Human Papilloma Virus ( HPV )-Related Cancers in Human Immunodeficiency Virus-Infected Women with a History of Cervical Dysplasia

Introduction: Cancer is one of the leading causes of death in people with HIV/AIDS, due to behavioral choices and overlapping risk factors. The purpose of this report is to determine the long-term incidence of HPV-associated cancer in women with pre-invasive cervical neoplasia and compliance with medication and cancer screening recommendations. Methods: HIV-infected women diagnosed with pre-invasive cervical neoplasia and an HPV-associated malignancy between 1995-2008 was identified from an inner-city gynecology clinic. Data collected includes: Demographics, HIV treatment/response, malignancy treatment/response, other healthcare utilization, use of health navigators and compliance. Rogg K1, Richter MA2 and Robinson WR2* 1University of Rochester School of Medicine, Rochester, New York, USA 2Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA Human Papilloma Virus (HPV) Related Cancers in Human Immunodeficiency Virus Infected Women with a History of Cervical Dysplasia Results: 71 subjects were identified with HIV infection, cervical dysplasia and at least ten years’ follow up. 17/71 (24%) were identified with an HPV-related malignancy. The mean age of those diagnosed with HPV-related malignancy was 39 years. Malignancies included: Cervix-9, Vulva-7, Anal-4, Vagina-3, Urethra/Bladder-2 and Oropharyngeal-3. Eight also had in situ neoplasms: Cervix-4, Vulva-3, and Oropharyngeal-1. Four subjects had 3 separate malignancies and two others had 2 malignancies. Compliance with HAART correlated strongly with immunocompetence, response to therapy, use of patient navigators and survival. 60/71 (84.5%) subjects underwent screening mammography, 57/71(80.3%) underwent colonoscopy, and 67/71 (94.3%) underwent Pap smear testing. Compliance with screening compared favorably with the general population and overall survival was similar. Discussion/Conclusion: The long-term incidence and mortality from cancer in women with HIV and cervical dysplasia appears to be comparable to that seen in the general population, with the possible exception of oropharyngeal cancers. Compliance with cancer screening recommendations appears to be higher than in the general population. This suggests that structured primary care programs for HIV-infected women are effective in prevention/early diagnosis of cancer. Standardized screening programs for oropharyngeal cancers should be considered in this population. Citation: Rogg K, Richter MA, Robinson WR (2018) Human Papilloma Virus (HPV) Related Cancers in Human Immunodeficiency Virus Infected Women with a History of Cervical Dysplasia. J AIDS Clin Res Sex Transm Dis 5: 021.


Introduction
Cancer is one of the leading causes of death in people with HIV/ AIDS [1,2]. With the introduction of Highly Active Anti-Retroviral Therapy (HAART) in the mid-1990s, the overall incidence and mortality of cancer has decreased in this population, largely due to striking declines in AIDS-defining cancers such as Kaposi sarcoma and Non-Hodgkin lymphoma [3]. However, the incidence of invasive cervical carcinoma, (also an AIDS-defining cancer) has been relatively stable, while a number of non-AIDS defining cancers have increased in incidence (presumably due to the increasing numbers and age of HIV-infected individuals) and now constitute the majority of cancers in this population [4,5]. Factors suspected to contribute to increased cancer incidence in HIV-infected persons include HIV viremia, immune deficiency, oncogenic virus co-infection and lifestyle exposures (e.g., tobacco, alcohol) [6][7][8]. In particular, among individuals with AIDS, a statistically significant elevated risk of Human Papilloma Virus (HPV) -associated cancers has been reported, with the level of risk strongly correlated with increased levels of immune suppression [9].
And although HIV-associated malignancies have been extensively analyzed and reported, the data on cancers in women, with the exception of invasive cervical cancer, has been relatively limited due to an overall paucity of women in study populations [10]. Further, many of these studies involved populations with multiple additional risk factors for cancer in addition to HIV infection, such as intravenous drug users or men who have sex with men [11]. In contrast to earlier reports, which typically included relatively few HIV-infected women, as well as a relatively short follow-up, the goal of this study is to determine the incidence and outcomes of HPV-related genital and non-genital tract malignancies in HIV-infected women with a diagnosis of pre-invasive cervical neoplasia (dysplasia) and at least a 10-year follow-up. Further, as screening programs have been shown to be very effective in reducing the incidence of invasive cervical cancer in HIV-infected women, the secondary goal of this study is to evaluate the degree of compliance with cancer screening recommendations in this cohort [12].

Methods
As part of a facility-based Quality Improvement (QI) program performed as a part of the accreditation process for the American College of Surgeons-Commission on Cancer (ACS-COC), all HIV-infected women diagnosed with an HPV-associated malignancy between 1995-2008 was identified. HIV testing was and is routinely offered to all subjects presenting to the gynecology clinic at this institution and approximately 97% agree to be tested. The data sources included standard medical records from the clinic, tumor registries and clinical research trial records. Data collected includes: Demographics, HIV treatment/response, malignancy treatment/response, other healthcare utilization, use of health navigators and compliance. Of note, data regarding multiple subgroups, such as all subjects who tested positive for HIV and all those with cervical dysplasia was lost in 2005 due to Hurricane Katrina. As a result, specific incidence rates cannot be calculated. The data from the study subjects was recoverable because it was separately reported to the ACS-COC, as described above. The data was analyzed using standard statistical tests, and the study was determined to be exempt from IRB review.

Results
71 subjects were identified with HIV infection, cervical dysplasia and at least ten years' follow up data from a large, inner-city academic gynecology clinic in New Orleans, Louisiana, out of over 6500 tested. 17/71 (24%) were identified with an HPV-related malignancy. The mean age of those diagnosed with HPV-related malignancy was 39 years and all were African-American. Invasive malignancies included: Cervix-9, Vulva-7, Anal-4, Vagina-3, Uretha/Bladder-2 and Oropharyngeal-3. Eight additional subjects had in situ neoplasms which included: Cervix-4, Vulva-3 and Oropharyngeal-1. Four subjects had 3 separate malignancies and two others had 2 malignancies correlated strongly with survival. Compliance with HAART correlated strongly with immunocompetence, (as measured by CD4>200/µL) response to anti-malignancy therapy and survival. Further, compliance correlated strongly with the use of patient advocate/navigators (Table 1)

Discussion
In this cohort, the long-term incidence and mortality from HPV-associated cancers in HIV-infected women with a history of cervical dysplasia was comparable to that seen in women with cervical dysplasia in the general population of this area. This appears to be in contrast with previous reports, which found an increased risk of both AIDS-defining and non-AIDS defining cancers in similar populations [14]. A possible explanation for these findings include strong compliance with HAART as seen here, which is known to be protective for both AIDS-defining and non-AIDS defining cancers. Another explanation could be the increased level of compliance with cancer screening recommendations in this group. While HIV-infected patients with cervical dysplasia are at risk for HPV-associated cancers, that risk does not seem to exceed that seen in the general population of this area, which has long been among the highest in the US [15,16]. This apparent success in cancer screening is likely due to the work of a well-organized and (relatively) well-funded clinic system for HIV-infected individuals in the New Orleans Metropolitan area. This system has been in existence for over 25 years, makes extensive use of patient advocate/navigators and has been credited with dramatic improvements in multiple health outcomes [17]. This suggests that communities where HIV infection is common will benefit from organized primary care delivery systems, with emphasis on adherence to HAART.
Another possible explanation for the findings reported here is that the baseline characteristics of this group differ from those in prior studies. This study population, while limited in size, was exclusively female and appeared to have both similar levels of personal risk factors and similar demographics to the general population of the area. Prior studies of cancer risks in HIV-infected persons typically comprised a cohort that was predominantly male and included many additional known risk factors for cancer, including high rates of intravenous drug use, alcohol use, smoking and infection with known cancer-causing viruses such as Hepatitis B and C viruses, (HBV and HCV) in addition to HPV [18].
It is well known that HIV-infected women from the pre-HAART era demonstrated an elevated risk for and mortality from cervical abnormalities and dysplasia [19]. A study by Ellerbrock et al., reported that 1 in 5 HIV-infected women without previous evidence of cervical dysplasia developed biopsy-confirmed cervical squamous intraepithelial lesions [20]. In addition, HIV-infected women with a greater level of immune suppression have an increased risk of persistent HPV infection and progression to cervical dysplasia [21]. Interestingly, a separate study showed that the incidence of cervical dysplasia in HPV-negative, cytology-negative HIV-infected women with CD4 counts greater than 500/µL was comparable to that in HIV-negative women [22]. Massad et al., found that while the risk for an abnormal Pap test was greater in HIV-infected women than seronegative women, once an HIV-infected woman develops an abnormality, her risk for high grade cervical dysplasia was only marginally greater than that of seronegative women [23]. Of importance for patient care, another study of HIV seropositive women from 1994-2001 from the same investigators found the risk of invasive cervical cancer to be indistinguishable from that of the general population when the HIV seropositive women were enrolled in a program of cervical cancer screening and prevention [24,25].
An intriguing finding from the current study is that the long-term incidence of oropharyngeal cancers may be higher than expected. This may be partially explained as a reflection of the overall increase in oral HPV infection and oropharyngeal cancers in recent years [26]. However, understanding of the pathophysiology of HPV is incomplete and may differ in the female genital tract compared to the oropharyngeal tract. Consistent with this, a study by Beachler, et al., found an elevated prevalence of oral HPV in HIV-infected persons after controlling for differences in cigarette smoking and sexual behavior [27]. This unexpected number of oropharyngeal cancers in HIV-infected persons suggests that standardized screening programs for oropharyngeal cancers should be considered. Compliance with cancer screening recommendations in this study group appeared to be higher than in the general population. Although there is limited data on certain cancers in HIV-infected women, prior studies have indicated benefits of screening these patients for cervical cancer, anal cancer, breast cancer and hepatocellular carcinoma [28]. Currently there is insufficient evidence to recommend lung cancer screening for HIV-infected women without other risk factors such as smoking. Although the incidence of lung cancer is elevated in HIV patients, it has also been reported that they have a greater cumulative pack-year smoking history [29].

Conclusion
The long-term incidence and mortality from cancer in women with HIV and cervical dysplasia in this small cohort appears to be comparable to that seen in the general population, with the possible exception of oropharyngeal cancers. Compliance with cancer screening recommendations appears to be higher than in the general population. This suggests that structured primary care programs for HIV-infected women are effective in prevention/early diagnosis of cancer. Standardized screening programs for oropharyngeal cancers should be considered in this population.