Abstract
Background
Understanding the natural history of human papillomavirus (HPV) infections is essential to cervical cancer prevention planning. We estimated HPV type-specific infection detection and clearance in young women.
Methods
The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study is a prospective cohort of 502 college-age women who recently initiated a heterosexual relationship. We tested vaginal samples collected at 6 clinical visits over 24 months for 36 HPV types. Using rates and Kaplan-Meier analysis, we estimated time-to-event statistics with 95% confidence intervals (CIs) for detection of incident infections and clearance of incident and present-at-baseline infections (separately). We conducted analyses at the woman- and HPV-levels, with HPV types grouped by phylogenetic relatedness.
Results
By 24 months, we detected incident infections in 40.4% (CI, 33.4%–48.4%) of women. Incident subgenus 1 (43.4; CI, 33.6–56.4), 2 (47.1; CI, 39.9–55.5), and 3 (46.6; CI, 37.7–57.7) infections cleared at similar rates per 1000 infection-months. We observed similar homogeny in HPV-level clearance rates among present-at-baseline infections.
Conclusions
Our analyses provide type-specific infection natural history estimates for cervical cancer prevention planning. HPV-level analyses did not clearly indicate that high oncogenic risk subgenus 2 infections persist longer than their low oncogenic risk subgenera 1 and 3 counterparts.
Keywords: Papillomaviridae, human papillomavirus, sexually transmitted infection, genital infection, prospective cohort study, incidence, clearance, persistence, natural history, cervical cancer
Using rates and Kaplan-Meier analyses, we characterized the natural history of human papillomavirus (HPV) infections in college-age women in new heterosexual relationships. Our HPV type-specific analyses indicated homogenous detection and clearance rates for infections grouped by Alphapapillomavirus subgenera.
Persistent genital infection with oncogenic human papillomavirus (HPV) types is a necessary cause of the majority of cervical precancerous lesions and cancers [1–5]. Most infections in young women are transient, but a minority persist [6], and a sizeable proportion of “incident” infections in older women are reactivations of infections acquired earlier in life [7].
While cervical cancer accounted for 3.1% of the global cancer burden in 2020 (604 127 cases) [8], the disease is highly preventable. The nonavalent HPV vaccine prevents infection with HPV types found in 89.5% of invasive cervical cancers [9], and molecular HPV testing is an efficacious screening strategy [10].
Studies of the natural history of HPV infection in young women [11–23] have informed primary and secondary cervical cancer prevention strategies. In these studies, the woman was the unit of analysis. When multiple HPV types are analyzed together, this “woman-level grouped” analysis strategy does not produce HPV type-specific results. Two important limitations arise: the detection of multiple HPV types may be counted as a single detection event, and the synchronous clearance of multiple HPV types may be counted as a single clearance event. Given that multiple HPV types can be transmitted simultaneously during sexual contact [5], these analytical simplifications pose a challenge. Conversely, “HPV-level grouped” analysis strategies (where the infection is the unit of analysis) produce HPV type-specific results when multiple types are analyzed together.
We described vaginal HPV infection prevalence, incidence, and persistence for individual HPV types, as well as types grouped by subgeneric classifications using woman-level grouped and HPV-level grouped analysis strategies. We based our analyses on a cohort of women who had recently initiated a sexual relationship with a male partner in the HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) study.
METHODS
Study Design and Procedures
We used data from female participants of the HITCH prospective cohort study; full details have been published elsewhere [24]. Briefly, we recruited university and college students (aged 18–24 years) who began a sexual relationship with a male partner ≤6 months prior. Enrolment occurred between 2005 and 2011 in Montréal, Canada, at university-run health clinics. At baseline, 4, 8, 12, 18, and 24 months postenrollment, women provided a vaginal sample and completed sociodemographic/sexual behavior questionnaires. Women were asked to refrain from sexual activity for 24 hours before each visit. Based on nurse instructions, participants self-collected vaginal samples using a polyester swab (diagnostic accuracy demonstrated [25–27]). We used the Linear Array genotyping assay (Roche Molecular Systems) to detect 36 HPV types [28], validating samples via β-globin DNA coamplification. After the 2006 licensing of the HPV vaccine, women were asked how many doses they had received.
The Institutional Review Boards of McGill University (study number A09-M77-04A), Concordia University, and the Centre Hospitalier de l'Université de Montréal approved the HITCH study; all participants provided written informed consent. The HITCH study complies with the Declaration of Helsinki and the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.
Taxonomic Groups
We described the natural history of individual HPV types separately. We did the same for 3 groups of HPV types, as defined by subgenera of the Alphapapillomavirus genus. This taxonomic scheme clusters phylogenetically related HPV types according to tissue tropism and oncogenic risk based on empirical evidence and differential mucosotropic type distributions. Subgenus 1 includes low oncogenic risk HPVs 6, 11, 40, 42, 44, and 54. Subgenus 2 includes HPVs 16, 18, 26, 31, 33, 34, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, 68, 69, 70, 73, and 82, which can cause cervical precancer or cancer given infection persistence [29]; all HPV types considered definite, probable, or possible carcinogens by the International Agency for Research on Cancer belong to subgenus 2 [1, 30]. Subgenus 3 includes commensal HPVs 61, 62, 71, 72, 81, 83, 84, and 89 [29–31]. Analyses designated “any HPV” or “all HPV” incorporated all 36 types.
Analytical Frameworks
We refer to time series as longitudinal records of a woman's HPV positivity across follow-up. We first performed “analyses of individual HPV types” using 1 HPV type-specific time series per at-risk woman. Then, we performed analyses of grouped HPV types using 2 different strategies: “woman-level grouped analyses” used 1 multi-HPV type composite time series per at-risk woman, whereas “HPV-level grouped analyses” used 1 HPV type-specific time series per at-risk HPV type per woman.
We used 2 event definitions for all analyses. Single detection of incident infections (Figure 1A) occurred at the first positive result in a time series; time series positive at baseline were not considered at risk. Liberal clearance occurred at the first negative result in a time series. We analyzed clearance in the context of infections present at baseline and incident infections, separately. In clearance analyses of infections present at baseline (Supplementary Figure 1), time series were considered at-risk when positive at baseline. In clearance analyses of incident infections (Figure 1B), time series became at-risk when a positive result was detected in a time series that was negative at baseline.
Figure 1.
A, Analytical framework for single detection of incident infection. (i) Analysis of an individual HPV type: woman A must be negative for HPVx at baseline. She has a single detection at 24 months, when she tests positive for HPVx. (ii) Woman-level grouped analysis of HPV types x, y, and z: woman A must be negative for all 3 types at baseline. She has a single detection at 12 months, the first time she tests positive for 1 (or more) types following a visit where she was negative for all 3 types. (iii) HPV-level grouped analysis of HPV types x, y, and z: HPV types must be absent at baseline. There will be a single detection each first time woman A tests positive for any type following a visit where she was negative for the same type. HPVx and HPVz have single detections at 24 and 12 months, respectively; HPVy is right censored (24 months). B, Analytical framework for liberal clearance of incident infection. (i) Analysis of an individual HPV type: woman B must be negative for HPVx at baseline. She later tests positive for HPVx, then has a liberal clearance after 14 months have elapsed, when she tests negative for HPVx. (ii) Woman-level grouped analysis of HPV types x, y, and z: woman B must be negative for all 3 types at baseline. After testing positive for HPVx, she never clears all 3 asynchronously detected infections at a single visit. She is right censored (20 months). (iii) HPV-level grouped analysis of HPV types x, y, and z: HPV types must be absent at baseline, then detected later in the study. There will be a liberal clearance each first time woman B tests negative for any type following a visit where she was positive for the same type. HPVx and HPVy have liberal clearances 14 and 12 months postdetection, respectively; HPVz is right censored 6 months after detection. Symbols. ♀♂ Indicates debut of woman's sexual relationship with a male partner occurred 0–6 months prebaseline. ↓ Indicates data are right censored. → Indicates time to discrete event of interest. Gradient arrows indicate that biological infection/clearance occurred at an unknown time before detection/clearance at the arrowhead. Solid arrow counts time at risk contributed before censorship at the arrowhead. Abbreviations: HPV, human papillomavirus; mo, months (1 month = 30.437 days); t, time.
Finally, we repeated all analyses substituting more stringent outcome definitions: double detection and conservative clearance. These events were akin to single detection and liberal clearance, respectively; however, the defining positive/negative results occurred at 2 consecutive visits. Event timing was based on the first of the 2 visits.
Statistical Analyses
For all HPV-level analyses, we accounted for potential intraparticipant correlation arising from the ability to detect multiple HPV types in the same woman [32]. We calculated, by visit, HPV prevalence with 95% exact confidence intervals (CIs). For HPV-level analyses, we accounted for intrawoman clustering using a degrees of freedom-adjusted effective sample size [33].
We estimated Kaplan-Meier product-limit rates at 6, 12, and 24 months to describe cumulative detection and percent of infections uncleared. Using the log-log approach, we assigned 95% CIs to woman-level estimates. For HPV-level estimates, we assigned pointwise percentile-based woman-clustered bootstrap 95% CIs [34, 35].
We estimated the rate of detection/clearance per 1000 woman-months for woman-level analyses, and per 1000 infection-months for HPV-level analyses. The 95% CIs around rates were estimated via quadratic approximation of Poisson log-likelihood for woman-level analyses. We extracted 95% CIs from a leave-1-woman-cluster-out jackknife procedure for HPV-level analyses.
We calculated all mean and median times to detection/clearance including censored observations (ie, actuarial measures of central tendency), then excluding censored observations (ie, event-conditional measures of central tendency). We estimated mean times to detection/clearance (restricted to longest follow-up) with parametric 95% CIs for woman-level analyses, and percentile-based woman-clustered bootstrap 95% CIs for HPV-level analyses. Based on log-log survival function CIs, we assigned 95% CIs to the woman-level median, and based on woman-clustered bootstrap survival function CIs, we assigned 95% CIs to the HPV-level median.
We performed sensitivity analyses to approximate the extent to which right censoring caused actuarial mean times to detection/clearance to be underestimated. We calculated separate mean time to event estimates based on a Kaplan-Meier survival function with fitted exponential decay to S(t) = 0 (hereafter, exponentially extended mean). For woman-level analyses, we assigned percentile-based bootstrap 95% CIs; for HPV-level analyses, bootstraps were resampled by woman-clusters. Analyses were conducted using Stata SE 17.0 (StataCorp, LLC).
RESULTS
Of 502 women enrolled, 453 provided 2 or more valid vaginal samples; 48 had only 1 valid sample and were included in prevalence estimates, but not survival analyses. For 6 women missing a valid vaginal sample at baseline, we treated samples provided at visit 2 as baseline samples. Loss to follow-up by visit 6 was 43.7% (Supplementary Figure 2). Among the 453 women included in survival analyses, median follow-up was 26.4 months (quartiles 1–3, 19.5–31.7). Most women identified with the following ethnicities: English Canadian (34.0%), French Canadian (27.4%), Italian (4.6%), Latin American (4.9%), and multiple or mixed ethnicities (5.1%). At baseline, the mean age was 20.7 years (SD 1.8). Women reported an average weekly vaginal intercourse frequency of 4.6 and, on average, 6.4 previous heterosexual relationships involving vaginal sex. Among 93 women who received the HPV vaccine, the mean number of doses was 2.6.
As shown in Table 1, the 3 most prevalent HPV types at baseline were HPV16 (16.8%; 95% CI, 13.6%–20.3%), HPV89 (10.6%; 95% CI, 8.0%–13.6%), and HPV51 (10.2%; 95% CI, 7.7%–13.2%). Across follow-up, HPV16 (10.7%–16.8%) and HPV89 (8.0%–10.6%) remained among the 3 most prevalent types. At baseline, the prevalence of any HPV infection was 57.1% (95% CI, 52.6%–61.5%) at the woman-level (woman-level sample size: nw = 501 women), and 4.3% (95% CI, 3.9%–4.8%) at the HPV-level (HPV-level sample size: nHPV = 501 women × 36 types = 18 036 detectable infections).
Table 1.
Prevalence of Individual HPV Types, Woman-Level Grouped Types, and HPV-Level Grouped Types per Visit, by Subgenus
| HPV Type | Visit 1 nw = 501, nHPV = 18 036 |
Visit 2 nw = 451, nHPV = 16 236 |
Visit 3 nw = 412, nHPV = 14 832 |
Visit 4 nw = 374, nHPV = 13 464 |
Visit 5 nw = 326, nHPV = 11 736 |
Visit 6 nw = 282, nHPV = 10 152 |
|---|---|---|---|---|---|---|
| Subgenus 1 | ||||||
| HPV6 | 19, 3.8 (2.3–5.9) | 17, 3.8 (2.2–6.0) | 19, 4.6 (2.8–7.1) | 22, 5.9 (3.7–8.8) | 21, 6.4 (4.0–9.7) | 18, 6.4 (3.8–9.9) |
| HPV11 | 3, 0.6 (.1–1.7) | 0, 0.0 (.0–.8)a | 0, 0.0 (.0–.9)a | 1, 0.3 (.0–1.5) | 2, 0.6 (.1–2.2) | 1, 0.4 (.0–2.0) |
| HPV40 | 12, 2.4 (1.2–4.2) | 6, 1.3 (.5–2.9) | 9, 2.2 (1.0–4.1) | 12, 3.2 (1.7–5.5) | 8, 2.5 (1.1–4.8) | 7, 2.5 (1.0–5.1) |
| HPV42 | 38, 7.6 (5.4–10.3) | 43, 9.5 (7.0–12.6) | 32, 7.8 (5.4–10.8) | 21, 5.6 (3.5–8.5) | 24, 7.4 (4.8–10.8) | 23, 8.2 (5.2–12.0) |
| HPV44 | 10, 2.0 (1.0–3.6) | 6, 1.3 (.5–2.9) | 5, 1.2 (.4–2.8) | 5, 1.3 (.4–3.1) | 7, 2.2 (.9–4.4) | 5, 1.8 (.6–4.1) |
| HPV54 | 30, 6.0 (4.1–8.4) | 23, 5.1 (3.3–7.6) | 16, 3.9 (2.2–6.2) | 18, 4.8 (2.9–7.5) | 16, 4.9 (2.8–7.9) | 14, 5.0 (2.7–8.2) |
| Any woman-level | 98, 19.6 (16.2–23.3) | 80, 17.7 (14.3–21.6) | 72, 17.5 (13.9–21.5) | 65, 17.4 (13.7–21.6) | 65, 19.9 (15.7–24.7) | 56, 19.9 (15.4–25.0) |
| Any HPV-levelb | 112, 0.6 (.5–.8) | 95, 0.6 (.5–.7) | 81, 0.6 (.4–.7) | 79, 0.6 (.5–.8) | 78, 0.7 (.5–.8) | 68, 0.7 (.5–.9) |
| Subgenus 2 | ||||||
| HPV16 | 84, 16.8 (13.6–20.3) | 66, 14.6 (11.5–18.2) | 59, 14.3 (11.1–18.1) | 40, 10.7 (7.8–14.3) | 37, 11.4 (8.1–15.3) | 33, 11.7 (8.2–16.0) |
| HPV18 | 18, 3.6 (2.1–5.6) | 13, 2.9 (1.5–4.9) | 8, 1.9 (.8–3.8) | 9, 2.4 (1.1–4.5) | 11, 3.4 (1.7–6.0) | 10, 3.6 (1.7–6.4) |
| HPV26 | 0, 0.0 (.0–.7)a | 0, 0.0 (.0–.8)a | 0, 0.0 (.0–.9)a | 1, 0.3 (.0–1.5) | 0, 0.0 (.0–1.1)a | 0, 0.0 (.0–1.3)a |
| HPV31 | 24, 4.8 (3.1–7.0) | 25, 5.5 (3.6–8.1) | 20, 4.9 (3.0–7.4) | 15, 4.0 (2.3–6.5) | 17, 5.2 (3.1–8.2) | 12, 4.3 (2.2–7.3) |
| HPV33 | 8, 1.6 (.7–3.1) | 2, 0.4 (.1–1.6) | 4, 1.0 (.3–2.5) | 2, 0.5 (.1–1.9) | 0, 0.0 (.0–1.1)a | 1, 0.4 (.0–2.0) |
| HPV34 | 3, 0.6 (.1–1.7) | 1, 0.2 (.0–1.2) | 0, 0.0 (.0–.9)a | 0, 0.0 (.0–1.0)a | 2, 0.6 (.1–2.2) | 0, 0.0 (.0–1.3)a |
| HPV35 | 4, 0.8 (.2–2.0) | 4, 0.9 (.2–2.3) | 5, 1.2 (.4–2.8) | 5, 1.3 (.4–3.1) | 3, 0.9 (.2–2.7) | 1, 0.4 (.0–2.0) |
| HPV39 | 34, 6.8 (4.8–9.4) | 32, 7.1 (4.9–9.9) | 18, 4.4 (2.6–6.8) | 22, 5.9 (3.7–8.8) | 15, 4.6 (2.6–7.5) | 15, 5.3 (3.0–8.6) |
| HPV45 | 8, 1.6 (.7–3.1) | 8, 1.8 (.8–3.5) | 3, 0.7 (.2–2.1) | 5, 1.3 (.4–3.1) | 6, 1.8 (.7–4.0) | 8, 2.8 (1.2–5.5) |
| HPV51 | 51, 10.2 (7.7–13.2) | 41, 9.1 (6.6–12.1) | 32, 7.8 (5.4–10.8) | 20, 5.4 (3.3–8.1) | 19, 5.8 (3.6–9.0) | 19, 6.7 (4.1–10.3) |
| HPV52 | 35, 7.0 (4.9–9.6) | 28, 6.2 (4.2–8.9) | 29, 7.0 (4.8–10.0) | 22, 5.9 (3.7–8.8) | 15, 4.6 (2.6–7.5) | 15, 5.3 (3.0–8.6) |
| HPV53 | 36, 7.2 (5.1–9.8) | 35, 7.8 (5.5–10.6) | 35, 8.5 (6.0–11.6) | 29, 7.8 (5.3–11.0) | 23, 7.1 (4.5–10.4) | 16, 5.7 (3.3–9.1) |
| HPV56 | 25, 5.0 (3.3–7.3) | 21, 4.7 (2.9–7.0) | 15, 3.6 (2.1–5.9) | 13, 3.5 (1.9–5.9) | 11, 3.4 (1.7–6.0) | 7, 2.5 (1.0–5.1) |
| HPV58 | 23, 4.6 (2.9–6.8) | 20, 4.4 (2.7–6.8) | 16, 3.9 (2.2–6.2) | 16, 4.3 (2.5–6.9) | 13, 4.0 (2.1–6.7) | 9, 3.2 (1.5–6.0) |
| HPV59 | 30, 6.0 (4.1–8.4) | 21, 4.7 (2.9–7.0) | 16, 3.9 (2.2–6.2) | 11, 2.9 (1.5–5.2) | 15, 4.6 (2.6–7.5) | 11, 3.9 (2.0–6.9) |
| HPV66 | 31, 6.2 (4.2–8.7) | 30, 6.7 (4.5–9.4) | 20, 4.9 (3.0–7.4) | 20, 5.4 (3.3–8.1) | 16, 4.9 (2.8–7.9) | 12, 4.3 (2.2–7.3) |
| HPV67 | 28, 5.6 (3.8–8.0) | 22, 4.9 (3.1–7.3) | 20, 4.9 (3.0–7.4) | 16, 4.3 (2.5–6.9) | 14, 4.3 (2.4–7.1) | 5, 1.8 (.6–4.1) |
| HPV68 | 14, 2.8 (1.5–4.6) | 11, 2.4 (1.2–4.3) | 13, 3.2 (1.7–5.3) | 10, 2.7 (1.3–4.9) | 8, 2.5 (1.1–4.8) | 7, 2.5 (1.0–5.1) |
| HPV69 | 0, 0.0 (.0–.7)a | 0, 0.0 (.0–.8)a | 0, 0.0 (.0–.9)a | 0, 0.0 (.0–1.0)a | 0, 0.0 (.0–1.1)a | 0, 0.0 (.0–1.3)a |
| HPV70 | 4, 0.8 (.2–2.0) | 3, 0.7 (.1–1.9) | 5, 1.2 (.4–2.8) | 5, 1.3 (.4–3.1) | 5, 1.5 (.5–3.5) | 3, 1.1 (.2–3.1) |
| HPV73 | 18, 3.6 (2.1–5.6) | 17, 3.8 (2.2–6.0) | 19, 4.6 (2.8–7.1) | 13, 3.5 (1.9–5.9) | 11, 3.4 (1.7–6.0) | 11, 3.9 (2.0–6.9) |
| HPV82 | 14, 2.8 (1.5–4.6) | 7, 1.6 (.6–3.2) | 5, 1.2 (.4–2.8) | 6, 1.6 (.6–3.5) | 3, 0.9 (.2–2.7) | 2, 0.7 (.1–2.5) |
| Any woman-level | 240, 47.9 (43.5–52.4) | 207, 45.9 (41.2–50.6) | 192, 46.6 (41.7–51.6) | 151, 40.4 (35.4–45.5) | 139, 42.6 (37.2–48.2) | 107, 37.9 (32.3–43.9) |
| Any HPV-levelb | 492, 2.7 (2.4–3.1) | 407, 2.5 (2.2–2.9) | 342, 2.3 (2.0–2.7) | 280, 2.1 (1.8–2.5) | 244, 2.1 (1.8–2.5) | 197, 1.9 (1.6–2.3) |
| Subgenus 3 | ||||||
| HPV61 | 12, 2.4 (1.2–4.2) | 13, 2.9 (1.5–4.9) | 15, 3.6 (2.1–5.9) | 13, 3.5 (1.9–5.9) | 12, 3.7 (1.9–6.3) | 14, 5.0 (2.7–8.2) |
| HPV62 | 40, 8.0 (5.8–10.7) | 43, 9.5 (7.0–12.6) | 32, 7.8 (5.4–10.8) | 28, 7.5 (5.0–10.6) | 24, 7.4 (4.8–10.8) | 22, 7.8 (5.0–11.6) |
| HPV71 | 2, 0.4 (.1–1.4) | 1, 0.2 (.0–1.2) | 0, 0.0 (.0–.9)a | 0, 0.0 (.0–1.0)a | 0, 0.0 (.0–1.1)a | 0, 0.0 (.0–1.3)a |
| HPV72 | 2, 0.4 (.1–1.4) | 2, 0.4 (.1–1.6) | 1, 0.2 (.0–1.3) | 1, 0.3 (.0–1.5) | 1, 0.3 (.0–1.7) | 1, 0.4 (.0–2.0) |
| HPV81 | 8, 1.6 (.7–3.1) | 7, 1.6 (.6–3.2) | 4, 1.0 (.3–2.5) | 0, 0.0 (.0–1.0)a | 0, 0.0 (.0–1.1)a | 3, 1.1 (.2–3.1) |
| HPV83 | 9, 1.8 (.8–3.4) | 10, 2.2 (1.1–4.0) | 6, 1.5 (.5–3.1) | 8, 2.1 (.9–4.2) | 4, 1.2 (.3–3.1) | 3, 1.1 (.2–3.1) |
| HPV84 | 48, 9.6 (7.2–12.5) | 38, 8.4 (6.0–11.4) | 32, 7.8 (5.4–10.8) | 19, 5.1 (3.1–7.8) | 14, 4.3 (2.4–7.1) | 24, 8.5 (5.5–12.4) |
| HPV89 | 53, 10.6 (8.0–13.6) | 45, 10.0 (7.4–13.1) | 39, 9.5 (6.8–12.7) | 36, 9.6 (6.8–13.1) | 26, 8.0 (5.3–11.5) | 23, 8.2 (5.2–12.0) |
| Any woman-level | 133, 26.6 (22.7–30.6) | 120, 26.6 (22.6–30.9) | 99, 24.0 (20.0–28.5) | 77, 20.6 (16.6–25.1) | 65, 19.9 (15.7–24.7) | 72, 25.5 (20.6–31.0) |
| Any HPV-levelb | 174, 1.0 (.8–1.1) | 159, 1.0 (.8–1.2) | 129, 0.9 (.7–1.1) | 105, 0.8 (.6–1.0) | 81, 0.7 (.5–.9) | 90, 0.9 (.7–1.1) |
| All 36 types | ||||||
| Any woman-level | 286, 57.1 (52.6–61.5) | 249, 55.2 (50.5–59.9) | 227, 55.1 (50.2–60.0) | 192, 51.3 (46.1–56.5) | 168, 51.5 (46.0–57.1) | 141, 50.0 (44.0–56.0) |
| Any HPV-levelb | 778, 4.3 (3.9–4.8) | 661, 4.1 (3.6–4.6) | 552, 3.7 (3.3–4.2) | 464, 3.5 (2.9–4.0) | 403, 3.4 (2.9–4.0) | 355, 3.5 (3.0–4.1) |
Data are No. positive, % (95% CI). Sample size at each visit is reported for woman- (nw) and HPV- (nHPV) level grouped analyses.
Abbreviations: CI, confidence interval; HPV, human papillomavirus.
aType not detected. One-sided 97.5% CI assigned.
bDegrees of freedom-adjusted effective sample size used to account for intrawoman clustering.
Table 2 summarizes single detection of incident HPV infections. Among women negative for all HPV types at baseline, cumulative detection of any incident infection(s) was 40.4% (95% CI, 33.4%–48.4%) by 24 months. The detection rate for any HPV type(s) was 20.0 (95% CI, 16.1–24.9) per 1000 woman-months. Rates per 1000 woman-months were higher for subgenus 2 type(s) (17.0; 95% CI, 13.7–20.9) compared to subgenera 1 (11.4; 95% CI, 9.3–13.9) and 3 (12.4; 95% CI, 10.1–15.1) type(s).
Table 2.
Single Detection of Incident Infection for Individual HPV Types, Woman-Level Grouped Types, and HPV-Level Grouped Types, by Subgenus
| HPV Type | No.a | Cumulative Detection of Infection, % (95% CI) | Detection Rateb (95% CI) | Time to Detection, mo (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|
| 6 mo | 12 mo | 24 mo | Actuarial Meanc | Actuarial Medianc | Conditional Meand | Conditional Mediand | |||
| Subgenus 1 | |||||||||
| HPV6 | 435 | 0.7 (.2–2.1) | 3.4 (2.1–5.7) | 7.5 (5.3–10.8) | 3.8 (2.8–5.2) | 44.8 (43.1–46.5) | NR | 17.3 (14.5–20.1) | 17.0 (11.5–19.7) |
| HPV11 | 451 | 0.0e | 0.0e | 0.9 (.3–2.8) | 0.4 (.1–.9) | 48.9 (48.3–49.5) | NR | 23.2 (16.0–30.4) | 19.6 (14.9–NR)f |
| HPV40 | 442 | 0.0e | 1.0 (.4–2.6) | 4.2 (2.5–6.9) | 1.9 (1.3–2.9) | 46.5 (44.6–48.4) | NR | 19.7 (15.9–23.4) | 16.8 (14.0–23.9) |
| HPV42 | 419 | 2.7 (1.5–4.8) | 6.0 (4.1–8.9) | 9.7 (7.1–13.2) | 5.1 (3.9–6.7) | 43.5 (41.8–45.1) | NR | 16.0 (13.2–18.7) | 12.9 (9.6–22.0) |
| HPV44 | 445 | 0.2 (.0–1.6) | 0.7 (.2–2.2) | 1.3 (.5–3.0) | 0.9 (.5–1.7) | 48.2 (47.4–49.0) | NR | 20.0 (13.6–26.4) | 16.8 (4.2–29.2) |
| HPV54 | 426 | 0.7 (.2–2.2) | 1.8 (.8–3.6) | 5.4 (3.5–8.3) | 2.7 (1.9–3.9) | 46.3 (45.1–47.4) | NR | 19.0 (15.7–22.3) | 18.0 (15.3–23.7) |
| Any woman-level | 367 | 3.6 (2.1–6.1) | 10.6 (7.8–14.3) | 21.5 (17.3–26.5) | 11.4 (9.3–13.9) | 38.2 (36.2–40.1) | NR | 16.3 (14.5–18.1) | 15.4 (12.3–18.0) |
| Any HPV-levelg | 2618 | 0.7 (.4–1.1) | 2.1 (1.5–2.9) | 4.8 (3.8–6.1) | 2.4 (2.0–2.9) | 46.4 (44.2–47.0) | NR | 17.8 (16.0–19.5) | 17.0 (14.9–19.7) |
| Subgenus 2 | |||||||||
| HPV16 | 374 | 1.6 (.7–3.6) | 2.5 (1.3–4.8) | 6.9 (4.6–10.3) | 3.3 (2.4–4.8) | 45.5 (44.1–46.9) | NR | 18.0 (14.7–21.3) | 17.5 (12.2–22.3) |
| HPV18 | 437 | 0.2 (.0–1.6) | 1.0 (.4–2.6) | 1.9 (.9–4.1) | 1.1 (.6–2.0) | 48.0 (47.2–48.8) | NR | 20.0 (14.4–25.6) | 22.7 (8.4–31.1) |
| HPV26 | 453 | 0.0e | 0.0e | 0.3 (.0–1.9) | 0.1 (.0–.6) | 49.4 (49.2–49.5) | NR | … | NR |
| HPV31 | 430 | 1.0 (.4–2.5) | 2.5 (1.3–4.6) | 4.2 (2.6–6.8) | 2.4 (1.6–3.5) | 45.3 (43.7–46.9) | NR | 17.4 (13.4–21.4) | 13.7 (10.6–25.0) |
| HPV33 | 448 | 0.0e | 0.5 (.1–2.0) | 1.0 (.4–2.7) | 0.5 (.2–1.2) | 48.6 (47.7–49.4) | NR | 18.8 (10.9–26.7) | 13.1 (9.6–NR)f |
| HPV34 | 450 | 0.0e | 0.0e | 0.6 (.1–2.3) | 0.2 (.0–.7) | 49.3 (49.0–49.5) | NR | 17.6 (12.4–22.8) | 13.8 (13.8–NR)f |
| HPV35 | 450 | 0.2 (.0–1.6) | 0.5 (.1–1.9) | 1.0 (.4–2.7) | 0.4 (.2–1.1) | 48.9 (48.5–49.4) | NR | 15.2 (6.9–23.4) | 12.0 (4.6–NR)f |
| HPV39 | 421 | 1.2 (.5–2.9) | 2.0 (1.0–3.9) | 5.9 (3.9–8.9) | 2.6 (1.8–3.8) | 46.3 (45.1–47.6) | NR | 16.4 (13.0–19.9) | 15.3 (11.4–20.2) |
| HPV45 | 445 | 0.7 (.2–2.1) | 0.7 (.2–2.1) | 2.1 (1.1–4.2) | 1.3 (.8–2.1) | 47.1 (45.3–49.0) | NR | 20.1 (14.4–25.9) | 19.6 (5.8–29.3) |
| HPV51 | 405 | 0.8 (.2–2.3) | 2.6 (1.4–4.8) | 6.1 (4.0–9.2) | 3.4 (2.4–4.8) | 44.9 (43.1–46.8) | NR | 19.1 (15.9–22.4) | 18.6 (12.2–25.0) |
| HPV52 | 418 | 1.2 (.5–2.9) | 3.5 (2.1–5.9) | 5.7 (3.7–8.6) | 2.8 (2.0–4.1) | 45.2 (43.1–47.3) | NR | 16.4 (12.6–20.3) | 14.0 (8.5–19.7) |
| HPV53 | 419 | 1.2 (.5–2.9) | 4.1 (2.5–6.6) | 7.8 (5.4–11.1) | 3.5 (2.5–4.8) | 45.7 (44.5–46.9) | NR | 15.4 (12.6–18.3) | 13.1 (9.7–16.9) |
| HPV56 | 432 | 0.9 (.4–2.5) | 2.7 (1.5–4.8) | 5.4 (3.5–8.3) | 2.2 (1.4–3.3) | 46.3 (44.5–48.2) | NR | 14.9 (11.0–18.7) | 13.5 (9.4–16.3) |
| HPV58 | 431 | 0.5 (.1–1.9) | 1.7 (.8–3.6) | 2.9 (1.6–5.3) | 1.4 (.8–2.3) | 47.8 (47.0–48.6) | NR | 16.2 (11.5–20.8) | 14.0 (7.1–22.8) |
| HPV59 | 426 | 1.0 (.4–2.6) | 1.5 (.7–3.3) | 4.8 (3.0–7.7) | 2.2 (1.5–3.3) | 46.6 (45.3–48.0) | NR | 17.8 (14.3–21.4) | 17.2 (12.6–21.5) |
| HPV66 | 426 | 2.2 (1.1–4.1) | 4.4 (2.8–7.0) | 11.4 (8.5–15.3) | 4.7 (3.5–6.2) | 43.6 (41.5–45.6) | NR | 15.9 (13.3–18.4) | 16.6 (11.7–18.4) |
| HPV67 | 427 | 1.2 (.5–2.9) | 3.2 (1.9–5.5) | 7.0 (4.8–10.2) | 2.9 (2.0–4.2) | 46.1 (44.9–47.3) | NR | 14.3 (11.4–17.2) | 13.1 (9.4–17.5) |
| HPV68 | 440 | 0.0e | 0.7 (.2–2.2) | 1.4 (.6–3.3) | 0.5 (.2–1.2) | 48.9 (48.4–49.3) | NR | 14.8 (8.3–21.3) | 7.4 (6.6–NR)f |
| HPV69h | 453 | 0.0 | 0.0 | 0.0 | 0.0 | … | NR | … | … |
| HPV70 | 450 | 0.0e | 0.5 (.1–1.9) | 1.1 (.4–2.9) | 0.5 (.2–1.2) | 48.8 (48.3–49.3) | NR | 18.2 (11.4–25.0) | 13.7 (7.6–NR)f |
| HPV73 | 435 | 1.4 (.6–3.1) | 2.7 (1.5–4.8) | 6.0 (4.0–9.0) | 2.5 (1.7–3.6) | 46.3 (44.8–47.8) | NR | 13.8 (10.4–17.2) | 12.3 (7.0–15.5) |
| HPV82 | 441 | 0.7 (.2–2.1) | 1.4 (.7–3.2) | 2.3 (1.2–4.4) | 0.9 (.5–1.7) | 48.5 (47.9–49.1) | NR | 11.8 (7.4–16.1) | 9.5 (4.1–16.8) |
| Any woman-level | 233 | 4.8 (2.7–8.4) | 14.3 (10.3–19.6) | 32.4 (26.4–39.4) | 17.0 (13.7–20.9) | 32.3 (29.6–35.0) | 36.6 (30.8–NR)f | 16.7 (14.8–18.6) | 14.2 (12.2–18.4) |
| Any HPV-levelg | 9511 | 0.7 (.5–.9) | 1.7 (1.4–2.1) | 3.8 (3.2–4.5) | 1.7 (1.5–2.0) | 47.2 (45.1–47.6) | NR | 16.5 (15.2–17.8) | 14.5 (12.9–16.9) |
| Subgenus 3 | |||||||||
| HPV61 | 443 | 0.9 (.4–2.5) | 1.9 (1.0–3.8) | 4.9 (3.1–7.7) | 2.1 (1.4–3.2) | 47.1 (46.1–48.0) | NR | 17.2 (13.7–20.8) | 20.2 (10.6–21.8) |
| HPV62 | 416 | 1.5 (.7–3.2) | 4.3 (2.7–6.9) | 8.4 (5.9–11.8) | 3.6 (2.6–5.0) | 43.9 (41.6–46.3) | NR | 15.3 (11.9–18.6) | 12.0 (7.1–17.0) |
| HPV71h | 451 | 0.0 | 0.0 | 0.0 | 0.0 | … | NR | … | … |
| HPV72h | 451 | 0.0 | 0.0 | 0.0 | 0.0 | … | NR | … | … |
| HPV81 | 446 | 0.0e | 0.5 (.1–1.9) | 0.8 (.3–2.5) | 0.4 (.2–1.1) | 48.9 (48.3–49.4) | NR | 20.2 (10.7–29.7) | 22.8 (7.1–NR)f |
| HPV83 | 444 | 0.5 (.1–1.8) | 1.0 (.4–2.5) | 1.5 (.7–3.3) | 0.6 (.3–1.3) | 48.8 (48.3–49.3) | NR | 11.9 (6.7–17.1) | 10.6 (4.3–19.4) |
| HPV84 | 413 | 2.0 (1.0–3.9) | 5.6 (3.8–8.4) | 9.2 (6.6–12.6) | 4.8 (3.6–6.3) | 43.4 (41.5–45.3) | NR | 16.1 (13.1–19.0) | 13.1 (10.1–16.4) |
| HPV89 | 405 | 2.8 (1.5–4.9) | 6.0 (4.0–8.9) | 12.5 (9.5–16.5) | 5.5 (4.2–7.2) | 43.6 (42.1–45.1) | NR | 15.1 (12.7–17.5) | 13.8 (9.8–18.2) |
| Any woman-level | 336 | 5.4 (3.5–8.5) | 13.3 (10.0–17.5) | 24.4 (19.9–29.7) | 12.4 (10.1–15.1) | 35.6 (33.1–38.1) | 40.5 (38.4–NR)f | 15.5 (13.5–17.6) | 12.6 (10.1–15.5) |
| Any HPV-levelg | 3469 | 0.9 (.6–1.3) | 2.3 (1.7–3.0) | 4.5 (3.7–5.3) | 2.0 (1.7–2.4) | 46.8 (44.5–47.3) | NR | 15.7 (14.1–17.4) | 13.1 (11.5–15.6) |
| All 36 types | |||||||||
| Any woman-level | 192 | 4.7 (2.5–8.9) | 16.6 (12.0–22.8) | 40.4 (33.4–48.4) | 20.0 (16.1–24.9) | 30.9 (27.9–33.9) | 32.1 (25.1–NR)f | 15.4 (13.7–17.2) | 13.1 (12.2–17.0) |
| Any HPV-levelg | 15 598 | 0.8 (.6–1.0) | 1.9 (1.6–2.3) | 4.1 (3.6–4.8) | 1.9 (1.7–2.2) | 47.0 (45.0–47.3) | NR | 16.6 (15.5–17.7) | 14.9 (13.1–16.9) |
… Indicates an insufficient number of women were at risk or experienced the event to estimate this value.
Abbreviations: CI, confidence interval; HPV, human papillomavirus; mo, months; NR, not reached.
aSample size does not apply to conditional mean/median; sample size for conditional statistics is the number of single detections.
bRate per 1000 woman-months, except analyses of HPV-level grouped types, which are provided as rate per 1000 infection-months.
cTime to detection including women/HPV types that were censored. Actuarial means were found to be unreliable estimates of average time to detection due to right censoring.
dTime to detection conditional on event of interest (ie, time to detection restricted to women/types that had a single detection during the study).
eHPV type was not detected by this time point among women included in this analysis.
fOne bound of the survival function's 95% CI never reached or fell below 50%.
gCIs for cumulative detection estimates generated using bootstrap resampling of woman-clusters; CIs for detection rate per 1000 infection-months estimated via woman-clustered jackknife; CIs for actuarial and conditional mean time to detection determined by woman-cluster resampling bootstrap; CIs for actuarial and conditional median time to detection affixed by the times at which each (woman-clustered bootstrap-based) CI bound of the actuarial and conditional survival functions (respectively) reached or fell below 50%.
hHPV type was never detected among women included in this analysis.
Contrastingly, HPV-level detection rates per 1000 woman-months were similar for any HPV type (1.9; 95% CI, 1.7–2.2), and any subgenera 1 (2.4; 95% CI, 2.0–2.9), 2 (1.7; 95% CI, 1.5–2.0), and 3 (2.0; 95% CI, 1.7–2.4) type. Kaplan-Meier graphs for single detection are displayed in Figure 2 (woman-level) and Supplementary Figure 3 (HPV-level). Supplementary Table 1 alongside Supplementary Figures 4 and 5 reproduce these results for double detection analyses.
Figure 2.
Single detection of incident infection with any (A) human papillomavirus type(s), (B) subgenus 1, (C) subgenus 2, and (D) subgenus 3 type(s) with 95% confidence intervals (shaded), at the woman-level.
Table 3 and Table 4 summarize liberal clearance analyses of present-at-baseline and incident infections, respectively. At the woman-level, the median times to clearance and clearance rates for all present-at-baseline and incident infection(s) were 27.0 (95% CI, 25.0–32.7) months; 23.6 (95% CI, 19.6–28.4) per 1000 woman-months and 22.3 (95% CI, 16.2–CI bound not reached) months; 25.5 (95% CI, 16.8–38.7) per 1000 woman-months, respectively. Among women with infection(s) at baseline, we observed a lower clearance rate per 1000 woman-months (27.4; 95% CI, 22.6–33.2) and a longer median time to clearance (23.7; 95% CI, 20.0–26.1 months) of all subgenus 2 infection(s) compared to subgenera 1 (rate, 56.6 [95% CI, 44.0–72.7]; median, 11.5 [95% CI, 8.5–13.5] months) and 3 (rate, 45.8 [95% CI, 36.6–57.4]; median, 14.2 [95% CI, 11.3–17.8] months) infection(s). Among women with incident infection(s), the clearance rate per 1000 woman-months (47.2; 95% CI, 34.1–65.5) and median time to clearance (13.5; 95% CI, 9.4–18.5 months) of all subgenus 2 infection(s) were similar to those of subgenera 1 (rate, 45.6 [95% CI, 32.7–63.5]; median, 14.3 [95% CI, 9.9–17.6] months) and 3 (rate, 51.0 [95% CI, 37.4–69.6]; median, 14.4 [95% CI, 10.8–19.7] months).
Table 3.
Liberal Clearance of Infection Present at Baseline for Individual HPV Types, Woman-Level Grouped Types, and HPV-Level Grouped Types, by Subgenus
| HPV Type | No.a | Uncleared Infection, % (95% CI) | Clearance Rateb (95% CI) | Time to Clearance, mo (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|
| 6 mo | 12 mo | 24 mo | Actuarial Meanc | Actuarial Medianc | Conditional Meand | Conditional Mediand | |||
| Subgenus 1 | |||||||||
| HPV6 | 18 | 59.3 (33.0–78.1) | 35.6 (14.6–57.3) | 29.6 (10.8–51.4) | 61.6 (35.8–106.2) | 13.7 (8.7–18.7) | 10.6 (5.2–NR)e | 8.8 (5.1–12.5) | 5.9 (4.6–11.3) |
| HPV11 | 2 | NR | NR | NR | 228.9 (57.2–915.0) | 4.4 (2.2–6.5) | 2.8 (2.8–NR)e | 4.4 (2.2–6.5) | 2.8 (2.8–NR)e |
| HPV40 | 11 | 61.4 (26.6–83.5) | 40.9 (12.7–67.9) | 13.6 (.8–44.0) | 74.5 (37.3–148.9) | 11.3 (6.5–16.1) | 8.0 (4.7–21.4) | 8.5 (4.6–12.3) | 5.2 (3.0–12.6) |
| HPV42 | 34 | 82.0 (64.1–91.5) | 48.0 (29.4–64.3) | 23.0 (9.1–40.6) | 59.3 (39.7–88.4) | 15.0 (11.1–18.8) | 11.7 (7.8–12.6) | 11.1 (8.1–14.1) | 8.0 (7.1–12.2) |
| HPV44 | 8 | 50.0 (15.2–77.5) | 50.0 (15.2–77.5) | 25.0 (3.7–55.8) | 61.2 (29.2–128.3) | 15.3 (6.5–24.0) | 5.8 (4.4–NR)e | 12.3 (4.4–20.2) | 5.8 (4.4–16.3) |
| HPV54 | 27 | 81.5 (61.1–91.8) | 46.9 (27.2–64.4) | 9.5 (1.7–25.8) | 71.4 (47.0–108.5) | 12.3 (9.9–14.7) | 11.5 (8.5–14.5) | 10.5 (8.7–12.3) | 9.9 (7.6–12.5) |
| All woman-level | 86 | 72.5 (61.6–80.8) | 48.2 (36.8–58.6) | 24.6 (15.3–35.0) | 56.6 (44.0–72.7) | 15.6 (13.0–18.2) | 11.5 (8.5–13.5) | 10.3 (8.5–12.0) | 8.1 (5.9–10.6) |
| Any HPV-levelf | 100 | 71.3 (60.7–80.1) | 43.7 (33.8–52.7) | 19.2 (10.5–26.8) | 65.8 (53.9–80.3) | 13.9 (11.6–16.1) | 10.6 (8.1–12.5) | 10.2 (8.7–11.7) | 8.0 (7.4–10.6) |
| Subgenus 2 | |||||||||
| HPV16 | 79 | 84.3 (74.0–90.8) | 63.5 (51.4–73.3) | 33.0 (21.8–44.6) | 39.3 (29.5–52.3) | 19.4 (16.5–22.3) | 16.1 (12.3–19.3) | 11.3 (9.7–13.0) | 10.1 (8.5–13.7) |
| HPV18 | 16 | 68.8 (40.5–85.6) | 43.8 (19.8–65.6) | 16.7 (3.2–39.3) | 73.0 (43.2–123.2) | 12.5 (8.9–16.2) | 11.7 (5.2–15.9) | 10.8 (7.6–14.0) | 11.7 (5.1–12.4) |
| HPV26 | 0 | … | … | … | … | … | … | … | … |
| HPV31 | 23 | 90.9 (68.1–97.6) | 67.0 (42.9–82.7) | 19.1 (6.0–37.9) | 60.9 (38.8–95.5) | 14.8 (11.2–18.4) | 12.6 (8.2–14.1) | 13.1 (9.9–16.2) | 12.2 (6.9–13.7) |
| HPV33 | 5 | 60.0 (12.6–88.2) | NR | NR | 89.4 (28.8–277.3) | 7.2 (4.7–9.7) | 7.6 (4.1–NR)e | 5.3 (3.6–7.1) | 4.3 (4.1–NR)e |
| HPV34 | 3 | 100.0g | 33.3 (.9–77.4) | NR | 107.4 (34.6–333.1) | 9.3 (5.5–13.1) | 7.3 (6.7–NR)e | 9.3 (5.5–13.1) | 7.3 (6.7–NR)e |
| HPV35 | 3 | 100.0g | 66.7 (5.4–94.5) | NR | 43.1 (10.8–172.5) | 15.7 (8.1–23.3) | 20.4 (6.2–NR)e | 13.3 (3.5–23.2) | 6.2 (6.2–NR)e |
| HPV39 | 32 | 79.7 (60.3–90.3) | 55.5 (35.9–71.2) | 7.5 (1.3–21.1) | 65.7 (44.7–96.5) | 13.4 (11.1–15.8) | 12.8 (7.8–17.7) | 12.3 (10.1–14.4) | 12.0 (6.9–15.8) |
| HPV45 | 8 | 60.0 (19.6–85.2) | 30.0 (4.4–62.8) | NR | 100.0 (47.7–209.8) | 9.4 (6.4–12.4) | 8.3 (5.5–12.6) | 9.2 (6.2–12.2) | 8.3 (5.5–12.6) |
| HPV51 | 48 | 86.7 (72.7–93.8) | 56.2 (39.5–69.9) | 18.8 (7.3–34.5) | 53.1 (37.6–75.2) | 15.5 (12.8–18.2) | 14.7 (11.0–18.4) | 12.8 (10.5–15.1) | 11.6 (7.0–14.9) |
| HPV52 | 35 | 72.8 (54.2–84.8) | 45.9 (27.9–62.2) | 13.4 (3.6–29.6) | 66.2 (45.1–97.2) | 13.1 (10.2–16.1) | 8.7 (6.9–17.7) | 10.6 (8.1–13.2) | 7.4 (5.1–15.6) |
| HPV53 | 34 | 90.7 (73.9–96.9) | 61.2 (41.9–75.9) | 31.7 (15.8–49.0) | 47.2 (31.9–69.9) | 18.5 (14.8–22.1) | 19.1 (9.7–22.9) | 15.7 (12.3–19.1) | 13.7 (8.7–20.4) |
| HPV56 | 21 | 85.7 (62.0–95.2) | 48.3 (24.7–68.5) | 9.2 (.6–32.4) | 59.5 (35.9–98.7) | 14.3 (9.3–19.3) | 11.5 (7.8–20.2) | 10.3 (7.5–13.1) | 8.5 (5.1–12.2) |
| HPV58 | 22 | 90.4 (66.8–97.5) | 62.2 (36.4–80.0) | 15.5 (2.8–37.9) | 50.8 (30.1–85.8) | 15.7 (11.6–19.8) | 12.9 (8.7–21.1) | 12.0 (9.1–15.0) | 9.9 (6.5–15.6) |
| HPV59 | 27 | 81.5 (61.1–91.8) | 36.7 (18.7–54.9) | NR | 82.6 (55.4–123.2) | 11.3 (9.2–13.3) | 9.5 (8.0–14.7) | 10.7 (8.7–12.6) | 9.4 (7.7–12.4) |
| HPV66 | 27 | 73.7 (52.6–86.5) | 41.0 (22.0–59.1) | 4.1 (.3–17.3) | 89.0 (60.2–131.8) | 10.9 (8.7–13.2) | 8.5 (7.5–14.3) | 10.8 (8.5–13.1) | 8.5 (7.5–14.3) |
| HPV67 | 26 | 73.1 (51.7–86.2) | 38.5 (20.4–56.3) | NR | 93.1 (63.4–136.7) | 10.7 (8.5–13.0) | 8.5 (6.6–13.1) | 10.7 (8.5–13.0) | 8.5 (6.6–13.1) |
| HPV68 | 13 | 91.7 (53.9–98.8) | 66.7 (33.7–86.0) | 33.3 (10.3–58.8) | 34.8 (17.4–69.6) | 19.9 (14.3–25.5) | 19.5 (8.5–NR)e | 13.8 (9.7–18.0) | 11.7 (3.7–19.7) |
| HPV69 | 0 | … | … | … | … | … | … | … | … |
| HPV70 | 3 | 66.7 (5.4–94.5) | 66.7 (5.4–94.5) | 33.3 (.9–77.4) | 55.4 (17.9–171.8) | 18.0 (5.4–30.7) | 17.4 (4.7–NR)e | 18.0 (5.4–30.7) | 17.4 (4.7–NR)e |
| HPV73 | 18 | 66.7 (40.4–83.4) | 24.4 (7.7–46.1) | 12.2 (2.1–32.1) | 86.1 (52.8–140.6) | 10.7 (7.4–13.9) | 9.8 (5.0–12.0) | 9.3 (6.7–12.0) | 9.7 (4.9–11.7) |
| HPV82 | 12 | 50.0 (20.9–73.6) | 8.3 (.5–31.1) | NR | 140.3 (79.7–247.0) | 7.1 (4.8–9.5) | 5.5 (3.1–9.3) | 7.1 (4.8–9.5) | 5.5 (3.1–9.3) |
| All woman-level | 220 | 91.5 (86.9–94.6) | 78.2 (71.8–83.3) | 48.0 (40.1–55.4) | 27.4 (22.6–33.2) | 24.7 (22.6–26.8) | 23.7 (20.0–26.1) | 14.6 (13.1–16.1) | 14.2 (11.7–15.8) |
| Any HPV-levelf | 455 | 80.5 (75.7–84.8) | 50.8 (45.8–55.6) | 16.3 (12.3–20.2) | 60.5 (55.4–66.2) | 14.9 (13.9–16.0) | 12.1 (10.8–13.2) | 11.5 (10.8–12.2) | 9.9 (8.7–11.0) |
| Subgenus 3 | |||||||||
| HPV61 | 10 | 77.8 (36.5–93.9) | 55.6 (20.4–80.5) | 44.4 (13.6–71.9) | 37.7 (16.9–84.0) | 18.7 (10.5–26.9) | 16.2 (3.9–NR)e | 11.6 (5.3–17.9) | 7.9 (3.9–NR)e |
| HPV62 | 37 | 88.6 (72.4–95.6) | 61.6 (43.1–75.6) | 37.0 (20.4–53.8) | 41.5 (28.0–61.4) | 19.3 (15.6–23.0) | 19.2 (8.8–25.0) | 15.1 (11.7–18.6) | 11.6 (8.2–19.5) |
| HPV71 | 2 | 100.0g | NR | NR | 122.0 (30.5–487.8) | 8.2 (5.8–10.6) | 6.5 (6.5–NR)e | 8.2 (5.8–10.6) | 6.5 (6.5–NR)e |
| HPV72h | 2 | 100.0 | 100.0 | 100.0 | 0.0 | ... | NR | ... | ... |
| HPV81 | 7 | 83.3 (27.3–97.5) | 66.7 (19.5–90.4) | NR | 68.9 (28.7–165.5) | 11.2 (8.2–14.2) | 12.8 (5.8–NR)e | 10.5 (7.3–13.7) | 12.8 (5.8–NR)e |
| HPV83 | 9 | 88.9 (43.3–98.4) | 64.8 (25.3–87.2) | 48.6 (12.8–77.6) | 35.9 (14.9–86.2) | 20.4 (11.3–29.5) | 12.6 (5.5–NR)e | 12.4 (4.4–20.4) | 7.9 (5.5–NR)e |
| HPV84 | 40 | 79.4 (63.0–89.1) | 28.9 (15.2–44.1) | 10.4 (2.9–23.6) | 86.9 (61.8–122.2) | 10.5 (8.1–12.8) | 7.5 (6.4–10.4) | 8.7 (7.0–10.4) | 7.3 (6.2–8.5) |
| HPV89 | 48 | 74.8 (60.0–84.9) | 38.4 (24.7–51.9) | 8.2 (2.2–19.4) | 78.7 (58.4–106.1) | 12.3 (9.7–15.0) | 9.4 (7.8–12.1) | 11.0 (8.7–13.3) | 8.9 (6.7–11.3) |
| All woman-level | 117 | 82.2 (73.8–88.2) | 57.1 (47.1–65.9) | 34.0 (24.6–43.6) | 45.8 (36.6–57.4) | 18.4 (15.8–21.0) | 14.2 (11.3–17.8) | 12.0 (10.2–13.9) | 9.3 (6.8–12.1) |
| Any HPV-levelf | 155 | 81.4 (73.9–86.7) | 45.1 (36.1–54.0) | 20.9 (13.6–29.6) | 61.0 (50.6–73.3) | 14.9 (12.7–17.1) | 10.4 (8.5–13.1) | 11.3 (10.0–12.6) | 8.5 (7.5–9.7) |
| All 36 types | |||||||||
| All woman-level | 261 | 91.7 (87.5–94.5) | 80.1 (74.5–84.6) | 57.3 (50.2–63.8) | 23.6 (19.6–28.4) | 26.0 (24.0–27.9) | 27.0 (25.0–32.7) | 14.8 (13.2–16.4) | 14.0 (11.6–15.6) |
| Any HPV-levelf | 710 | 79.4 (74.4–82.8) | 48.6 (44.1–52.6) | 17.7 (13.9–21.2) | 61.3 (56.2–66.9) | 14.8 (13.7–15.8) | 11.7 (10.3–12.6) | 11.3 (10.6–11.9) | 9.3 (8.5–10.2) |
… indicates an insufficient number of women were at risk or experienced the event to estimate this value.
Abbreviations: CI, confidence interval; HPV, human papillomavirus; mo, months; NR, not reached.
aSample size does not apply to conditional mean/median; sample size for conditional statistics is the number of liberal clearances.
bRate per 1000 woman-months, except analyses of HPV-level grouped types, which are provided as rate per 1000 infection-months.
cTime to clearance including women/infections that were censored.
dTime to clearance conditional on event of interest (ie, time to clearance restricted to women/infections that had a liberal clearance during the study).
eOne bound of the survival function's 95% CI never reached or fell below 50%.
fCIs for uncleared infection estimates generated using bootstrap resampling of woman-clusters; CIs for clearance rate per 1000 infection-months estimated via woman-clustered jackknife; CIs for actuarial and conditional mean time to clearance determined by woman-cluster resampling bootstrap; CIs for actuarial and conditional median time to clearance affixed by the times at which each (woman-clustered bootstrap-based) CI bound of the actuarial and conditional survival functions (respectively) reached or fell below 50%.
gHPV type was not cleared by this time point among women included in this analysis.
hHPV type was never cleared among women included in this analysis.
Table 4.
Liberal Clearance of Incident Infection for Individual HPV Types, Woman-Level Grouped Types, and HPV-Level Grouped Types, by Subgenus
| HPV Type | No. a | Uncleared Infection, % (95% CI) | Clearance Rateb (95% CI) | Time to Clearance, mo (95% CI) | |||||
|---|---|---|---|---|---|---|---|---|---|
| 6 mo | 12 mo | 24 mo | Actuarial Meanc | Actuarial Medianc | Conditional Meand | Conditional Mediand | |||
| Subgenus 1 | |||||||||
| HPV6 | 32 | 79.4 (59.8–90.2) | 35.2 (16.8–54.2) | NR | 66.4 (41.8–105.3) | 12.1 (9.3–14.8) | 9.3 (7.6–12.8) | 8.4 (6.5–10.2) | 7.6 (5.3–9.3) |
| HPV11 | 1 | NR | NR | NR | 172.9 (24.4–1227.7) | … | NR | … | NR |
| HPV40 | 14 | 85.7 (53.9–96.2) | 47.6 (20.3–70.8) | NR | 73.9 (40.9–133.4) | 11.5 (9.1–13.8) | 10.2 (6.1–16.2) | 10.5 (7.9–13.0) | 9.9 (5.2–15.1) |
| HPV42 | 34 | 82.0 (64.3–91.5) | 52.1 (33.3–67.9) | 23.1 (9.1–40.9) | 55.1 (36.3–83.7) | 14.7 (11.4–18.0) | 12.4 (8.6–16.0) | 9.7 (8.0–11.4) | 8.6 (5.7–12.4) |
| HPV44 | 4 | 100.0e | 33.3 (.9–77.4) | NR | 74.2 (23.9–230.2) | 11.3 (5.7–16.9) | 8.5 (7.2–NR)f | 11.3 (5.7–16.9) | 8.5 (7.2–NR)f |
| HPV54 | 19 | 89.5 (64.1–97.3) | 44.2 (17.5–68.2) | 22.1 (1.6–57.5) | 50.6 (27.2–94.0) | 15.0 (10.8–19.3) | 10.6 (7.9–NR)f | 10.8 (6.5–15.1) | 8.0 (3.0–10.6) |
| All woman-level | 69 | 86.8 (76.1–92.9) | 55.0 (40.9–67.1) | 19.9 (6.5–38.6) | 45.6 (32.7–63.5) | 15.6 (13.0–18.2) | 14.3 (9.9–17.6) | 9.8 (8.2–11.4) | 8.7 (7.3–10.0) |
| Any HPV-levelg | 104 | 83.5 (74.8–89.4) | 52.3 (41.1–62.1) | 34.7 (24.2–44.8) | 43.4 (33.6–56.4) | 18.5 (15.4–21.1) | 13.1 (9.9–17.6) | 9.6 (8.6–10.9) | 8.5 (7.6–9.9) |
| Subgenus 2 | |||||||||
| HPV16 | 22 | 83.3 (56.8–94.3) | 67.3 (36.6–85.6) | NR | 36.5 (17.4–76.6) | 14.0 (10.7–17.3) | 15.3 (6.7–NR)f | 8.5 (5.7–11.4) | 6.7 (4.8–13.0) |
| HPV18 | 10 | 80.0 (40.9–94.6) | 50.0 (18.4–75.3) | 50.0 (18.4–75.3) | 34.7 (14.5–83.4) | 18.6 (11.4–25.8) | 10.2 (4.6–NR)f | 7.1 (5.4–8.8) | 7.4 (4.6–NR)f |
| HPV26 | 0 | … | … | … | … | … | … | … | … |
| HPV31 | 19 | 78.0 (51.5–91.1) | 36.0 (13.6–59.3) | NR | 69.1 (39.2–121.7) | 11.3 (8.4–14.1) | 9.8 (6.8–NR)f | 8.6 (6.2–10.9) | 8.0 (4.6–10.0) |
| HPV33 | 4 | 50.0 (5.8–84.5) | NR | NR | 153.1 (57.5–408.0) | 6.5 (4.5–8.5) | 5.5 (3.7–NR)f | 6.5 (4.5–8.5) | 5.5 (3.7–NR)f |
| HPV34 | 2 | 50.0 (.6–91.0) | NR | NR | 168.6 (42.2–674.2) | 5.9 (5.8–6.0) | 5.8 (5.8–NR)f | 5.9 (5.8–6.0) | 5.8 (5.8–NR)f |
| HPV35 | 4 | 75.0 (12.8–96.1) | 75.0 (12.8–96.1) | NR | 55.3 (17.8–171.5) | 16.6 (9.7–23.5) | 18.5 (5.0–NR)f | 15.4 (6.9–23.8) | 18.5 (5.0–NR)f |
| HPV39 | 19 | 89.5 (64.1–97.3) | 57.0 (29.7–77.1) | 19.0 (3.2–44.9) | 54.0 (29.9–97.5) | 14.1 (9.5–18.7) | 12.6 (8.1–14.8) | 9.6 (7.6–11.6) | 8.5 (5.6–12.6) |
| HPV45 | 8 | 75.0 (31.5–93.1) | 20.8 (1.0–58.6) | NR | 90.7 (40.8–201.9) | 9.4 (5.3–13.4) | 7.6 (4.7–NR)f | 8.6 (4.9–12.3) | 6.2 (4.7–NR)f |
| HPV51 | 23 | 86.7 (64.3–95.5) | 47.2 (23.4–67.8) | 12.6 (1.0–39.3) | 61.8 (37.3–102.6) | 13.7 (9.9–17.5) | 11.3 (6.3–16.3) | 11.1 (7.6–14.7) | 9.4 (4.9–15.1) |
| HPV52 | 19 | 89.2 (63.2–97.2) | 50.2 (26.1–70.2) | 13.7 (1.1–41.7) | 59.1 (34.3–101.8) | 13.6 (9.9–17.3) | 12.6 (6.8–23.0) | 10.0 (7.1–12.8) | 9.0 (6.2–12.6) |
| HPV53 | 25 | 78.7 (56.1–90.6) | 64.1 (40.5–80.3) | NR | 56.0 (33.2–94.5) | 13.7 (10.5–16.9) | 14.1 (6.4–18.4) | 10.0 (6.8–13.3) | 6.4 (3.7–14.9) |
| HPV56 | 16 | 85.7 (53.9–96.2) | 39.6 (12.8–65.9) | NR | 70.4 (37.9–130.8) | 10.7 (8.2–13.2) | 8.6 (6.3–15.5) | 9.7 (7.2–12.1) | 8.2 (5.3–12.7) |
| HPV58 | 13 | 92.3 (56.6–98.9) | 92.3 (56.6–98.9) | 20.2 (.9–58.0) | 31.8 (14.3–70.7) | 21.5 (15.4–27.6) | 22.3 (12.2–NR)f | 19.1 (11.6–26.5) | 18.2 (4.5–NR)f |
| HPV59 | 18 | 70.8 (43.5–86.7) | 27.0 (6.9–52.7) | 27.0 (6.9–52.7) | 67.5 (37.4–121.9) | 13.7 (7.8–19.5) | 9.4 (5.1–NR)f | 9.1 (4.8–13.3) | 7.1 (4.6–9.9) |
| HPV66 | 35 | 73.2 (54.8–85.1) | 33.1 (16.6–50.6) | NR | 91.8 (63.0–133.9) | 9.7 (7.9–11.4) | 8.8 (6.2–13.1) | 8.7 (7.0–10.4) | 7.6 (5.3–10.2) |
| HPV67 | 25 | 88.0 (67.3–96.0) | 37.8 (19.2–56.3) | NR | 80.4 (52.4–123.3) | 10.9 (9.0–12.8) | 8.5 (7.2–14.0) | 9.8 (8.0–11.7) | 8.3 (6.9–11.3) |
| HPV68 | 6 | 80.0 (20.4–96.9) | 26.7 (1.0–68.6) | NR | 57.7 (18.6–179.0) | 11.0 (8.0–14.0) | 11.5 (5.6–NR)f | 9.2 (6.2–12.1) | 10.5 (5.6–NR)f |
| HPV69 | 0 | … | … | … | … | … | … | … | … |
| HPV70 | 5 | 80.0 (20.4–96.9) | 40.0 (5.2–75.3) | 40.0 (5.2–75.3) | 65.6 (24.6–174.7) | 14.4 (5.8–23.0) | 7.3 (5.6–NR)f | 11.4 (2.8–19.9) | 6.2 (5.6–NR)f |
| HPV73 | 21 | 81.0 (56.9–92.4) | 40.7 (18.7–61.8) | NR | 79.7 (48.8–130.1) | 11.0 (8.9–13.2) | 9.6 (7.5–16.1) | 10.0 (7.8–12.3) | 8.8 (5.3–15.8) |
| HPV82 | 9 | 77.8 (36.5–93.9) | 22.2 (3.4–51.3) | NR | 81.2 (38.7–170.3) | 9.6 (7.1–12.1) | 9.3 (3.8–NR)f | 7.8 (6.3–9.4) | 8.9 (3.8–9.4) |
| All woman-level | 68 | 87.7 (76.8–93.6) | 57.1 (42.8–69.2) | 18.4 (6.3–35.5) | 47.2 (34.1–65.5) | 17.2 (13.4–21.0) | 13.5 (9.4–18.5) | 10.1 (8.4–11.9) | 8.3 (6.4–11.3) |
| Any HPV-levelg | 303 | 81.7 (76.1–86.2) | 51.9 (45.0–57.7) | 31.0 (24.1–36.5) | 47.1 (39.9–55.5) | 19.1 (15.9–21.2) | 12.7 (9.4–15.1) | 9.7 (8.9–10.6) | 8.1 (7.3–8.9) |
| Subgenus 3 | |||||||||
| HPV61 | 16 | 81.3 (52.5–93.5) | 48.8 (17.1–74.7) | NR | 42.8 (20.4–89.9) | 14.5 (10.0–18.9) | 11.9 (7.9–NR)f | 8.0 (5.3–10.8) | 7.9 (3.0–11.9) |
| HPV62 | 25 | 79.5 (57.5–90.9) | 46.0 (24.3–65.3) | 12.6 (1.1–38.9) | 65.7 (40.8–105.7) | 13.1 (9.4–16.7) | 11.7 (6.8–14.4) | 10.4 (7.4–13.3) | 8.2 (5.7–12.2) |
| HPV71 | 0 | … | … | … | … | … | … | … | … |
| HPV72 | 0 | … | … | … | … | … | … | … | … |
| HPV81 | 2 | 100.0e | 100.0e | NR | 44.8 (6.3–318.2) | … | 12.2 (NR–NR)f | … | NR |
| HPV83 | 7 | 100.0e | 17.1 (.8–52.6) | NR | 82.5 (34.4–198.3) | 9.1 (7.4–10.8) | 8.8 (6.2–NR)f | 8.2 (7.0–9.5) | 8.5 (6.2–NR)f |
| HPV84 | 34 | 63.9 (45.2–77.7) | 37.0 (19.7–54.4) | 14.8 (4.1–31.9) | 79.2 (53.5–117.1) | 11.5 (8.6–14.5) | 8.5 (5.6–15.1) | 8.8 (6.4–11.1) | 6.1 (4.6–9.9) |
| HPV89 | 43 | 88.0 (73.6–94.8) | 51.4 (34.7–65.8) | 20.9 (6.7–40.5) | 57.5 (39.7–83.3) | 14.4 (11.6–17.2) | 12.9 (8.1–20.1) | 11.3 (8.7–13.9) | 8.1 (6.7–11.3) |
| All woman-level | 71 | 80.1 (68.7–87.7) | 59.1 (45.6–70.3) | 26.7 (13.2–42.3) | 51.0 (37.4–69.6) | 15.3 (12.9–17.7) | 14.4 (10.8–19.7) | 10.4 (8.2–12.5) | 6.8 (5.7–11.8) |
| Any HPV-levelg | 127 | 80.3 (72.4–85.6) | 50.9 (40.3–58.8) | 35.0 (24.5–42.0) | 46.6 (37.7–57.7) | 17.3 (14.8–19.4) | 12.2 (9.7–15.1) | 9.9 (8.6–11.4) | 8.0 (6.7–9.6) |
| All 36 types | |||||||||
| All woman-level | 65 | 93.5 (83.6–97.5) | 74.1 (60.1–83.9) | 39.8 (19.2–59.7) | 25.5 (16.8–38.7) | 24.2 (19.6–28.9) | 22.3 (16.2–NR)f | 11.1 (8.7–13.5) | 8.7 (6.4–13.5) |
| Any HPV-levelg | 534 | 81.7 (77.1–86.0) | 51.7 (46.6–56.4) | 32.7 (27.4–36.8) | 46.2 (41.1–52.0) | 19.3 (16.9–20.8) | 12.6 (10.3–14.8) | 9.8 (9.1–10.5) | 8.2 (7.6–8.8) |
… Indicates an insufficient number of women were at risk or experienced the event to estimate this value.
Abbreviations: CI, confidence interval; HPV, human papillomavirus; mo, months; NR, not reached.
aSample size does not apply to conditional mean/median; sample size for conditional statistics is the number of liberal clearances.
bRate per 1000 woman-months, except analyses of HPV-level grouped types, which are provided as rate per 1000 infection-months.
cTime to clearance including women/infections that were censored.
dTime to clearance conditional on event of interest (ie, time to clearance restricted to women/infections that had a liberal clearance during the study).
eHPV type was not cleared by this time point among women included in this analysis.
fBound(s) of the survival function's 95% CI never reached or fell below 50%.
gCIs for uncleared infection estimates generated using bootstrap resampling of woman-clusters; CIs for clearance rate per 1000 infection-months estimated via woman-clustered jackknife; CIs for actuarial and conditional mean time to clearance determined by woman-cluster resampling bootstrap; CIs for actuarial and conditional median time to clearance affixed by the times at which each (woman-clustered bootstrap-based) CI bound of the actuarial and conditional survival functions (respectively) reached or fell below 50%.
At the HPV-level, the median time to clearance for any HPV infection was similar between infections present at baseline (11.7; 95% CI, 10.3–12.6 months) and incident infections (12.6; 95% CI, 10.3–14.8 months). The corresponding clearance rates per 1000 infection-months were 61.3 (95% CI, 56.2–66.9) and 46.2 (95% CI, 41.1–52.0). HPV-level clearance rates were comparable between taxonomic groupings. Amongst infections present at baseline, rates of clearing any subgenera 1, 2, and 3 infection were 65.8 (95% CI, 53.9–80.3), 60.5 (95% CI, 55.4–66.2), and 61.0 (95% CI, 50.6–73.3) per 1000 infection-months, respectively. The corresponding median infection durations were 10.6 (95% CI, 8.1–12.5), 12.1 (95% CI, 10.8–13.2), and 10.4 (95% CI, 8.5–13.1) months. Amongst incident infections, clearance rates for subgenera 1, 2, and 3 infections were 43.4 (95% CI, 33.6–56.4), 47.1 (95% CI, 39.9–55.5), and 46.6 (95% CI, 37.7–57.7) per 1000 infection-months, respectively. Corresponding median infection durations were 13.1 (95% CI, 9.9–17.6), 12.7 (95% CI, 9.4–15.1), and 12.2 (95% CI, 9.7–15.1) months. In HPV-level liberal clearance analyses, a larger proportion of incident infections (35.4%) were right censored compared to infections present at baseline (23.7%). Right censoring was similar for analyses of subgenera 1, 2, and 3 among infections present at baseline (24.0%, 23.7%, and 23.2%, respectively) and among incident infections (37.5%, 35.0%, and 34.6%, respectively). Figure 3 depicts, at the woman-level, survival functions for liberal clearance analyses; Supplementary Figure 6 presents the same at the HPV-level. Supplementary Tables 2 and 3, alongside Supplementary Figures 7 and 8 reproduce all aforementioned results for conservative clearance analyses.
Figure 3.
Liberal clearance of all (A) human papillomavirus type(s), (B) subgenus 1, (C) subgenus 2, and (D) subgenus 3 type(s) for infection present at baseline (blue) and incident infection (red) with 95% confidence intervals (shaded), at the woman-level.
Exponentially extended means are presented in Supplementary Table 4 (detection) and Supplementary Table 5 (clearance). Average differences between exponentially extended and actuarial mean times to single detection were 1538.7 months for analyses of individual HPV types, 28.4 months for woman-level grouped analyses, and 363.5 months for HPV-level grouped analyses. These large average differences suggest the actuarial mean time to detection was underestimated. For liberal clearance analyses, the corresponding average differences were 1.4, 3.1, and 0.2 months for infections present at baseline and 1.7, 6.2, and 7.3 months for incident infections. These small average differences suggest the mean time to clearance was reliable.
DISCUSSION
This study described the natural history of vaginal HPV infections in young women who recently initiated a new sexual relationship. We observed different event rates between taxonomically grouped HPV types at the woman-level, but these differences were not evident in type-specific HPV-level estimates.
Woman-level natural history event rates are difficult to compare between studies due to differences in genotyping strategies, follow-up, and participant characteristics/behavior. Nonetheless, we observed a higher woman-level rate of detection for any HPV type(s) compared to pooled rates in women under 30 years of age (20.0 vs 15.6 detections per 1000 woman-months, respectively) [12]. Our estimate for cumulative detection of any HPV by 24 months was similar to cumulative detection reached by 12 to 36 months in other studies of young women [13–15, 20, 21]. Specifically, detection rates in this cohort are comparable to a previous study of college-age women in Montréal [19].
The woman-level rate of detection for incident subgenus 2 (ie, oncogenic) infection(s) was higher than the corresponding rates for subgenera 1 and 3. This finding is consistent with studies observing elevated detection rates among high-risk HPV types [12]. Conversely, our HPV-level detection rate estimates for incident subgenus 1, 2, and 3 infections were relatively homogenous. While we did not use the traditional high-risk versus low-risk HPV type grouping scheme, comparing subgenus 2 infections to subgenera 1 and 3 infections is a viable analogue based on biological rationale [29, 31].
Our woman-level estimates of median time to clearance of all infection(s) present at baseline (27.0 months) and clearance of all incident infection(s) (22.3 months) were larger than a meta-analyzed estimate (9.8 months) [11]. In particular, it took women in our study longer, on average, to clear all incident infection(s) compared to an earlier cohort of college-age women in Montréal [19]. Follow-up intervals in the present cohort were spaced similarly to those of the earlier Montréal cohort per protocol (4–6 months vs 6 months, respectively). However, most women attended follow-up visits late in the present cohort, so interval censoring may have prolonged the time to infection clearance. In HPV-level analyses, the median duration of infections of any HPV type was similar between incident and present-at-baseline infections. However, incident infections were more prone to right censoring, so we cannot rule out the possibility that women were under observation for an inadequate period to clear incident infections.
Among women with infections at baseline, we observed a lower woman-level clearance rate and longer median time to clearance of all subgenus 2 infection(s) compared to subgenera 1 and 3 infection(s). A meta-analyzed estimate [11] and several longitudinal studies specific to young women [4, 14, 17–19] corroborate lower clearance rates for high-risk versus low-risk HPV types. However, in our HPV-level analyses, we did not observe systematic differences in the persistence of high oncogenic risk subgenus 2 infections compared to low oncogenic risk subgenera 1 and 3 infections, as indicated by clearance rate and median time to clearance. This was the case for both incident and present-at-baseline infections. It is unlikely that these results are an artefact of disproportional censoring, because subgenus 2 infections were no more right censoring prone than infections belonging to other subgenera. As a stark outlier from our HPV-level time-to-event estimates for subgenus 2 infections, it is worth noting HPV16's high prevalence, high detection rate, low clearance rate, and long average duration, consistent with previous studies [11, 12, 14–16, 18–21].
Our results suggest that natural history estimates using woman-level grouped analysis strategies are influenced by the number of HPV types included in the grouping under consideration. Groupings that contain more types may artificially raise the rate of detection and lower the rate of clearance. Detection may appear to occur frequently in groups containing larger numbers of HPV types because the event is more probable. When infections with multiple HPV types are present simultaneously, a single clearance event requires a woman to test synchronously negative for all previously present infections, which is less probable in groups containing more types. Past studies have generally genotyped more high- than low-risk HPV types, which may have contributed to a similar conundrum. In contrast to woman-level analyses, type-specific HPV-level analyses treat the detection/clearance of each unique infection as a separate event of equal probability (assuming the null hypothesis: infections belonging to different taxonomic groupings are detected/cleared at equal rates). As an illustration of this phenomenon, groupings containing larger numbers of HPV types produced increasing woman-level detection rates per 1000 woman-months: subgenera 1 (11.4; 6 types), 3 (12.4; 8 types), and 2 (17.0; 22 types), and any HPV (20.0; 36 types). At the HPV-level, the corresponding detection rates per 1000 infection-months (2.4, 2.0, 1.7, and 1.9) were homogenous. Similarly, groupings containing larger numbers of HPV types produced decreasing woman-level rates of clearance per 1000 woman-months for infection(s) present at baseline: subgenera 1 (56.6), 3 (45.8), and 2 (27.4), and all HPV (23.6). At the HPV-level, the corresponding clearance rates per 1000 infection-months were homogenous for present-at-baseline (65.8, 61.0, 60.5, and 61.3) and incident (43.4, 46.6, 47.1, and 46.2) infections.
The limitations of this study relate to infection latency, transmission timing, HPV DNA deposition, interval censoring, and estimation of the mean time to detection. First, HPV latency muddles assumptions defined in our analytical frameworks. We attempted to maximize infections acquired during current sexual relationships in analyses of incident infections by including only women/HPV types that were negative at baseline. However, latent reactivation has the same HPV positivity signature as incident detection, and the transition of infections into a latent state has the same signature as clearance. While latency and genuine natural history events are impossible to distinguish, we previously estimated that in the HITCH study, up to 39% of incident infection detections are attributable to latent reactivation [36]. To counter the effects of latency, we performed more stringent analyses that reject single-visit reactivation (ie, double detection) and single-visit latency (ie, conservative clearance) as events. Secondly, we attempted to maximize infections acquired during previous relationships in analyses of infections present at baseline by including only women/HPV types that were positive at baseline. However, these infections may have been transmitted by the current male partner in the ≤6 months of sexual activity allowed before baseline. Thirdly, although women were asked to refrain from sex for 24 hours before providing specimens, a substantial proportion of samples may be false positives as a result of HPV DNA deposition from a male partner [37]. Fourthly, due to interval censoring, discrete times assigned to all HPV results surpass true viral infection and clearance. Our analyses overestimate the times at which incident infections are acquired and present-at-baseline infections are cleared. The time elapsing between detection and clearance of incident infections could be over- or underestimated, depending on the extent of (predetection) left and (postclearance) right censoring. Interval censoring may have also bypassed transient infections (decreasing detection rates) and overlooked clearances that occurred before a subsequent HPV positive follow-up visit (increasing average time to clearance). Finally, according to our sensitivity analyses, actuarial mean times to detection were unreliable estimates as a result of heavy right censoring [38]. Fortunately, the actuarial mean was a reliable indicator of average time to clearance.
We described the incidence and clearance of vaginal HPV infections in young women shortly after initiating a heterosexual relationship. Woman-level grouped analyses appeared to be influenced by unequal numbers of HPV types between comparator groups. HPV type-specific estimates from our analyses of individual HPV types and our HPV-level grouped analyses provide descriptive natural history estimates for cervical cancer prevention planning. Notably, our HPV-level estimates did not clearly indicate that high oncogenic risk subgenus 2 infections are more persistent than their low oncogenic risk and commensal subgenera 1 and 3 counterparts.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Supplementary Material
Contributor Information
Andrew W Arthur, Division of Cancer Epidemiology, McGill University, Montréal, Québec, Canada.
Mariam El-Zein, Division of Cancer Epidemiology, McGill University, Montréal, Québec, Canada.
Ann N Burchell, MAP Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St.Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
Pierre-Paul Tellier, Department of Family Medicine, McGill University, Montréal, Québec, Canada.
François Coutlée, Département Clinique de Médecine de Laboratoire, Service de Diagnostique Moléculaire, Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada.
Eduardo L Franco, Division of Cancer Epidemiology, McGill University, Montréal, Québec, Canada.
Notes
Acknowledgments. We thank the volunteer participants and employees of the HITCH cohort study, as well as the staff of the Student Health Services Clinics at McGill and Concordia Universities. We also thank Cassandra Laurie, Samantha Morais, Suganthiny Jeyaganth, and Talía Malagón for their guidance in selecting and operationalizing statistical analyses.
Author contributions. E. L. F. and A. N. B. designed HITCH and obtained funding. E. L. F. was the principal investigator for the study. A. N. B. oversaw recruitment, data collection, provision of HPV test results to participants, and database design. P. P. T. oversaw clinical activities and recruitment. F. C. supervised laboratory analyses and the quality of polymerase chain reaction assays. M. Z. and A. N. B. managed the HITCH database. A. W. A., under the supervision of M. Z. and E. L. F., performed statistical analyses and drafted the manuscript. A. N. B. provided statistical analysis consultation. All authors read, provided feedback, and approved the final manuscript.
Disclaimer. The funders played no role in study design, data collection/analysis, preparation of the manuscript, or the decision to submit it for publication.
Data availability. HITCH participant consent forms specified that data would be published in aggregate form and that individual-level data would only be available to study investigators. To access individual-level data, please contact E. L. F. (eduardo.franco@mcgill.ca). The protocol for the HITCH cohort study has been published [24]. Analytical codes and data dictionary are available on the McGill University Dataverse [39].
Presented in part: McGill University, Department of Oncology Seminar, Montréal, QC, Canada (March 2022); 22nd Annual McGill Biomedical Graduate Conference, Montréal, QC, Canada (March 2022); McGill University, Celebration of Research and Training in Oncology, Montréal, QC, Canada (June 2022); and Canadian Society for Epidemiology and Biostatistics Conference, Halifax, NS, Canada (June 2023).
Financial support. This work was supported by the Canadian Institutes of Health Research (grant number MOP-68893 and team grant number CRN-83320 to E. L. F.); and the US National Institutes of Health (grant number RO1AI073889 to E. L. F.). A. N. B. is a Canada Research Chair in Sexually Transmitted Infection Prevention and a recipient of a University of Toronto Department of Family and Community Medicine Non-Clinician Scientist award. A. W. A. received a graduate stipend from the Gerald Bronfman Department of Oncology, McGill University and a presenter's award from the Experimental Medicine Graduate Students’ Society, McGill University. A. W. A. thanks Dr Vera Hirsh for her contributions to his stipend on behalf of the Hirsh and Schulman Education Fund. Supplementary and unconditional funding support was provided by Merck-Frosst Canada and Merck & Co.
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