In the present study, among PLWH visiting a southeastern US HIV clinic between 2006 and 2018, HPV-related CC, particularly anal lesions and cancer were much more frequently diagnosed among men than women. By contrast, the rate of HSV-related ulcers was greatly elevated among HIV+ women compared to men. The incidence rate of anogenital warts constantly increased over the study period. Although cervical HSIL and herpetic ulcers 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 and herpetic ulcers, which did not generate 0 cases 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. Although the sub-population for HPV analyses only had 59.2% MSM, 64.4% of incident HPV cases were diagnosed among them. 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). By contrast, HPV-related anal lesions and cancers are more common in women than men in the general population . There is a huge gap in screening guidelines for non-AIDS defining comorbidities, such as HPV-related anal precancerous lesions and cancers.. The current HPV screening guidelines, the cervical cancer screening program, are only applicable to women . 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 and HSV .
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 . 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, 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 men, did not include a site in the Deep South of the US, and our findings provides evidence of the severity of HPV comorbidities in this high-risk 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 . 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.
In contrast to HPV-related CC, our data suggest that more women with HIV experienced symptomatic anogenital herpetic ulcers than men. Unlike HPV-CC in the present study, the HSV-cohort consisted of 59.8% MSM and 51.8% of them presented incident herpetic ulcers during the follow-up. To our knowledge, only one study has reported that HIV+ men are more likely to develop HSV-related anogenital ulcers . Most published studies implicate that anogenital herpetic ulcerations are more likely to be clinically manifested in HIV+ women [22–24]. Unlike HPV, HSV is not an oncogenic virus and does not generally lead to any fatal disease sequelae. Thus, preliminary studies have usually focused on its serologic impacts on PLWH. In our study, women showed a 1.8x higher incidence rate of anogenital ulcers than men. Similarly, a study in Uganda estimated the prevalence of anogenital ulcers was 1.4 times higher in women, and HIV viremia was found to be higher among people with symptomatic anogenital ulcers (mean log10 VL = 4.4 copies/mL) . A similar association between higher viral load and symptomatic herpetic ulcers was observed in our cohort (mean log10 VL = 5.5 copies/mL, P<0.05 compared with people with neither conditions). This could imply that PLWH with active HIV viral replication were more likely to have outbreaks of symptomatic anogenital ulcers. By contrast, most previous studies only reported the risk of the patients who presented symptomatic herpetic ulcers before they became HIV infected [22–24].
This southeastern US region bears a heavy public health burden of HIV and STDs . The incidence rates of HPV- and HSV-related CC in our study were much higher among PLWH than the general population, based on national statistics. Both infections are incurable, but interventions alleviate symptoms and prevent the HPV-related neoplasia and chronic herpetic ulcers. 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- and HSV-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.
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 are primarily recommended by providers and thus could reflect potential bias. 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. HPV- and HSV- related CC are often initiated from self-reported pain and physical presentations of lesions, warts, and ulcers. It is common practice to make prompt diagnoses and immediate treatment for most HPV and HSV-related CC without testing for viral infections.