Two prophylactic vaccines against human papillomavirus (HPV) infection are now available: a bivalent and a quadrivalent vaccines. Although both vaccines are effective against HPV 16 and 18, the types causing 70% of cervical cancer,1 the quadrivalent vaccine is also effective against HPV 6 and 11, responsible for 85% of anogenital warts.1 Policymakers and clinicians are being asked to make recommendations regarding which vaccine should be used in public programs. As only the quadrivalent vaccine protects against anogenital warts, the burden of this disease will be a determining factor in the relative cost-effectiveness of the 2 vaccines. Furthermore, given that the quadrivalent vaccine has been licensed for use in males,2 the burden of anogenital warts will be considered when making decisions about vaccinating males against HPV.
Although the epidemiologic and economic burden of anogenital warts has been described for several countries,3–8 data are scarce regarding the burden from the patient's perspective. A small number of studies have shown a negative psychosocial impact of having anogenital warts.5,9–12 However, these studies recruited convenience samples of patients from a single sexual health clinic5,9,10,12 or by advertisement in the media.11 Moreover, none of these studies followed subjects across time to assess the evolution of the psychosocial impact of having anogenital warts and to prospectively estimate the quality-adjusted life-years (QALYs) lost due to anogenital warts, which is essential for cost-effectiveness studies of HPV vaccination.
We undertook the first multicenter prospective study to describe the impact of anogenital warts on the quality of life of men and women seeking medical care for this condition. The first article published about this study presented the impact of anogenital warts on the quality of life of subjects at recruitment,13 whereas the main objective of this article was to assess this impact over time. More specifically, the objectives of the current analyses are to (1) assess the change over time in the impact of anogenital warts on quality of life and (2) prospectively estimate the QALYs lost due to anogenital warts.
Participants and procedures have been previously described.13 Briefly, between September 2006 and February 2008, 42 physicians across Canada (34 general practitioners, 2 obstetrician/gynecologists, 5 dermatologists, and 1 infectious disease specialist) recruited men and women who were aged ≥18 years, with a first or recurrent episode of anogenital warts. Participants provided written informed consent. The study was approved by the Canadian SHIELD Ethics Review Board and the College of Physicians and Surgeons of Alberta.
At recruitment, the physician documented the severity (from 0, “very mild” to 7, “very severe”), duration of the current anogenital warts episode, and whether it was a first or recurrent episode. For recurrent episodes, physicians reported the number of reactivations and past treatment.
Participants were asked to complete 3 self-administered questionnaires at recruitment, and after 2 and 6 months. The baseline questionnaire asked for detailed information on sociodemographic characteristics, sexual activity, and history of anogenital warts, such as date of onset, time between onset and first consultation. All 3 questionnaires included questions on treatment, lesions severity (from “0,” no warts to “7,” worst warts have ever been), quality of life, mental health, and anogenital wart-specific burden.
Main Outcome Measures
Quality of Life and Utilities.
Quality of life was assessed using the EuroQol (comprised of a descriptive system [EQ-5D] and a visual analog scale [VAS]) and the Short-Form (SF)-12. The EuroQol is a utility instrument widely used in cost-effectiveness analysis that can be used as a generic measure of quality of life.14 Canadian population norms are available for this instrument,15 which permits external comparisons. For the VAS, participants rated their current health state on a scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).16 The EQ-5D descriptive system consists of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.14 Subjects indicate their level of problems in each dimension (no problem, some problems, or severe problems). The combination of the answers to the 5 dimensions results in 243 different health states. We used the British scoring system to translate the health states of study participants into utility scores ranging from 0 (worst health) to 100 (perfect health).17 The SF-12 is also a multipurpose generic measure of health status,18 and similar to the EQ-5D and the VAS, it can be used to estimate utility measures (SF-6D).
Because previous studies indicated that anogenital warts had an impact on mental health, we specifically assessed this health domain with the (1) SF-36 mental health scale19 and (2) short version of the Spielberg State-Trait anxiety Inventory-6,20 widely used to measure state anxiety in adults. Canadian population norms are available for the SF-36 mental health scale.21 However, because there are no Canadian population norms for the State-Trait anxiety Inventory-6, we used population norms from Sweden,22,23 and data (adjusted for sociodemographic and sexual activity characteristics) from a parallel study using similar instruments in which women with a normal Papanicolaou smear were recruited across Canada to provide reference values.24
Anogenital Wart-Specific Psychosocial Burden.
The anogenital wart-specific psychosocial burden was assessed with the HPV impact profile (HIP), a questionnaire developed to capture the burden associated with HPV-related diseases.25 The HIP contains 29 items that can be grouped into 7 different scales and has demonstrated good psychometric characteristics among subjects with HPV-related conditions.25
We used growth curve analysis with general linear model26 to describe the change in all outcomes over time and compare this change between different subgroups of subjects. Growth curve models are particularly useful to describe the change in an outcome as a function of time. These models take into consideration the correlation between the different measures of the outcome over time for one individual, and because time is conceptualized as a continuous variable, the exact timing of measurement is considered. Finally, by including an interaction term between time and the different subgroups in the model, it was possible to simultaneously assess the effect of time on the quality of life outcomes and the effect of the different subgroups (e.g., men vs. women; first vs. recurrent episode) on these outcomes.
Using the question on the current state of anogenital warts available in the 3 questionnaires, we considered that subjects' lesions had cleared up during follow-up study if they reported a score of 0 in at least one questionnaire and continued to report the absence of lesions in the subsequent questionnaire(s) (if any). We used Kaplan-Meier curves to estimate the proportions of subjects whose lesions cleared up during follow-up period. We assessed the changes over time in quality of life according to whether subjects had lesions that had cleared up during follow-up. In this way, we could verify whether (1) quality of life returns to normal levels once lesions have cleared up and (2) quality of life remains impaired throughout the episode.
The QALYs lost as a result of anogenital warts is the sum of overall impairment in quality of life over the duration of the episode. Previously, we have shown that the impairment in quality of life due to anogenital warts at recruitment was independent of sociodemographic characteristics, and delay between disease onset and recruitment (Appendix 1, Supplemental Digital Content, online only, available at: https://links.lww.com/OLQ/A23, and Senecal et al.13). However, including prevalent cases may overestimate the duration of anogenital wart episodes and thus QALYs lost. For this reason, we restricted QALYs lost calculations to the 51 incident cases with a first episode of anogenital warts and recruited within 90 days of disease onset. To estimate the QALYs lost during the follow-up study, we used our general linear model to first calculate the difference in the quality of life of subjects with anogenital warts and age/gender adjusted population norms (i.e., impairment in quality of life or utility difference) and then to aggregate these differences over time. To estimate the QALYs lost between onset of anogenital and recruitment, we assumed that quality of life decreased linearly from the value of Canadian norms to the quality of life measured at recruitment. The EQ-5D was our main utility outcome and the Canadian norms, our reference value. We verified that our results were consistent with the VAS and when using population norms from the United Kingdom and the United States.
The characteristics of subjects are summarized in Table 1 and have previously been presented in detail.13 A total of 272 eligible subjects were recruited, 74% completed all 3 questionnaires and 92% completed at least 2 questionnaires. The median delay between the first time subjects noticed they had anogenital warts and their first consultation for this condition was much longer for men (76 days) than for women (30 days) (P < 0.0001).
Evolution of Anogenital Warts During Study Follow-Up
All patients were treated and 50% received at least 2 different types of treatment. The most frequent treatments were cryotherapy and Aldara/Imiquimod. At the end of follow-up, 51% of subjects still had anogenital warts (Table 2). This proportion was significantly higher for men (68% for first episode; 59% for recurrent episode) than for women (41% for first episode; 39% for recurrent episode) (P = 0.003 and 0.01). However, the mean severity of anogenital warts among subjects whose lesions had not cleared up at different time points was similar for men and women (P > 0.28) and did not vary significantly over the 6-month follow-up (Table 2).
Impact of Anogenital Warts on Quality of Life
Quality of Life and Mental Health.
The psychosocial impact of having a first or recurrent episode was similar and we therefore present aggregated results. At recruitment, having anogenital warts had a significant impact on usual activities, pain/discomfort, and anxiety/depression (Fig. 1). Compared with age-matched Canadian norms, anxiety/depression was the most affected domain in women (29% more women with anogenital warts reported these symptoms), whereas pain/discomfort was the most affected domain in men (20% more men with anogenital warts reported pain/discomfort). The 3 health domains affected at recruitment remained significantly altered over time for subjects who still reported lesions at the end of follow-up, but they returned to normal levels for those whose lesions had cleared up. Similar patterns of change over time were observed with the overall measures of quality of life and mental health (Table 3).
Anogenital Wart-Specific Burden.
The HIP domains most affected by anogenital warts were self-image, sexual activity, and worries about partner and possible transmission (Fig. 2). Men consistently reported significantly lower mean values than does women (at baseline, P < 0.05, except for sexual impact with P = 0.26). However, the ranking of the domains was similar for men and women. The mean scores of all domains were generally lower at the end of follow-up for subjects whose lesions had cleared up, whereas they remained unchanged for subjects with persistent disease (Fig. 2, Table 3).
QALYs Lost Due to Anogenital Warts
The median duration of an anogenital warts episode amongst the 51 incident cases was 125 days (Appendix 2, Supplemental Digital Content, online only, available at: https://links.lww.com/OLQ/A23). This resulted in an average QALY loss of 0.017 to 0.041, equivalent to 6 to 15 days of healthy life lost, depending on the delay between disease onset and recruitment (Table 4).
Our results indicate that anogenital warts had a negative impact on the quality of life for both men and women. This impact was as important for a first or recurrent episode, and persisted as long as disease persisted. The domains of usual activities, pain/discomfort, and anxiety/depression were particularly affected. Moreover, having anogenital warts had the greatest impact on self-image, sexual activity, and worries about partner and transmission. The QALYs lost due to anogenital warts among incident cases (0.017-0.041) were equivalent to 6 to 15 days of healthy life lost.
To our knowledge, this is the first study to prospectively estimate the QALYs lost due to incident anogenital warts, which is essential to assess the cost-effectiveness of vaccination. At recruitment, the difference in EQ-5D scores between subjects with anogenital warts and population norms exceeds a proposed cutoff of 0.07 for clinically meaningful differences in EQ-5D27,28 and is slightly higher than previous estimates (0.04–0.06).10,11 When aggregating the differences over time, our QALYs estimates among incident cases (0.017–0.041 equivalent to 6–15 days of healthy life lost) are at the upper limit of previous estimates (2–8 days) obtained with cross-sectional data,5,10 although they are likely to be underestimated given that not all subjects had cleared their anogenital warts at the end of follow-up study. Given that our QALYs lost are estimated among cases that seek care, in their base case analysis, cost-effectiveness studies should apply these QALY losses to the predicted number of cases that seek care rather than all anogenital warts episodes.
Our sample of 127 men recruited across Canada contributes significant knowledge about the experience of having anogenital warts from the men's perspective. Although one previous study was restricted to women,12 the other cross-sectional studies recruited small sample of men in a single clinic (n = 43)10 or from advertisement in the media (n = 36).11 Interestingly, our results indicated that the delay between the first time men noticed anogenital warts and its diagnosis was more than double of women. This observation has been previously reported29,30 and is supported by other studies on differences in health-seeking behavior between men and women.31 Men are often slower at noticing signs of illness and even when they do, they delay seeking health care.31,32 These observations might partly explain why fewer men cleared their anogenital warts during follow-up.
Although we used an improved recruitment procedure compared with previous studies,9–11 the main limitation of our study remains the possibility of selection bias. To make large-scale recruitment feasible and to reproduce real-life clinic conditions, we imposed minimal additional workload on recruiting physicians beyond that needed to treat their patients. For this reason, participation was not necessarily offered to all eligible patients and the proportion of eligible patients who declined participation was not documented. However, the mean age of our participants was similar to the mean age at diagnosis of a first episode of anogenital warts in population-based data from Canada (men = 30 years and women = 28 years),33 and the duration of anogenital warts was longer for men than women as previously reported.3,33 Also, as including prevalent cases would have overestimated duration of anogenital warts and thus QALYs lost, we restricted our QALYs lost calculation to the 51 incident cases. Importantly, the median duration of an episode among our incident cases of 125 days was similar to the most valid estimate in the literature of 180 days (interquartile range, 118–244).34 Although inclusion of prevalent cases would have biased our estimates of QALYs lost, they had no impact on the impairment in quality of life (i.e., impairment was independent of time since disease onset; Appendix 1, Supplemental Digital Content, online only, available at: https://links.lww.com/OLQ/A23).
Even though the use of population norms to estimate the impairment in quality of life is common practice and is recommended by the National Institute for excellence,35 it nonetheless represents a limitation. When using Canadian population norms, the analysis can only be adjusted for age and gender, whereas other factors can be confounders. For example, factors that increase the risk of getting anogenital warts might also decrease the quality of life. Consequently, the differences observed in the quality of life of subjects with anogenital warts and the general population might be partly attributable to these factors rather than to anogenital warts. However, we have previously reported an extensive sensitivity analysis showing consistent results obtained with additional adjustment for potential confounders available with the US norms which are also risk factors for anogenital warts (family income, education level, ethnicity, current smoking, and marital status).13 In addition, the quality of life of our cases, once lesions have cleared, is very similar to Canadian norms.
In conclusion, given that the lifetime probability of consulting for anogenital warts is 6.5%,33 and the negative psychosocial impact of anogenital warts is significant and persists throughout the episode, the population-level burden of anogenital warts is likely to be substantial. This burden should be considered by physicians and public health officials when making recommendations about HPV vaccination.
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