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Original Studies

Recurrence of Human Papillomavirus External Genital Wart Infection Among High-Risk Adults in Montréal, Canada

Thomas, Réjean MD*; Steben, Marc MD; Greenwald, Zoë MSc*; Stutz, Melissa BSc; Rodier, Caroline MPH§; DeAngelis, Fern MSc§; Rampakakis, Emmanouil PhD

Author Information
doi: 10.1097/OLQ.0000000000000666
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Human papillomavirus (HPV) is a highly contagious virus transmitted through oral, anal or genital sexual contact, or through nonpenetrative sex involving skin-to-skin contact.1,2 It is the most frequently transmitted viral infection in the world, affecting an estimated 70% of sexually active individuals at one point in their lifetime.3 Before the introduction of the HPV quadrivalent vaccine, half of new HPV infections occurred in young adults aged 15 to 24 years.2,4 However, the post-HPV vaccination era has seen a shift in demographic incidence rates: in Quebéc, 83.5% of 17- to 19-year-old females have been vaccinated against HPV compared with only 19.1% of 23- to 29-year-olds, translating into prevalence rates that increase with age from 31.7% in women aged 17 to 19 years compared to 47.6% in women aged 23 to 29 years.5

Of the over 120 HPV genotypes identified, about 40 are capable of infecting the anogenital track, and are categorized into low and high risk based on their capacity to induce malignancy.2,6,7 Low-risk genotypes are associated with non-cancerous HPV-related conditions, such as external genital warts (EGW), and recurrent respiratory papillomatosis,8 and have also been identified as a minor risk factor for the development of anogenital cancer.9 EGWs are caused, in 90% of cases, by infection with the low-risk genotypes HPV-6 and HPV-11.10 In Canada, the annual incidence of new diagnoses of EGWs has been estimated between 113.3 and 154.0 per 100,000 men and 94.6 to 121.0 per 100,000 women.4,11,12 Known risk factors for EGW include those for HPV infection, in addition to male gender, unprotected intercourse, history of other sexually transmitted infections, use of long-term oral contraceptives, and smoking.13 Conversely, HPV infection has also been found to be associated with increased risk of HIV seroconversion in high-risk populations.14 In addition to causing pain and discomfort,2,6 EGWs may also result in high levels of psychological and social morbidity, with patients reporting guilt, shame and loss of self-esteem, depression, and anxiety.15 Furthermore, the majority of EGWs recur within 3 months of clearance, regardless of treatment administered,2 with recurrence rates observed in clinical trials and observational studies of EGWs variable, ranging from 26% to 67%,16 depending on the therapy used. As such EGWs, especially recurrent episodes, may have a negative impact on relationships, including a patient’s sex and love life, as well on overall quality of life.6,17 This psychological morbidity, although significant, is often overlooked.18

Although data on the incidence and prevalence of genital warts (GWs) are well defined, few studies have specifically assessed the incidence of EGW recurrence and the associated burden of illness.19 This is especially true in the post-HPV vaccination treatment landscape. The purpose of this study was to address this knowledge gap in a population of high-risk patients with documented first episode EGW followed, as per routine clinical care, in a sexual health clinic.

METHODS

Study Design and Patient Population

This was a retrospective chart review study conducted at Clinique médicale l’Actuel, a sexual health clinic in Montréal, Québec, Canada. Ethics approval for was obtained from IRB Services, Aurora, Ontario, Canada, and this study was conducted as per the tenets of the Helsinki Agreement.

Patients meeting eligibility criteria were 18 to 45 years of age with first diagnosis of EGW associated with an HPV infection recorded in their medical charts between July 1, 2006, and June 30, 2012. Patient charts were also required to have follow-up information available for at least 1 year subsequent to the diagnosis of the primary EGW episode. Eligible patients were followed up from the time of initial EGW diagnosis at the clinic, until the most recent date with available information. The following parameters were extracted: sociodemographic characteristics, medical history and comorbidities at time of first EGW diagnosis, characteristics of EGW (HPV type, number and location of warts, and treatments used) and risk factors at the time of first and subsequent EGW episodes. A subsequent episode of EGW was defined as the occurrence of a confirmatory genital lesion 3 months or longer after a “complete full destructive” medical intervention (including podophyllin, cryotherapy, trichloroacetic acid, excision) or after the end of pharmacologic treatment (including podophyllotoxin or imiquimod). For patients who did not receive treatment for the first EGW episode, recurrence was established by a confirmatory genital lesion after 3 months or longer of disease-free status. An EGW episode was considered to be resolved (clearance) after 3 months of absence of any genital lesions.

Study Objectives

The primary objective of the study was to assess the incidence rate of subsequent EGW in male and female adults presenting with a first episode of EGW. The secondary objectives of the study were to assess time to occurrence of the first subsequent EGW episode; clinical manifestations of first and subsequent EGW episodes; time to clearance of the first episode; and the burden of illness associated with subsequent EGW episodes, including the number of subsequent episodes per person time and the type and number of interventions used for treatment of EGW.

Statistical Analyses

Assuming incidence of a subsequent EGW episode equal to the midpoint of that previously reported in the literature (26% to 67%),16 that is, 46.5%, the inclusion of 380 patient charts was decided to produce a precision of ±5% for the study estimate.

Descriptive statistics were produced for all study variables, including mean, median, standard deviation, and 95% confidence interval (CI) of the mean for continuous variables, and frequency distributions for categorical variables. The cumulative risk of subsequent EGW was calculated as the proportion of patients having at least one subsequent episode, and the incidence density rate was calculated as the number of subsequent EGW episodes per 100 patient-years. Descriptive statistics were used to assess sociodemographics, comorbidities, risk factors and EGW disease characteristics (including number of warts, HPV genotype, and treatment used) reported by the entire cohort at the time of first EGW diagnosis. EGW disease characteristics and risk factors were also assessed at all subsequent episodes. MedDRA (version 16.0) and WHO Drug Dictionary classifications (version 2014) were used to code medical conditions and medications, respectively. The Kaplan-Meier estimator of the survival function was used to describe time to occurrence of the first subsequent EGW episode and time to clearance of the first episode. All analyses were performed on the Full Analysis Set (FAS) using SAS version 9.4.

RESULTS

Demographic and Patient Characteristics

A total of 400 first-episode EGW cases were extracted from patient medical charts between July 1, 2006, and June 30, 2012. At the time of diagnosis of the first EGW episode, mean age of the patient population was 28.5 ± 6.5 years, and the majority of patients were male (n = 306; 76.5%), white (n = 231; 57.8%) and single (n = 253; 63.3%) (Table 1), with almost half of patients (n = 196; 49.0%) reporting greater than 10 lifetime sexual partners.

T1
TABLE 1:
Sociodemographic Characteristics—First External Genital Warts Episode

Overall, at first EGW diagnosis, 57.8% of patients (n = 231) reported a past/current significant comorbidity, which was ongoing in 61 patients (15.3%). Of these, 54.4% (n = 218) of the patients reported a past/current infection, most frequently herpes virus infection (n = 127; 31.8%), chlamydial infection (n = 71; 17.8%), and gonorrhea (n = 49; 12.2%). Infections ongoing at the date of diagnosis included chlamydia (n = 41; 10.2%), herpes virus infection (n = 10; 2.5%), and HIV (n = 12; 3.0%) (Table 2).

T2
TABLE 2:
Comorbidities at First External Genital Warts Episode

Incidence Rate and ClearanceFirst and Subsequent Episodes

In total, 194 patients reported a first subsequent EGW episode, corresponding to a risk of EGW recurrence of 48.5% (95% CI, 41.5–55.5%). The proportion of patients steadily declined as the number of subsequent episodes increased, from 23% (n = 92; 95% CI, 14.4–31.6%) to 0.3% (n = 1; 95% CI, 0.0–10.0%) of patients reporting a first and sixth subsequent episode, respectively (Table 3). When evaluated by gender, a slightly higher percentage of male patients reported a first subsequent episode (49.0% vs 46.8%), third subsequent episode (9.5% vs 6.4%), and fourth or higher subsequent episodes (5.2% vs 4.2%), whereas 24.5% of females (vs 22.5% of males), reported a second subsequent episode (Fig. 1).

T3
TABLE 3:
Incidence Rate of Subsequent External Genital Warts Episodes
F1
Figure 1:
Incidence of subsequent external genital wart episodes by gender.

Median time to occurrence of the first subsequent EGW episode was 3.97 years (95% CI, 2.59–5.89 years) (Fig. 2A), with 17.0% of patients reporting this subsequent episode within 1 year post-clearance of the first EGW episode. Overall, the incidence density rate of all subsequent EGW episodes was 0.18 per 100 patient-years (95% CI, 0.16–0.20).

F2
Figure 2:
A, Kaplan Meier survival estimates: time to occurrence of the first subsequent external genital warts episode. Mean (95%) and median (95% CI) time to first subsequent episode was 4.52 (4.16–4.89) and 3.97 (2.95–5.89) years, respectively. B, Kaplan Meier survival estimates: time to clearance of the first external genital warts episode. Mean (95%) and median (95% CI) time to clearance was 0.53 (0.39–0.68) and 0.30 (0.17–0.34) years, respectively.

Disease CharacteristicsFirst and Subsequent Episodes

At diagnosis of the first episode, 61.5%, 17.0%, and 8.5% of patients presented with 1 to 5, 6 to 10, and greater than 10 warts, respectively (Table 4). At subsequent episodes, fewer warts were observed, with 71.4% to 81.0% of patients presenting with 1 to 5 warts. The most common anatomical external sites for EGW distribution at the first diagnosis were perianal (n = 168; 42.0%) and penile (n = 118; 29.5%), whereas anal (n = 122; 30.5%) was the most common internal anatomical site. Although slight variation in the proportion of reported site locations was observed across subsequent visits, the predominance of perianal and penile external warts, as well as anal internal warts, remained (Table 4).

T4
TABLE 4:
Disease Characteristics and Treatment—First and Subsequent External Genital Warts Episodes

Regardless of episode, most patients (>95%) were administered treatment for their EGW, with rates attaining 100% at subsequent episodes 3 and 4 (Table 4). Cryotherapy was the preferred treatment, administered to 98.3% of patients receiving treatment for their first episode (n = 393), and to 94.3% to 100% of patients receiving treatment for subsequent episodes. In addition to cryotherapy, 13.2% (n = 53), 5.5% (n = 22), 2.8% (n = 11), and 3.0% (n = 12) of patients were administered imiquimod cream, podophyllin resin, podophyllotoxin, or underwent surgical excision, respectively, for the treatment of their first episode of EGW.

Risk BehaviorFirst and Subsequent Episodes

Table 5 summarizes patient risk behavior at all EGW episodes. The most prevalent risk behavior at diagnosis of the first episode was sexual intercourse without condom use (n = 272; 68%), followed by sexual intercourse with a partner of unknown sexual history (n = 195; 48.8% patients), and same-sex intercourse (n = 129; 32.3% patients). Current smokers and drinkers constituted 13.0% (n = 52) and 21.3% (n = 85) of the patient population, respectively, with non-injectable drug use reported by 19.0% of patients (n = 76), and marijuana use reported by 5.8% (n = 23).

T5
TABLE 5:
Patient Risk Behavior—First and Subsequent External Genital Warts Episodes

At subsequent episodes, the proportion of patients reporting high-risk sexual behavior reduced across all categories. Most notably, the proportion of patients engaging in sexual intercourse without a condom decreased to 44.3% (n = 86/194), 41.3% (n = 38/92), 45.7% (n = 16/35), and 31.3% (n = 5/16) at subsequent episodes 1, 2, 3, and 4, as did the proportion of patients engaging in sexual intercourse with a partner of unknown sexual history (approximately 30% at subsequent episodes 1 [n = 60/194], 2 [n = 28/92], and 3 [n = 11/35], and to 12.5% [n = 2/16] at subsequent episode 4).

Risk behavior related to illicit/nonillicit substance also decreased; the proportion of current drinkers fell to 14.9% (n = 29/194) at the first subsequent episode to less than 7% at the fourth episode (n = 1/16). Non-injectable drug use and marijuana consumption also diminished to approximately 10% and 5%, respectively, at subsequent episodes 1, 2, and 3, with no patients at subsequent episode 4 reporting any drug use.

ClearanceFirst and Subsequent Episodes

Although the majority of the patients cleared their first and subsequent EGW episode(s), rates decreased with increasing number of episodes from 92.8% (n = 371) clearance for the first, to 75.8% (n = 147), 72.8% (n = 67), 60.0% (n = 21) and 68.8% (n = 11) clearance for the first second, third, and fourth subsequent episodes, respectively (Table 5). The median (95% CI) time to clearance of the first EGW episode was 0.30 (95% CI, 0.17–0.34) years (Fig. 2B).

DISCUSSION

In this clinic's patient population, we report patient characteristics which align with known risk factors for EGW, most notably, male predominance, mean age below 30 years, a high number of lifetime sexual partners, sexual intercourse without condom use, as well as a high rate of past/active sexually transmitted infections.20,21 Interestingly, an inverse relationship was observed between subsequent episodes and risk behavior. This was most evident with respect to high-risk sexual activity. Several studies have found that disruption of a patient's social, sex, and love life is often a profound effect of EGWs,17,18,22 holding true in hypothetical scenarios: a 2012 study by Steben and LaBelle used an online survey to assess perceptions and attitudes of 1520 healthy general population of adult Canadians had toward GW.15 Over 40% of participants responded they would “stop having sex until unrecognized spots on their genitals were gone” and over 50% of patients admitted that their self-esteem would dramatically decrease if they were to contract GW.15 Conversely, conscious lifestyle changes concerning sexual relationships have been reported by up to two thirds of patients with GW.23 Nevertheless, these results suggest that EGWs, and especially recurrent EGWs, have a considerable impact on patient behavior, even in high-risk populations.

The results of this study also indicate that proportion of patients receiving treatment for EGWs is high, with cryotherapy administered to approximately 95% to 100% of patients across all subsequent episodes. This is in addition to the use of patient-administered topical modalities such as imiquimod and podophyllotoxin. As cryotherapy, podophyllin, or trichloroacetic acid are necessarily physician-administered, the associated burden of illness related to the management of EGW may also be due in part to the time-off work/school required to visit the doctor’s office. A study by Mortensen and Larsen,18 which assessed quality of life in patients with genital warts, found a major concern was that many patients had to take significant time away from their studies/work that was not easy to explain; this is in addition to associated productivity losses and missed pay.17 Furthermore, EGW treatment modalities, physician- and patient-applied alike, are geared toward lesion destruction, and as such, are associated with adverse events and complications, such as pain, ulceration, blisters, and the development of scar tissue, that understandably impact quality of life.24

Overall, our findings show that half of patients diagnosed with first EWG present with a first subsequent episode within a median of 4 years, and an additional quarter of all patients may experience a second subsequent EGW episode. Due to lack of HPV genotyping data, the nature of recurrence, either due to reinfection with the same HPV genotype, infection with a new HPV genotype or to reactivation of latent virus, cannot be determined. As the majority of EGW recurrences occur within the first 3 months,2 the observed four year interval between the first episode and first subsequent EGW infection, indicates that reinfection may have been the dominant cause of recurrence seen in this high-risk population. Furthermore, only 17.0% of patients reported recurrence within the first year post-clearance. This 1-year recurrence rate is also low compared with the 39% of patients that have been found to recur by month 2 post-cryotherapy.25 Also of interest was the almost 92.8% clearance rate of first EGW episodes, which was slightly higher than what has been reported in the literature for cryotherapy (80–88%).16,25–27 The median time to clearance of the first EGW episode (approximately 4 months) reported here, however, is in line with that previously reported by Drolet et al19 in a Canadian cohort of first-episode genital wart patients.

The discrepancies between the findings presented herein, and previously reported clearance and recurrence rates, however, may be due to the fact that, in this patient population, approximately 99% of patients received cryotherapy for their first episode, with approximately 14% and 6% of patients reporting use of imiquimod and podophyllin use, respectively. This indicates that an aggressive, multimodal approach to the treatment of EGW may be the most effective strategy for eradication of a first episode, warranting further investigation in real-world clinical settings, because data are limited regarding effectiveness and side effects of combination regimens.20

The results of the study must be interpreted in consideration of the known limitations of chart review studies. Specifically, the use of data extracted from medical charts carries a possibility of information bias related to the validity of the data reported, including missing, inconsistent or erroneous information, and the likelihood of human error during transcription. A further limitation of the study was the lack of genotyping data available. As such, HPV as a cause of the first EGW episode and all subsequent episodes may not always have been confirmed by a laboratory and may have been based on clinical diagnosis alone. Lastly, with respect to the time to EGW clearance, the EGW resolution dates ascertained from patient’s charts were based on approximate end-of-treatment dates, and as such may not precisely reflect the true time to clearance.

Despite these limitations, this study assessed recurrence of EGWs in a Canadian clinical setting, providing long-term epidemiological information related to risk factors, clinical manifestations, type of interventions, and frequency of subsequent EGW episodes. In addition, rates of incidence and recurrence reported herein, assessed in a prevaccination Québec health care system, may eventually be compared to future EGW rates to fully assess the impact of province-wide HPV vaccination. In Québec, a publically funded HPV immunization program has been offered to all girls aged 9 to 17 years since 2008 with the quadrivalent Gardasil HPV vaccine. In January 2016, the same vaccine was offered free to all immunocompromised persons and MSMs age of up to the age of 26 years, and since September 2016, the Gardasil 9-valent vaccine has been administered in schools to all grade 4 children.28 Additionally, since 2006, the HPV vaccine has been available privately in clinics and universities to patients 18 years or older, for fee, or through private insurances. In this postvaccination era, incidence rates of HPV infections, genital warts, and low- and high-grade cytological abnormalities, are reportedly declining, both in Canada and worldwide.29,30 As such, further investigation is warranted not only further characterize the effectiveness of HPV immunization in real-world, postvaccination, clinical settings, but also to evaluate the effect on the individual and the society with respect to preventing burden of illness related to EGWs and their subsequent episodes.

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