Review Article

International Journal of STD & AIDS

0(0) 1–11
Patterns of incident genital human ! The Author(s) 2019
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DOI: 10.1177/0956462418824441
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Bradford S Wheeler1, Anne F Rositch2, Charles Poole1,

Sylvia M Taylor3 and Jennifer S Smith1,4

Abstract
Human papillomavirus (HPV) infection acquisition is a necessary step in the development of cervical cancer. No study
has systematically quantified the rate of newly acquired HPV infections from the published literature and determined its
relationship with age. We performed a systematic review and meta-analysis to describe incident HPV infections in
women. MedlineVR and Thomson Reuters Web of Science via PubMedVR databases were searched. A total of 46 of 5136
studies met inclusion criteria and contributed results. We conducted a meta-regression analysis of 13 studies, which
reported incidence rate estimates on over 13 high-risk HPV types, to provide pooled stratum-specific incidence rates
and rate ratios for key population and study characteristics among 8488 women. Studies with mean age < 30 years
had relatively higher HPV incidence rates compared to studies with mean age
30 years: relative risk ¼ 3.12; 95% CI:
1.41–6.93. HPV-16 was most frequently detected, followed by HPV-18: relative risk ¼ 0.47; 95% CI: 0.33–0.67, and by
HPV-58: relative risk ¼ 0.45; 95% CI: 0.27–0.74. Younger age is a key predictor of genital HPV incidence in women.
These data on the relative distribution of incident HPV infections will provide a baseline comparison for monitoring of
changes in HPV incidence following the implementation of population-level HPV vaccination.

Keywords
Human papillomavirus, viral disease, women, other, vaccination, other
Date received: 23 June 2018; accepted: 29 November 2018

Introduction
Infection with human papillomavirus (HPV) is a nec-
essary cause of cervical cancer,1,2 the fourth most diag-
nosed cancer in women worldwide.3 Acquisition of
HPV infection is a prerequisite step for development
of cervical intraepithelial neoplasia (CIN) and cervical
cancer. Two prophylactic vaccines including oncogenic
HPV types 16 and 18 were the first to be approved and
were shown to successfully reduce persistence of newly
acquired incident HPV-16 and -18 infections and asso-
ciated cervical lesions.4–7 Recently, a nonavalent vac-
cine has been approved in the United States for the
prevention of HPV types 16, 18, 31, 33, 45, 52, 58, 6,
and 11.8
HPV incidence rates have been observed to be
higher in women under age 30 years,9,10 with rates of
acquisition highest in years closely following sexual
debut.10,11 However, other population-based studies
have shown that relatively older women also remain
at risk for incident HPV infection.9,12–15 While these
studies define incident HPV as newly detected
infections across the study period, HPV incidence
may represent both newly acquired HPV infections
as well as recently reactivated latent HPV among
women previously exposed.9,15–17 Definitions of
HPV incidence across studies vary by HPV laboratory
detection methods, testing intervals, HPV status
1
Department of Epidemiology, Gillings School of Global Public Health,
University of North Carolina, Chapel Hill, NC, USA
2
Department of Epidemiology, Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA
3
GlaxoSmithKline Biologicals Vaccines, Wavre, Belgium
4
SALineberger Comprehensive Cancer Center, University of North
Carolina, Chapel Hill, NC, USA
Corresponding author:
Jennifer S Smith, Gillings School of Global Public Health, University of
North Carolina at Chapel Hill, 2101 McGavran-Greenberg Hall, CB
#7435, Chapel Hill, NC 27599-7435, USA.
Email: JenniferS@unc.edu
2 International Journal of STD & AIDS 0(0)
(e.g., type-specificity), HPV categories included (e.g.,
overall, carcinogenic, individual types), and baseline
HPV status.
Systematic reviews of the point-prevalence of HPV
infection show that cervical HPV infection in women
varies across age and geographic region.18,19 A similar
systematic review of global patterns of the incidence of
HPV infection would be helpful to obtain a clearer
understanding of how studies have estimated HPV inci-
dence. Thus, we performed a systematic review and
meta-analysis to describe the magnitude of and varia-
tions in HPV incidence among women worldwide, and
influence of population and study design characteristics
on observed incidence estimates.
Methods
We identified original peer-reviewed journal articles
published without language restriction by searching
Thomson Reuters Web of Science and MedlineVR via
PubMedVR databases through 1 July 2010. We also
searched article reference lists from all eligible articles
and relevant review articles. Broad search term catego-
ries included HPV; human papillomavirus, papilloma
virus and incidence; incidence, acquisition, cohort
study, newly detected, over time, and natural history
(see Supplementary Appendix 1).
Eligible articles were required to present one or
more estimates of incident HPV infection, regardless
of baseline HPV infection status. Studies testing for
cervical HPV infections at more than one-time point
using polymerase chain reaction (PCR) or Hybrid
Capture (HC; QIAGEN Gaithersburg, Inc.) DNA-
based detection methods were included. Serology-
based results, male-based results, and studies reporting
low-risk HPV (LR-HPV)-only were excluded. Studies
reporting baseline cervical abnormalities in excess of
15% were excluded to reflect the characteristics of pop-
ulations of average risk; however, a study was included
if it did not state a baseline prevalence of cervical
abnormalities. Articles reporting human immunodefi-
ciency virus (HIV) prevalence in the study population
over 5% were excluded, unless stratified by HIV status.
If an article did not state the prevalence of HIV in the
study population, it was assumed to be less than 5%
and was included.
Abstracted incidence data included (i) incidence rate
(IR) of HPV infection and the standard error (SE) or
confidence interval (CI), (ii) cumulative incidence and
SE or CI along with the time interval over which inci-
dence was measured, and (iii) HPV incidence estimates
extracted from Kaplan–Meier curves. For studies in
which estimated SE for cumulative
qffiffiffiffiffiffiffiffiffiffiincidence
ffi was not
pð1pÞ
reported, it was calculated as n where p was the
observed proportion incident and n was the sample
size. All IR abstracted were re-calculated using a stan-
dard denominator of 100 woman-months to ensure
data comparability across studies. For studies in
which estimated SE pffiffiffi for the IR was not reported, it
was calculated as n where n is the number of incident
cases. We also abstracted data on population charac-
teristics, demographics, and study method variables;
including study design, sample size, population, and
HPV detection method. Variables used to define
incidence included HPV testing interval, number of
HPV-negative visits preceding an incident infection,
HPV type, and whether the unit of analysis was
based on women or HR-HPV infection. All data were
independently double-abstracted using a standardized
database (EL, AFR, and BSW).
Number and proportion of HPV incidence estimates
were calculated for each category of a given study char-
acteristic. If an article reported multiple results that fell
into different categories of study characteristics, the
article was included in all relevant categories; conse-
quently, the proportion of study results could add to
over 100%. Plots of cumulative incidence and IR were
generated for overall (e.g., any tested type), HR, and
LR-HPV groups and HPV-types with at least eight
results using GraphPad Prism, (GraphPad Software,
San Diego, CA).
Some articles that met inclusion criteria were based on
the same study populations. To maintain independence
of results, we chose the article with the larger number of
women in the HPV incidence analysis, or the most recent
date of published study results if study sample sizes did
not vary. Most articles presented multiple IR estimates
of HPV incidence. Therefore, a set of decision rules was
applied to select one IR result for inclusion into the
meta-regression analysis. Rules to choose a result for
each analysis were to select the overall-HPV grouped
IR estimate first. If no overall-HPV IR was reported,
then the HR-grouped IR estimate was selected.
To formally compare HPV IRs across studies by key
study characteristics, meta-regression was used to pro-
duce absolute and relative pooled stratum-specific esti-
mates of HPV incidence per 100 women-years.20 Only
studies which employed HPV testing methods that
measured at least 13 HPV types were included in
meta-regression to ensure data comparability across
studies. Random-effects meta-regression was used,
with among-study variance estimated by restricted
maximum likelihood.20 Models were adjusted for cate-
gories of age (<30/
30 years), as other characteristics
were not statistically significant. Relative measures of
effect presented in these models may be interpreted as
the ratio of average rates of incident HPV infection
between two strata, and are reported as rate ratios
(RRs). Pooled stratum-specific estimates allowed
Wheeler et al. 3

descriptive comparisons across individual categories of
study characteristics by providing separate estimates and
95% CI for each category. Heterogeneity was assessed
by the I2 statistic21 which is based upon Cochran’s Q.
Meta-regression analysis was conducted in STATA ver-
sion 11 (StataCorp, College Station, TX).
For type-specific HPV analyses, the meta-regression
model included all grouped and type-specific IR results,
adjusted for categories of age (<30/
30 years) using a
random effects model. When a study provided more
than one result for HPV incidence, an indicator term
was included for each result to control for potential
non-independence of results within a given study.
Results
Of 5136 abstracts identified, 46 studies met inclusion
criteria. Over half of studies were among women with
an average age of 30 years or younger (59%) (Table 1).
Study populations consisted of women who attended
gynecologic clinics or hospitals (41%), population-
based screening programs (24%), college-aged women
at university clinics (20%) and women who served as
controls in HPV vaccination trials (15%). Nearly half
of studies were conducted in North America (46%),
with remaining studies conducted in Europe (20%),
Central and South America (20%), and other countries
(15%). Most studies (87%) reported one or more meas-
ures of HPV cumulative incidence, whereas slightly
more than half reported IRs (59%).
Most studies defined an incident HPV infection as a
single negative HPV test result followed by a single
positive HPV result, at any point during study
follow-up (85%), while others defined incident infec-
tion as two consecutive negative HPV test results fol-
lowed by a positive result (Table 1). Most studies
reported overall HPV incidence (70%) and type-
specific results for HPV types 16 (54%) and 18
(52%). Incidence of any HR-HPV type detected was
reported in 43% of eligible studies. SPF10, PGMY09/

Table 1. Characteristics of HPV incidence studies and study results.

All results Included in meta-regressiona

No. of % of No. of % of
Characteristic results results results results Referenceb

Mean age of womenc

30 years 19 41 1 8 9,12,13,17,22–36

<30 years 27 59 12 92 37–63

Study region
23–25,28,32,39–45,47,48,51–53,55,56,60,63
North America 21 46 2 15
12,13,17,22,26,27,29–31,33,34,36,49,54,58,59,61,62
Europe, Central, and South America 18 39 9 69
9,37,38,46,35,50,57
Africa, Asia, Australia, Multi-Region 7 15 2 15
HPV DNA detection method
17,22,26,32,37,39,61
Hybrid Capture II 7 15 1 8
13,23,30,33,34,36,40,41,42,53,55,56,63
MY09/MY11 primers 13 28 5 38
12,24,27,29,31,38,48–52,54,57,59,62
SPF10, PGMY09/11, GP5þ/6þ primers 15 33 6 46
Unspecified HPV L1 primersd 10 22 1 8 9,25,28,43–47,58,60
56
SPF1/GP6þ primers 1 2 0 0
HPV testing interval
< 6 months 13 28 4 31 13,24,22,30,36,39,42,51–53,55,57,58

6 to <12 months 26 57 7 54 9,12,23,25–29,31,33,34,37,38,40,41,43–49,54,56,60,63

12 months 7 15 2 15 17,32,35,50,59,61,62

Mean length of follow-upe

24 months 18 41 5 38 13,24–26,30,32,36,38,39,41,43,46,47,50,57,60–62

>24 months 28 59 8 62 9,12,17,22,23,37,40,42,27,44,45,48,28,29,31,

33–35,49,51–56,58,59,63

Genital sample collection

37,50
Female self-collected 2 4 1 8
9,12,13,17,22–36,38–49,51–63
Healthcare worker-collected 44 96 12 92
Incidence visit requirement
9,12,13,17,22–27,29–42,49–63
Negative, positive 39 85 12 92
28,43–48
Negative, negative, positive 7 15 1 8
Unit of analysis for incidence results
9,12,13,17,22,24–28,30–33,35,36,38,40–51,54–62
Women 38 83 11 85
(continued)
4 International Journal of STD & AIDS 0(0)

Table 1. Continued
All results Included in meta-regressiona

No. of % of No. of % of
Characteristic results results results results Referenceb
9,29,34,37,52,63
Infections 6 13 2 15
23,39
Both 2 4 0 0
Measure of HPV incidence
9,12,13,22–27,29,30,33,35,37–43,45–47,51–53,57
Incidence rates 27 59 13 100
9,12,13,17,22,25–27,29–36,39–45,47–63
Cumulative incidence 40 87 9 69
Baseline HPV DNA definition criteria
12,22,26,29,32,33,35,36,43,47,48,51–55,57,61
Completely HPV-negative 18 39 4 31
9,13,17,23–25,27,28,30,31,34,37–39,41,42,
Mixed baseline, incident type negative 26 57 9 69
44–46,49,50,56,58–60,63
40,62
Baseline positive, incident type negative 2 4 0 0
Baseline HPV seropositivity
43,47,57
0% Positive 3 7 0 0
9,58
1–49% Positive 2 4 0 0
12,13,17,22–42,44–46,48–56,59–63
Not stated 41 89 13 100
Baseline cervical abnormalities
12,22,24,26,28,29,35,39,41,43–45,48,54,57,62,63
0% Abnormal 17 37 4 31
13,27,30,31,34,36,38,40,42,47,51,53,55,56,59,60
1–15% Abnormal 16 35 6 46
9,17,23,25,37,32,33,46,49,50,52,58,61
Not stated 13 28 3 23
Study populations
9,43–47,57
Controls for HPV vaccine trials 7 15 0 0
12,13,17,26,27,30,33–35,37,61
Population-based/screening 11 24 7 54
40,41,42,50–53,55,56
University students 9 20 1 8
22–25,28,29,31,32,36,38,39,48,49,54,58–60,62,63
Hospital/clinic/high-risk patients 19 41 5 38
Reported HPV type
12,13,22,24,25,27,29–33,35,38–42,45,47–60
Overall HPV 32 70 10 77
12,13,17,23,24,27,29,30,34,35,37–39,41,48,50,51,56,61,62
HR-HPV 20 43 8 62
12,13,24,29,34,35,38,39,41,48,50,56
LR-HPV 12 26 4 31
12,13,23,24,27,30,34,35,38,39,41–46,50,52–57,61,63
HPV-16 25 54 9 69
12,13,23,24,27,29,30,35,38,39,41–46,50,52–54,56,57,61,63
HPV-18 24 52 9 69
12,13,23,27,29,39,41,42,46,50,52,53,56,63
HPV-31 14 54 5 38
12,23,27,29,39,46,50,52,56,63
HPV-33 10 22 4 31
23,27,39,46,50,52,56,63
HPV-35 8 17 3 23
12,27,29,42,46,50,52,53,56,63
HPV-45 10 22 4 31
12,13,23,27,29,39,46,50,52,56,63
HPV-52 11 24 4 31
12,13,23,27,29,39,46,52,56,63
HPV-58 10 22 3 23
12,23,27,39,41,42,44,45,50,52,53,56
HPV-6 12 26 5 38
12,23,27,39,42,44,45,50,52,53
HPV-11 10 22 4 31

HPV: human papillomavirus; LR: low-risk; HR: high-risk.

a
Studies included in meta-regression.12,22–27,37–42
b
Studies included are limited to those that have HPV incidence results among populations or sub-populations where 15% of women have abnormal
cervical status at baseline and where 5% of women are HIV-positive.
c
The median age of the study population was used when the mean age was not reported.12,22,23,25,37,38 Age was defined as the midpoint of the median
age in years for reference.61
d
The L1 primer type was not specified in article.
e
The median length of follow-up was used when the mean length was not reported.
Wheeler et al.
11, and GP5/GP6þ primers were used in 15 studies
(33%), while MY09/11 primers were used in 13
(28%), and unspecified L1-based primers in 10 studies
(22%). HC was used for HR-HPV detection or initial
triage of specimens in seven studies (15%). More than
half of studies (61%) enrolled populations with some
level of HPV DNA positivity, and thus women were at
risk for other type-specific incident HPV infections.
Remaining studies included women who were
completely negative for all HPV tested types at baseline
(39%).
Study populations with mean age less than 30 years
had higher HPV incidence (range: 1.9–2.9 infections/
100 woman-months across studies) than populations
with an average age of 30 years and older (range:
0.1–1.4 infections/100 woman-months) (Figure 1).
The same pattern was evident for HR-HPV incidence
in younger (range: 1.4–1.7 infections/100 woman-
months) compared to older populations (range: 0.3–
0.9 infections/100 woman-months). Reported incidence
for most commonly reported type, HPV-16, was also
higher in younger populations (range: 0.4–0.9 infec-
tions/100 woman-months) than in older populations
(range: 0.0–0.2 infections/100 woman-months). The
range of point estimates for HPV-18 appeared to over-
lap for results from younger (range 0.1–0.5 infections/
100 woman-months) and older populations (0.0–0.1
infections/100 woman-months). Among four studies
presenting age-stratified incidence,9,13,22,37 rates gener-
ally decreased with increasing category of older age
(Figure 2). Furthermore, plots of cumulative incidence
estimates against study follow-up time (Supplementary
Appendix 2), showed a similar age-related pattern of
incidence, with younger populations having higher
HPV incidence than older participants.
Of 27 studies reporting HPV IRs, 13
studies12,22–27,37–42 met selection criteria for inclusion
into meta-regression models that included 8488
women (Table 2). Younger age was associated with
higher HPV incidence (p < 0.05): studies with a mean
age <30 years had a stratum-specific pooled IR of 1.56
infections/100 woman-months (95% CI: 0.98–2.48)
compared to 0.51 (95% CI: 0.37–0.69) infections/100
woman-months in studies with mean age
30 years:
RR: 3.12 (95% CI: 1.41–6.93). After controlling for
age (Table 2), RRs for most study characteristics atten-
uated after age-adjustment; lower HPV IRs were noted
for studies with >24 months follow-up, indicating
potential confounding by age. High I2 residual
(>90%) in all meta-regression models is indicative of
substantial heterogeneity arising from differences
between study populations that could not be explained
by model terms.21 Age appeared to be the only factor
explaining significant heterogeneity (p value for
Cochran’s Q < 0.001) in estimates of HPV incidence.
5
Analyses of HPV incidence, stratified by HPV type
group (Table 3) and genotype (Table 4), included a
total of 80 HPV group-based and type-specific results
from the 13 studies. The stratum-specific pooled rate of
overall HPV infection was 0.63 (95% CI: 0.43–0.92)
infections/100 woman-months, and stratum-specific
pooled rate of HR-HPV was 0.53 (95% CI: 0.33–
0.83) infections/100 woman-months. Incident infection
with any LR-HPV type compared with any HR-HPV
type was less frequent: RR: 0.59 (95% CI: 0.34–1.00).
Highest type-specific HPV IR occurred for type HPV-
16 at 0.14 (0.08–0.25) infections/100 woman-months,
which is at least twice the rate as infection with
the next most common infections: HPV-18 at 0.07
(0.04–0.12), HPV-31 at 0.06 (0.04–0.12) and HPV-52
at 0.06 (0.03–0.12). Age-adjustment resulted in negligi-
ble changes to type-specific HPV IR ratios when com-
paring individual types with HR-grouped types.
Discussion
To our knowledge this review, of 43,598 women, is the
first systematic review of the incidence of cervical HPV
infection worldwide. Age was the main predictor of
HPV incidence, with younger populations (<30 years)
having over three times HPV incidence rates than rel-
atively older populations. Nevertheless, newly detected
HPV infections in women 30 years and older were non-
negligible with a stratum-specific pooled HPV IR of
0.56 infections/100 woman-months. The rate of HR-
HPV infection was 1.7 times that of LR-HPV, while
HPV-16 had at least twice that of any other individual
high-risk HPV type (e.g., HPV-18, HPV-31).
This systematic review of incident HPV infections
builds upon previous reviews describing worldwide
HPV point prevalence, stratified by age.18,19 HPV
point prevalence has peak at varying ages for different
geographic regions, with Central and South America
and Africa showing higher HPV point prevalence
among women aged 45 and older than relatively youn-
ger women.18,19 One large incidence-based study in
Colombia noted similar age-related patterns of inci-
dence, with peak overall and HR-HPV incidence
between ages of 15 and 20 and a minor increase in
HPV incidence around age 50, before declining again
at relatively older ages.12 Findings in our meta-analysis
show a consistently higher risk of HPV acquisition
among relatively younger-aged women. However, lim-
ited data were available on age-stratified HPV inci-
dence with sufficiently large sample sizes, limiting our
ability to thoroughly explore relationships between
HPV incidence and age groupings. Our age-based
dichotomization of studies at mean/median population
age of 30 years was a relatively crude method for clas-
sifying a study population’s age distribution in the
6 International Journal of STD & AIDS 0(0)
Figure 1. HPV incidence rates, stratified by HPV type.
Figure 2. HPV incidence rates, stratified by age in years.
meta-regression analysis that may have masked subtle
differences in HPV incidence within relatively broad
age categories. We found significant heterogeneity (p
values for Cochran’s Q < 0.001) in estimates of HPV
incidence that could partially be explained by age. This
is consistent with systematic reviews of HPV preva-
lence, which noted heterogeneous estimates of HPV
prevalence across global studies and a clear influence
of age.18,19
Since this review was conducted, there have been a
number of studies that have reported on HPV inci-
dence, including large studies from China,64 India,65
the Netherlands,66 and smaller studies from Finland67
and Tanzania.68 Reported incidence of type-specific
HPV infections observed in these studies is comparable
to published results from this review; with high rates of
HPV-16 infection compared to other tested HPV types.
Current models of the natural history indicate
that HPV infection is generally acquired shortly after
sexual debut. A proportion of these HPV infections
persist, increasing risk high-grade precancerous cervi-
cal lesions that either regress or develop into cancer.16
While newly detected HPV infections seem to decline
with age, those in older women may result from both
newly acquired HPV infection or reactivation of previ-
ously acquired infections.17 A more recent study of
Wheeler et al. 7

Table 2. Meta-regression analysis of independent HPV incidence rates by study characteristics among 13 studies assessing 13 or
more HPV types.

Stratum-specific pooled Ratio of average Age adjusted ratio

No. of incidence rate per 100 incidence rates of average incidence
Characteristic results woman-months (95% CI) (95% CI) rates (95% CI)

Mean age of womena,b

30 years 7 0.51 (0.37–0.69) 1.0 1.0
<30 years 6 1.56 (0.98–2.48) 3.12 (1.41–6.93) 3.12 (1.41–6.93)
Study region
North America 7 1.19 (0.76–1.85) 1.0 1.0
Europe, Central and South America 4 0.43 (0.28–0.68) 0.36 (0.12–1.09) 0.70 (0.23–2.17)
Africa, Asia, Australia, Multi-Region 2 1.01 (0.34–2.94) 0.85 (0.21–3.44) 0.51 (0.14–1.84)
HPV DNA detection method
Hybrid Capture II 4 0.69 (0.23–2.06) 1.0 1.0
MY09/MY11 primers 3 0.92 (0.44–1.95) 1.33 (0.24–7.27) 1.09 (0.31–3.80)
SPF10, PGMY09/11, GP5þ/6þ primers 5 0.99 (0.59–1.65) 1.45 (0.33–6.42) 1.67 (0.56–4.99)
Unspecified HPV L1 primers 1 0.66 (0.53–0.82) N/Ac N/Ac
HPV testing interval
< 6 Months 4 0.96 (0.31–2.91) 1.0 1.0
6–12 Months 7 0.86 (0.56–1.33) 0.90 (0.24–3.32) 0.96 (0.36–2.60)
> 12 Months 2 0.61 (0.53–0.70) 0.64 (0.11–3.91) 0.64 (0.16–2.49)
Mean length of follow-upd
24 Months 5 1.47 (1.04–2.08) 1.0 1.0
>24 Months 8 0.60 (0.42–0.87) 0.41 (0.16–1.06) 0.51 (0.24–1.09)
Baseline cervical abnormalitiese
0% Abnormal 6 0.77 (0.39–1.52) 1.0 1.0
1–15% Abnormal 3 1.15 (0.54–2.47) 1.50 (0.35–6.45) 1.03 (0.32–3.33)
Not stated 4 0.77 (0.40–1.46) 1.00 (0.26–3.79) 0.82 (0.29–2.35)
Study populations
Population-based/screening 4 0.60 (0.46–0.78) 1.0 1.0
University students 3 1.68 (1.23–2.29) 2.75 (0.67–11.34) 1.26 (0.28–5.62)
Hospital/clinic/high-risk patients 6 0.73 (0.37–1.45) 1.17 (0.35–3.88) 1.08 (0.38–3.09)
HPV: human papillomavirus; LR: low-risk; HR: high-risk.
a
The median age of the study population was used when the mean age was not reported.12,22,23,25,37,38
b
The age analysis includes all age-stratified within-studies results or results classified by mean age of cohort.
c
Rate ratio estimates based on one result not shown.
d
The median length of follow-up was used when the mean length of follow up was not reported.
e
Studies included are limited to those that have HPV incidence results among populations or sub-populations where 15% of women had abnormal
cervical status at baseline and where 5% of women are HIV-positive.

35- to 60-year-old US women found that most newly
detected HPV infections occurred in sexually active
women who self-reported no new sexual partners or
during periods of abstinence.15 Together, these data
imply that HPV viral latency and subsequent reactiva-
tion may represent an important source of “incident”
HPV infections in older women.16 We were unable to
examine the role of individual or population-level
measures of sexual behavior in younger and older
women in our analysis to examine these potentially
mediating risk factors.
Major strengths of this investigation are the notably
large sample size, based on inclusion of a broad range
of original peer-reviewed journal articles dating back to
1995. Further, publications were systematically identi-
fied after careful review using an a priori inclusion and
exclusion criteria. Two independent readers entered
study results to ensure accuracy of transcription. Our
use of random effects meta-regression is unique and
allowed for weighting of relative contributions of mul-
tiple studies while accounting for between-study and
within-study variability.
Limitations of this study include a relatively small
number of articles (n ¼ 13) reporting HPV IRs with 13
types or more limited precision of our meta-regression
analysis. For articles that only reported cumulative
HPV incidence, we were unable to convert cumulative
HPV incidence results into HPV IRs using formulaic
conversion (i.e., based on the exponential distribution).
This is because a sensitivity analysis among the small
subset of studies reporting both cumulative and
rate-based incidence measures showed that HPV IRs
8 International Journal of STD & AIDS 0(0)

Table 3. Meta-regression analysis of grouped-type HPV incidence among 13 studies assessing 13 or more HPV types.

Stratum-specific pooled Age adjusted ratio

No. of incidence rate per 100 of average incidence
Reported HPV typea results woman-months (95% CI) rates (95% CI)

Overall-HPV 10 0.63 (0.43–0.92) N/Ab

HR-HPV (referent) 8 0.53 (0.33–0.83) 1.0
LR-HPV 4 0.31 (0.17–0.57) 0.60 (0.36–1.02)
HPV: human papillomavirus; LR: low-risk; HR: high-risk.
a
The type analysis contains all reported type-specific HPV results among the selected studies. To control for non-independence within studies reporting
more than one grouped type HPV result, study-specific regression terms were included in these meta-regression models (not shown).
b
Comparison between non-independent HPV type groups (i.e. overall vs. HR) was not performed.

Table 4. Meta-regression analysis of type-specific HPV incidence among 13 studies assessing 13 or more HPV types.

Stratum-specific pooled Age adjusted ratio

No. of incidence rate per 100 of average incidence
Reported HPV typea results woman-months (95% CI) rates (95% CI)

HPV-16 (referent) 9 0.14 (0.08–0.25) 1.0

HPV-18 9 0.07 (0.04–0.13) 0.47 (0.33–0.67)
HPV-31 5 0.06 (0.03–0.13) 0.43 (0.30–0.64)
HPV-33 4 0.03 (0.02–0.07) 0.23 (0.14–0.39)
HPV-35 3 0.05 (0.02–0.10) 0.31 (0.18–0.56)
HPV-42 1 0.04 (0.02–0.11) N/Ab
HPV-43 1 0.03 (0.01–0.08) N/Ab
HPV-45 4 0.04 (0.02–0.09) 0.29 (0.18–0.46)
HPV-52 4 0.06 (0.03–0.13) 0.41 (0.26–0.65)
HPV-56 5 0.05 (0.02–0.10) 0.34 (0.22–0.52)
HPV-58 3 0.07 (0.03–0.14) 0.45 (0.27–0.74)
HPV-68 1 0.05 (0.02–0.17) N/Ab
HPV-70 1 0.03 (0.01–0.07) N/Ab
HPV-6 5 0.05 (0.03–0.11) 0.35 (0.22–0.55)
HPV-11 4 0.02 (0.01–0.04) 0.11 (0.06–0.20)
HPV: human papillomavirus.
a
The type analysis contains all reported type-specific HPV results among the selected studies. To control for non-independence within studies reporting
more than one type-specific result, study-specific regression terms were included in these meta-regression models (not shown).
b
Rate ratio estimates based on one result not shown.

were not constant across study follow up. Additionally,
we had limited covariate data on other factors that
influence observed differences in HPV incidence
(e.g. type-specific seropositivity, sexual partnerships,
smoking status).
Understanding differences in HPV detection meth-
ods and definitions is crucial to describing HPV inci-
dence. Most studies defined type-specific incident HPV
infection as a subsequent positive test result following a
negative result for that HPV type. To limit large differ-
ences in the sensitivities of detection assays, we restrict-
ed our review to PCR and HC-II detection methods.
While HPV DNA detection methods are highly sensi-
tive, the possibility of a sample containing HPV below
the detection limit may have resulted in misclassifica-
tion of HPV incidence. Seven studies defined type-
specific infection as a subsequent positive test result
following two consecutive negative results28,43–48;
their inclusion may have led to a potential underesti-
mation of HPV incidence. Alternatively, a single detec-
tion of HPV DNA may indicate only recent exposure
to HPV without establishment of a true infection, lead-
ing to a potential overestimation of incidence of
HPV infection.
Current U.S. Advisory Committee on Immunization
Practices guidelines recommend universal vaccination
for girls aged 11–12 years before the onset of sexual
intercourse given relatively high rates of HPV acquisi-
tion following sexual debut and the high vaccine effi-
cacy in HPV-naı̈ve vaccine recipients.69–71 A study of
the quadrivalent HPV vaccine in women aged 24–45
years observed high efficacy against HPV infections
Wheeler et al.
appearing after the seventh month of follow-up.72
However, this study did not provide specific estimates
of vaccine efficacy for individual HPV types in this 24–
45 age group, and also found that prophylactic HPV
vaccination was less effective among women with pre-
existing infection at enrollment. The question remains
as to what extent vaccination should be recommended
in women
26 years. Our results indicate that while
women
30 years are less likely to have newly detected
infections, HPV-16/18 accounts for many of
these infections.
Acquisition of cervical HPV infection presents a risk
to women’s health as a necessary cause of high-grade
lesions and cervical cancer. Worldwide, women 30
years present with a higher rate of incident HR-HPV
infections, yet older women also remain at risk of inci-
dent infection. Though we present no single estimate of
HPV incidence, the summary data presented here high-
light the distribution of incident HPV infection prior to
the global introduction of prophylactic HPV vaccines,
and will be useful for the monitoring of changes in
HPV incidence after implementation of population-
level HPV vaccination.
Authors’ contributions
BSW collected data, performed analyses, and prepared the
manuscript. AFR reviewed data collection, provided analytic
support and assisted with manuscript preparation. CP pro-
vided methodological support. SMT provided manuscript
feedback. JSS directed the research process and provided
manuscript feedback. All authors revised the manuscript,
approved of the final version, and agreed to be accountable
for all questions regarding the accuracy and integrity of
the manuscript.
Declaration of conflicting interests
The authors declared the following potential conflicts of
interest with respect to the research, authorship, and/or pub-
lication of this article: Sylvia Taylor is an employee of the
GlaxoSmithKline group of companies and holds shares as
part of her employee remuneration. Jennifer Smith has
received unrestricted research grants or served on paid advi-
sory boards for BD, GlaxoSmithKline, Hologic, Merck, and
Trovagene over the past five years.
Funding
The authors disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: This study was funded by GlaxoSmithKline
Biologicals SA, Wavre, Belgium.
ORCID iD
Jennifer S Smith http://orcid.org/0000-0002-1256-0422
9
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