group and HPV negativity in the control group. (a) Forest plot of HPV positivity and CIN1 disease progression; (b) Forest plot of HPV positivity and CIN1 disease persistence; (c) Forest plot of HPV positivity and CIN1 disease regression.
In subgroup analyses, the risk of the persistence of CIN1 was higher in American than European or Asian populations (
Long or short HR-HPV infection times had different effects on CIN1 lesion history. Persistent HR-HPV infection means that, in two or more times, the HR-HPV detected was positive and transient HR-HPV infection means that, in only one time, the HR-HPV detected was positive [
The influence of HR-HPV infection time on CIN1 lesions.
Disease outcome | Infection time | Number of studies | Heterogeneity test results | Merged effect RR value (95% CI) |
| ||
---|---|---|---|---|---|---|---|
|
|
|
|||||
Progression | Persistent | 3 | 2.49 | 0.290 | 20 | 13.91 (3.46, 55.90) | 0.000 |
Transient | 2 | 0.05 | 0.820 | 0 | 1.06 (0.12, 9.01) | 0.960 | |
Persistent | Persistent | 2 | 0.22 | 0.640 | 0 | 2.15 (0.75, 6.18) | 0.160 |
Transient | 2 | 0.02 | 0.890 | 0 | 0.57 (0.17, 1.92) | 0.360 | |
Regression | Persistent | 2 | 1.86 | 0.170 | 46 | 0.61 (0.47, 0.80) | 0.000 |
Transient | 2 | 0.22 | 0.640 | 0 | 1.03 (0.86, 1.24) | 0.750 |
RR, relative risk; CI, confidence interval.
We conducted a sensitivity analysis for the progression, persistence, and regression of CIN1 disease, respectively (see Appendix
A total of 38 studies were included in the current study. Of these, 23 studies examined HR-HPV infections and three of these also considered LR-HPV infection. Three studies assessed HPV infection times. Studies have shown that HPV infections are associated with an extended disease course in CIN1, increasing the risk of disease progression and hampering the reversal of CIN1. Persistent HR-HPV infection was a major factor associated with CIN1 progression. This finding provides important data for the clinical management of CIN1 disease, in order to avoid excessive or inadequate treatment. Regional population distribution and follow-up time were also associated with CIN1 disease outcome.
In the HPV-positive group, the risks of CIN1 progression, persistence, and regression, respectively, were 3.02, 1.45, and 0.65, compared to the HPV-negative group. A randomized controlled study from the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion (ASCUS-LSIL) (ALTS) group [
Our research on the impact of HPV type and infection duration on CIN1 disease history found that persistent HR-HPV infection was a major risk factor for CIN1 progression to CIN2+, while LR-HPV and transient infections were not significantly associated with increased risk of CIN1 progression. The results are corroborated in a large prospective study by Dalstein et al. [
Regional population distribution and follow-up time were the two main factors influencing CIN1 disease history. The risk of disease progression in HPV-positive CIN1 patients in the Americas was lower than that of patients in Asian and European countries (
This study has the following advantages. First, the well-designed studies provided strong evidence for the analysis of the influence of HPV infection on CIN1 disease history. Furthermore, the full search was relatively comprehensive and included a large number of studies, significantly increasing the sample size compared with using the single original research study criteria; therefore, the combined effect size was more accurate. Second, subgroup analyses were performed according to HPV type, study design, regional population distribution, sample size, and follow-up time, in order to explore potential confounders. Some limitations should be considered when interpreting the results of this study. First, CIN1 is affected by many factors and we were unable to control for parameters such as age at first sexual intercourse, number of pregnancies and delivery times, and individual immune status. Second, most studies included a larger age range; therefore, we did not conduct subgroup analysis by patient age. Third, more papers from China were included in the present study, which would limit the significance. This conclusion needs to be further testified in the people from other countries. Finally, there are few studies on low-risk HPV infection potentially affecting the results of subgroup analysis of HPV type. Therefore, we will research low-risk HPV infection in future studies to improve the accuracy of these results.
HPV infection resulted in an increased risk of CIN1 progression and reducing disease reversibility. Persistent high-risk HPV infection resulted in a further increased risk of CIN1 progression. Furthermore, regional population distribution and follow-up times influenced CIN1 disease history.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors have declared that no conflicts of interest exist.
Mingzhu Liu performed the data analysis and drafted the manuscript. Mingxia Jing and Shugang Li conceived and designed the study and led the writing of the paper. Mingzhu Liu and Xiaolong Yan jointly developed the search strategy for this study and assessed the titles and abstracts for their relevance to this study. Mingzhu Liu, Xiaolong Yan, Mei Zhang, and Xiaoju Li assessed full articles for inclusion. Mingxia Jing resolved disagreements between authors. All authors read and approved the final manuscript. Mingzhu Liu and Xiaolong Yan contributed equally to this work and should be considered co-first authors.
The authors acknowledge funding from the Science and Technology Plan Project of Xinjiang Production and Construction Corps (no. 2013BB015).