Comorbidities associated with HPV infection among people living with HIV-1 in the southeastern US: a retrospective clinical cohort study

Human papillomavirus (HPV) is a common sexually transmitted infection (STIs) in the general population and specifically among people living with HIV infection (PLWH) [1, 2]. While the infection is treatable, it has chronic sequelae including development of cancer [3]. In 2013–2014, the prevalence of anogenital HPV infection was estimated at 42.5% among US adults aged 18–59 years [4]. There were more than 14 million new diagnoses during this period [4]. Genital HPV infection is 1.5–2.5 times higher in HIV-positive (HIV+) women than HIV-negative (HIV-) women. HIV+ women have higher HPV acquisition, lower HPV clearance, higher incidence of low- (LSIL) and high- grade squamous intraepithelial lesions (HSIL) [5]. HPV prevalence is higher in HIV+ women than in HIV- for all cervical cytology group [6, 7]. Anal HPV infections among HIV+ women and MSM are 3 times higher than their HIV- counterparts [8‐10].

HPV infection is common in the US, with over 80% of sexually active individuals being infected at least once during their lifetime [2]; however, most resolve on their own within 2 years. There are 12 types of low-risk HPV (LR-HPV) and at least 13 types of high-risk HPV (HR-HPV) [11]. LR-HPV cause warts and very mild cell changes in infected tracts, whereas persistent infection with HR-HPV cause LSIL and HSIL that can progress to cancer [12]. Over 99.7% of cervical is linked to HR-HPV infection [2]. Additionally, other anogenital cancers, including 95% of anal, 65% of vaginal, 50% of vulvar, and 35% of penile cancers are linked to HR-HPV infections [13]. HPV-associated cancers are diagnosed in 17,600 women and 9300 men every year in the US [14].

In the state of Alabama, racial disparities in new HIV infections and STDs have been documented; black women and men are highly susceptible to incident HIV [15]. While the epidemiology of HIV infection in Alabama is well-studied and reported, HPV-related clinical conditions (CC) among PLWH have not been comprehensively characterized. Neither the country nor the state of Alabama implements mandatory screening programs for anogenital HPV-related (excluding cervical cancer) conditions. Therefore, there is a substantial lack of knowledge of the comorbidities among PLWH. In this study, we retrospectively studied PLWH at risk of HPV- CC for over 12 years from the patients in the University of Alabama at Birmingham (UAB) 1917 Clinic, an academic institute with the largest HIV patient catchment in Alabama, and estimated HPV-CC incidence rates and comorbidity trends.

A total of 4803 PLWH attended the 1917 Clinic between January 1st 2006 and March 30th, 2017, however, 4484 patients met the inclusion/exclusion criteria (Fig. 1) with 3429, (76.5%) men, 1031 (23.0%) women, and 24 (0.5%) transgender individuals, 2676 (59.7%) blacks, 1632 (36.4%) whites, and 176 (3.9%) others. Among all the eligible participants, 1038 (23.1%) presented HPV-related CC (Table 1). The mean ages at the time of HPV-related CC presentation over the study follow-up were 41.8 (±10.6) years. The mean log10 VL (copies/mL) was higher in patients with HPV-CC compared to the non-case group, however the difference was not significant. The median nadir CD4 counts (cells/uL) were statistically higher in the non-cases (333, IQR: 139–853) than in patients with HPV-CC (237 [IQR: 72–701). Compared with women, men had much higher rates of HPV-related warts, anal LSIL, anal HSIL, and anal HPV-related cancer (P < 0.0001 for each comparison, Table 2). Overall, whites were more likely to be diagnosed with anal LSIL and cancer (P < 0.05, Table 2). Among women, whites were more likely to present cervical HSIL and cervical, vaginal and vulvar LSIL (P < 0.0001 for each comparison). HIV+ men had a higher rate than women to present anogenital warts (IR 190.4 vs 68.5 per 10,000 person-years), anal LSIL (188.2 vs 14.7 per 10,000 person-years), anal HSIL (43.2 vs 5.5 per 10,000 person-years), and anal cancer (25.8 vs 0 per 10,000 person-years) (Table 2). White men presented more frequently with anal LSIL and anal and penile cancers than black men (P < 0.03 for each comparison) (Table 2). MSM accounted for 54.9% of the total study population, and 62.5% of total HPV diagnoses made during the study period were attributed to them, with 14, 15.8, 2.8, 1.5, 0.17, and 0.12% diagnosed with warts, anal LSIL, anal HSIL, anal cancer, penile cancer, and Bowen’s disease, respectively.

HPV-related anogenital warts showed significant upward trends in both genders (AAPC: 19.5, P < 0.0001) and races (AAPC: 20.4, P < 0.0001) (Fig. 2). However, there were no distinct patterns between these two trends (P > 0.05 for test for parallelism, Table 3). The AAPC of anal HSIL among black men also showed an increasing incidence trend (AAPC: 25.6, P < 0.0001). Cervical HSIL and cancer did not show significant changes over time, but APC gave the joins that reflected periodic changes between 2006 and 2013 and 2016–2018 (P < 0.05 for each period) (Table 3, Fig. 3).

The present study indicate that HPV-related CC, particularly anal lesions and cancer were observed more in HIV+ men than women in the region. The incidence rate of anogenital warts constantly increased over the study period. Although cervical HSIL did not have monotonic trends, significant periodic increases in trends were detected. Although crude rates were reported, we computed the age-adjusted rates for warts, which did not generate 0 case over the follow-up. The alternative rates were similar to our results (data not shown). These observations and trends have never been reported in a clinical setting and this study with sufficient follow-up provides the broader scenario of these conditions among PLWH in the area. Our findings attempt to help clinicians better understand the burden of these comorbidities and drive better care in clinical settings.

HPV-related conditions were observed predominantly in men as compared to women. HIV+ men had almost a 3-fold greater risk of anogenital warts compared with women (Table 2), with no racial disparity observed. The trend of warts, however, increased approximately 20% each year (Table 3) regardless of gender and race. HIV+ men were also 8 and 25 times more likely to be diagnosed with anal HSIL and cancers, respectively, than HIV+ women (Table 2). However, in the general US population, HPV-related anal lesions and cancers are observed more in women than men [22]. There is a huge gap in screening guidelines for non-AIDS defining comorbidities, such as HPV-related anal precancerous lesions and cancers. Only women are currently screened for anogenital HPV-infection through the cervical cancer screening program [23]. The present study consisted of 76% men with limited anal cancer screenings. MSM were particularly susceptible for HPV-related CC. MSM are known to have an elevated risk of HIV acquisition. HIV+ MSM tend to be more likely infected with other STIs, such as HPV [24]. The study population consisted of 54% MSM, while they contributed to 62.5% total incident HPV diagnoses during the study period. That accounted for 72.2, 81.4, 92, 83.7, 100, and 50% of warts, anal LSIL, HSIL, and cancer, penile caner, and Bowen’s disease, respectively.

One of the largest HIV cohort, Multicenter AIDS Cohort Study (MACS), reported an overall incidence rate of anal cancer of 7 per 10,000 person-years among HIV+ MSM between 1984 and 2006 [25]. The finding from our study was over 3-fold greater than that rate (IR = 25.8 per 10,000 person-years among men) between 2006 and early 2018. In spite of the better immune status of PLWH in our cohort compared to MACS, specifically before ART regimen in 1996 [25], the median nadir CD4 counts were still significantly lower in patients with HPV-related CC than the non-cases (Table 1). Further, the rates of anal lesions and cancers increased exceptionally compared to the MACS. Geographically, the MACS, which predominantly includes white MSM, did not include a site in the Deep South of the US, and our findings provide evidence of higher trend in our self-reported MSM sub-population. Overall, there have not been many studies conducted among black MSM in the south regarding HIV and HPV comorbidities.

Although, we did not observe a monotonic trend of cervical HSIL or cancer, we were able to identify the periodic changes. For example, both conditions seemed to be growing in numbers of new diagnoses between 2016 and 2018 (Table 3) in both races. However, we have to take the screening programs implemented into account. In March 2016, the US Health Resources and Services Administration issued new screening guidelines for cervical cancer among HIV+ women, which included both cytology pap smears and serologic testing [23]. As an academic clinic, the UAB 1917 Clinic actively advocates HPV-related screenings for HIV+ women. The implementation of the new screening program could temporarily boost the number of new diagnoses of HPV-related cervical lesions and cancers. However, it does not necessarily mean an increase in cervical HPV infections.

This southeastern US region bears a heavy public health burden of HIV and STDs [26]. According to the US CDC’s national statistics, the incidence rates of HPV-related CC in our study were much higher among PLWH than the general population [2]. Although HPV infection is not curable if it persists, interventions may alleviate symptoms and prevent the HPV-related neoplasia. We had a long clinical follow-up in this clinical cohort, which allowed us to estimate incidence rates, while most other studies were only able to report incident HPV-related CC as percentages of new cases among PLWH. We specifically used the Joinpoint regression analysis to examine trends, which enabled us to report the statistical significance of changes in trends as well as compare trends between different sexes and races. However, we are aware that crude incidence rates were used for trend analysis, because log transformed Joinpoint regression model was conducted. Although PLWH are at higher risks of HPV-related anogenital conditions compared to the general population [1], most of these HPV-related HSIL and cancers were still not common among them. In order to normalize the distribution of the diagnosed cases over the study period, a log transformed rate model needs to be adopted. However, we would only be allowed to the log transformed models if there were cases presented every year throughout the follow-up. The JTAS would automatically add 0.5 if certain years have 0 cases. However, this procedure may be hard to achieve if age-adjusted rate is expected, because the addition of 0.5 is not recommended by the program in such scenario [17].

It is important to note that clinical diagnoses were based on patient willingness to seek medical attention. Unlike cervical cancer screening, anogenital screenings and examinations, especially for warts are not routinely performed in most clinical settings and are primarily recommended by providers and thus could reflect potential bias. In addition, since most of these infection related conditions except for cervical cancer are non-AIDS-defining, and hence, the Ryan White funding program provides limited coverage in the clinic. While this can under-estimate the number of cases, with a pro-active screening approach in this academic clinic setting, our estimated incidence shows a substantially higher rate than the estimates from the previous HIV studies. Diagnoses of HPV-related anogenital conditions are often initiated from physical presentations of warts and lesions. It is common practice to make prompt diagnoses and immediate treatment for most HPV-related CC without testing for viral infections.

Our findings show that PLWH are at higher risks for anogenital HPV-related CC. However, screening for these conditions is not routinely conducted in clinics. Additional studies in southeast and other regions of US would be helpful to understand the epidemiology and trend of these conditions in PLWH. The present study attempts to provide information about these understudied conditions to guide screening and prevention strategies in clinical practices.