Clonal Hematopoiesis in Patients With Human Immunodeficiency Virus and Cancer.

BACKGROUND: Cancer-related deaths for people with human immunodeficiency virus (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. METHODS: We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. RESULTS: In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, P = .07). After adjusting for patient characteristics, PWH were 4 times more likely than PWoH to have CH (odds ratio, 4.1 [95% confidence interval, 1.3-13.9]; P = .02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). CONCLUSIONS: This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.

A cross-sectional study of the association of dental health factors with progression and all-cause mortality in men diagnosed with HPV-associated oropharyngeal cancer.

BACKGROUND: Human Papillomavirus-associated oropharyngeal cancer (HPV-OPC) incidence is increasing among men in the United States. Poor dental health has previously been associated with risk of head and neck cancers, oral HPV infection, and persistence but it is not understood whether dental health is associated with outcomes. We sought to determine the association of dental health with progression free survival and overall mortality among men with an HPV-OPC. METHODS: A cross sectional study of men diagnosed with HPV-OPC between 2014-2020 at Moffitt Cancer Center in Tampa, FL was conducted. Dental records were abstracted for assessment of dental fitness prior to cancer treatment. Five dental factors including number of teeth lost, pocket depth, gingival score, loss of attachment, and bone loss were individually examined. Risk factor and outcome data were collected from a patient risk questionnaire and medical record. Using item response theory, an overall dental fitness score from five dental factors was developed in which missing data were multiply imputed. Cox proportional hazards model was used to assess whether dental factors were associated with progression-free survival or overall mortality. RESULTS: Among 206 HPV-OPC cases, median follow-up was 3.4 years (IQR: 2.4-4.4) during which 40 cases involved progression or mortality and 25 deaths occurred. Overall dentition was significantly associated with progression free survival (p = 0.04) and with overall survival (p = 0.03) though findings were not significant after adjustment for age at diagnosis, stage, and smoking history (p = 0.146 and p = 0.120, respectively). A pocket depth of 7 mm or more was associated with overall survival (HR: 5.21; 95% CI: 1.43-19.11) and this remained significant after adjustment for confounding (aHR: 4.14; 95% CI: 1.72-16.26). CONCLUSIONS: Among men diagnosed with an HPV-associated OPC in the US, worse dental health was associated with reduced progression free survival and overall survival, but not after adjustment for confounders. Further studies are needed to examine whether dental health is associated with other prognostic factors and subsequent treatment-related outcomes.

Control of Epstein-Barr Virus (EBV) in the Oral Cavity Is Associated With Persistence of Oral Human Papillomavirus (HPV)16/18 Among Men From the HPV Infection in Men Study.

BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal cancer (OPC) incidence is increasing among men. Biomarkers that can identify oral HPV16/18 infections likely to persist, the obligate precursor for HPV-OPC, are needed. METHODS: We assessed the association between oral Epstein-Barr virus (EBV) and oral HPV16/18 persistence among 63 men in the HPV Infection in Men Study who tested positive for HPV16/18 at the baseline visit. Control of oral coinfections, including EBV, could serve as a biomarker of immune competence and the ability to control oral HPV. RESULTS: Detection of oral EBV was significantly associated with oral HPV16/18 ≥12-month persistence. CONCLUSIONS: Detection of oral EBV deserves evaluation as a biomarker for oral HPV persistence and HPV-related OPC.

Hepatitis C virus (HCV) seroprevalence, RNA detection, and genotype distribution across Florida, 2015-2018.

Chronic hepatitis C virus (HCV) infection is a leading cause of hepatocellular carcinoma (HCC) in the U.S. Due to high rates of HCV among baby boomers (born 1945-1965), it was recommended they receive universal screening. This was expanded to all U.S. adults in 2020 due to evidence of increasing rates of chronic HCV in younger adults. An assessment of HCV burden across demographics is crucial to understand the future burden of HCC and target under-screened adults for HCV. Using the OneFlorida Clinical Research Consortium, of more than one million individuals in Florida, all HCV antibody and viral RNA tests completed from 2015 to 2018 were identified. HCV seroprevalence, HCV viral load (active infection), and HCV genotype distribution by risk groups were assessed. Overall, HCV seroprevalence and active infection were highest among White non-Hispanic individuals, males, and baby boomers. However, odds of a positive HCV antibody test were higher among Black non-Hispanic individuals born before 1945 (aOR: 2.74; 95% CI: 1.98-3.78) or 1945-1965 (aOR: 1.46; 95% CI: 1.36-1.56) compared to White non-Hispanic individuals. In contrast, among individuals born after 1965, Black non-Hispanics were less likely than White non-Hispanics to test HCV antibody positive (aOR of 0.5-0.28). A similar age/race pattern was observed for active HCV infection. There was a higher prevalence of genotype 1A and 3 and lower prevalence of 1B in younger adults. Patterns of HCV seroprevalence and active HCV infection identified in our study support the recent shift from age and risk-based screening guidelines to universal adult screening.

Gynecological radiotherapy in people living with human immunodeficiency virus: a semi-systematic literature review.

Appropriate diagnosis and treatment of gynecological cancers in people living with human immunodeficiency virus (HIV) remains a clinical challenge given rapid changes in both HIV and cancer management and a lack of prospective clinical trial data inclusive of the HIV population. A semi-systematic literature review was performed to identify published studies addressing risk factors, screening, treatment efficacy, treatment toxicity, and prognosis for people living with HIV diagnosed with gynecological malignancies, with a focus on radiotherapy and cervical cancer, given the relative paucity of literature on uterine, ovarian, and vulvovaginal cancers in people living with HIV. People living with HIV are more likely to be co-infected with human papilloma virus and more likely to develop human papilloma virus-associated malignancies. People living with HIV are less likely to receive cancer treatment compared with HIV-uninfected cancer patients, even after adjusting for differences in clinical features and sociodemographic variables. The literature on cervical cancer outcomes is mixed, with some studies demonstrating that people living with HIV have inferior treatment tolerability, response rates, and survival following chemoradiotherapy, and others showing no difference in these outcomes, particularly in patients receiving antiretroviral therapy. Importantly, even in the series showing inferior outcomes in people living with HIV, there were long-term survivors after administration of curative therapy. Consistent with published cancer management guidelines, people living with HIV diagnosed with gynecological cancers should be treated with standard cancer therapy. Co-management with the patient's HIV specialist is critical to avoid overlapping toxicities and provide optimal supportive care. The morbidity and mortality caused by gynecologic cancers in this population can be mitigated by early diagnosis, appropriate treatment delivery including inclusion of people with HIV in cancer clinical trials, and diligent HIV management.

Sequential acquisition of human papillomavirus infection between genital and oral anatomic sites in males.

Oral human papillomavirus (HPV) is associated with increasing rates of HPV-associated oropharyngeal cancer (OPC) in men. Sequential infection from one site to another has been demonstrated at the cervix and anus. Thus, risk of an oral HPV infection after a genital infection of the same type in the HPV infection in men study was investigated. Samples from 3140 men enrolled in a longitudinal cohort were assessed for sequential genital to oral infection with one of nine HPV types (HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58); and then also sequential, same-type oral to genital infection. Incidence rate ratios (IRRs) compared rates of oral HPV among men with and without prior genital infection of the same type. Risk of sequential HPV infections were assessed using Cox proportional hazards model. Incidence of an oral HPV infection was significantly higher among men with a prior genital infection of the same type for any of the 9 HPV types (IRR: 2.3; 95% CI: 1.7-3.0). Hazard ratio of a sequential genital to oral HPV infection was 2.3 (95% CI: 1.7-3.1) and 3.5 (95% CI: 1.9-6.4) for oral to genital infection. Both changed minimally after adjustment for age, country, circumcision, alcohol use, lifetime sexual partners and recent oral sex partners. HPV infections at one site could elevate risk of a subsequent genital or oral HPV infection of the same type in men, emphasizing the importance of vaccination to prevent all HPV infections.

An Updated Systematic Review of Human Papillomavirus Genotype Distribution by Cervical Disease Grade in Women Living With Human Immunodeficiency Virus Highlights Limited Findings From Latin America.

ABSTRACT: Cervical cancer is 5 times more likely among women living with human immunodeficiency virus (WHIV), likely due to higher prevalence of human papillomavirus (HPV). Despite evidence of higher rates with multiple HPV genotypes in WHIV, there are no recommendations for triage by HPV genotyping specific to WHIV. In Latin America/Caribbean rates are high and vary significantly. To guide optimization of HPV-based cervical cancer screening among WHIV in Latin America/Caribbean, review of current literature was completed to assess HPV genotype distribution by cervical disease grade in WHIV in this region; and further expanded globally for comparison across regions.A systematic review of the literature from June 2016 to January 2020 revealed 15 studies reporting human papillomavirus (HPV) genotype distribution by cervical disease state (normal, low-grade disease, high-grade disease, and invasive cervical cancer) across different global regions.Across all studies, there were 6928 WHIV from 4 global regions, 3952 of whom were HPV-positive. Three studies from Latin America/Caribbean (LAC) countries were reviewed, with 1 providing enough detail to describe HPV genotypes by cervical disease grade and identified types 31 and 35 in high-grade cervical lesions. Of the studies included, 4 from Africa and Europe/North America each, and 1 from Asia included data that were able to be summarized.Latin America, a region which experiences high rates of HPV, human immunodeficiency virus (HIV), and cervical disease, had few published studies reporting HPV genotypes by cervical disease grade, with 1 reporting individual HPV genotype and specific cervical disease grade. Identifying HPV types associated with CIN2+ in WHIV in this region has the potential to improve screening and treatment for cervical cancer prevention and should be the focus of future research.

Identification of a Biomarker Panel from Genome-Wide Methylation to Detect Early HPV-Associated Oropharyngeal Cancer.

As oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) increases in men, the need for a screening test to diagnose OPC early is crucial. This study agnostically identified differentially methylated CpG sites to identify additional biomarkers to improve screening for early OPC.DNA was extracted from oral gargles of 89 early cases and 108 frequency matched healthy controls, and processed for genome-wide methylation using the Illumina Infinium MethylationEPIC BeadChip. Selected sites were combined with our prior methylation data in the EPB41L3 gene (CpG sites 438, 427, and 425) and oral HPV16 and HPV18 status were considered as binary variables (positive/negative). Lasso regression identified CpG sites strongly associated with early OPC. ROC curves with AUC were generated. The panel was validated utilizing bootstrap resampling.Machine learning analyses identified 14 markers that are significantly associated with early OPC, including one EPB41L3 CpG site (438) and oral HPV16 status. A final model was trained on all available samples using the discovered panel and was able to predict early OPC compared with controls with an AUC of 0.970 on the training set. In the bootstrap validation sets, the average AUC was 0.935, indicating adequate internal validity.Our data suggest that this panel can detect OPC early, however external validation of this panel is needed. Further refinement of a panel of biomarkers to diagnose OPC earlier is urgently needed to prevent complex treatment of OPC and associated comorbidities, while reducing risk of recurrence. PREVENTION RELEVANCE: This study identified biomarkers using genome-wide methylation to create a panel capable of discerning early oropharyngeal cancer (OPC) from those without OPC. Such a biomarker panel would be an effective tool to detect OPC early and prevent complications of treatment associated with later diagnosis.

The Association of HIV Control and Immunosuppression With Risk of Non-AIDS-Defining Cancer Risk Among Patients on Antiretroviral Therapy.

BACKGROUND: People living with HIV (PWH) are experiencing an increased prevalence of non-AIDS-defining cancers (NADCs). Our study investigated the association of immunosuppression and HIV control with NADCs among PWH on antiretroviral therapy (ART) in the United States. METHODS: Among patients across 8 clinical cohorts on ART between 1996 and 2016, we assessed immune function and HIV control using 3 parameterizations of CD4 count and HIV-RNA viral load (VL): (1) CD4 or VL at ART initiation; (2) change in CD4 or VL after ART initiation; and (3) proportion of follow-up time at CD4 >500 cells/µL or VL <50 copies/mL. Cox models were used to ascertain the association of these measures with risk of a viral NADC or nonviral NADC. RESULTS: Among 29,568 patients on ART, there were 410 nonviral NADCs and 213 viral NADCs. PWH with a CD4 <200 cells/µL at ART initiation had an 80% elevated risk for developing a viral NADC. Each increase of 100 cells/µL in CD4 after ART initiation decreased risk by 14%. For viral and nonviral NADCs, 10% more follow-up time spent with a CD4 >500 cells/µL was associated with decreased risk [viral, adjusted hazard ratio (aHR): 0.82; 95% confidence intervals (CI): 0.78 to 0.86; nonviral, aHR: 0.88; 95% CI: 0.86 to 91], even after accounting for CD4 at ART initiation. When examining HIV control only, 10% more time with VL <50 copies/mL was significantly associated with decreased viral (aHR: 0.85; 95% CI: 0.82 to 0.89) and nonviral NADC risk (aHR: 0.88; 95% CI: 0.85 to 0.90). CONCLUSIONS: This study demonstrates that even for PWH on ART therapy, maintaining HIV control is associated with lower risk of both viral and nonviral NADCs.

Multinational epidemiological analysis of oral human papillomavirus incidence in 3,137 men.

Oral human papillomavirus (HPV) is associated with oropharyngeal cancer (OPC). Although OPC incidence is increasing globally, knowledge of oral HPV infection rates is limited. Here we carried out an observational epidemiological analysis of oral HPV incidence in 3,137 men enrolled from the United States, Mexico and Brazil between 2005 and 2009. Individuals were followed for new HPV infection for a median of 57 months. Cumulative incidence and factors associated with acquisition were also assessed. The incidence rate of oral oncogenic HPV was 2.4 per 1,000 person-months, did not vary with age and was constant throughout the study period. Risk of oral HPV acquisition was significantly associated with alcohol consumption, having male sexual partners, more lifetime female sexual partners, more oral sex given and higher educational attainment. These data indicate that men are at risk of acquiring oral HPV throughout their lifetime, suggesting that catch-up vaccination may reduce new infection incidence.

Differences in epigenetic age by HIV status among patients with a non-AIDS defining cancer.

OBJECTIVE: People with HIV (PWH) are living longer and experiencing higher numbers of non-AIDS-defining cancers (NADC). Epigenetic aging biomarkers have been linked to cancer risk, and cancer is now a leading cause of death in PWH, but these biomarkers have not been investigated in PWH and cancer. DESIGN: In order to compare epigenetic age by HIV status, HIV-uninfected participants were matched to PWH by reported age, tumor site, tumor sequence number, and cancer treatment status. METHODS: DNA from blood was assayed using Illumina MethylationEPIC BeadChip, and we estimated immune cell composition and aging from three epigenetic clocks: Horvath, GrimAge, and epiTOC2. Age acceleration by clock was computed as the residual from the expected value, calculated using linear regression, for each study participant. Comparisons across HIV status used the Wilcoxon rank sum test. Hazard ratios and 95% confidence intervals for the association between age acceleration and survival in PWH were estimated with Cox regression. RESULTS: Among 65 NADC participants with HIV and 64 without, biological age from epiTOC2 ( P  < 0.0001) and GrimAge ( P  = 0.017) was significantly higher in PWH. Biological age acceleration was significantly higher in PWH using epiTOC2 ( P  < 0.01) and GrimAge ( P  < 0.0001), with the difference in GrimAge remaining statistically significant after adjustment for immune cell composition. Among PWH, GrimAge acceleration was significantly associated with increased risk of death (hazard ratio 1.11; 95% confidence interval (CI) 1.04-1.18). CONCLUSION: We observed a higher epigenetic age in PWH with a NADC diagnosis compared with their HIV-uninfected counterparts, as well as a significant association between this accelerated biological aging and survival for patients diagnosed with a NADC.

Utility of Epstein-Barr virus (EBV) antibodies as screening markers for nasopharyngeal carcinoma: a narrative review.

Background and Objective: Nasopharyngeal carcinoma (NPC) is a tumor of the head and neck that arises from the mucosal epithelium of the nasopharynx. Epstein-Barr virus (EBV) is a human herpes virus and the necessary cause for NPC. The 5-year survival rate for NPC patients is higher when diagnosed at an earlier stage of disease. Therefore, NPC screening should be prioritized for early detection. The objective of this narrative review is to synthesize the existing literature from the past decade describing evaluations of EBV-based serological markers for NPC screening. Methods: We performed a literature search in PubMed for studies published from 2010 to 2020. Studies were required to be English-language articles. Twelve articles fulfilled all inclusion criteria, including eight studies conducted among the general population in southeastern China, three studies in genetically high-risk Taiwanese families, and one study comparing EBV serology versus circulating EBV DNA for NPC prediction. Key Content and Findings: Studies suggest that EBV-based serology has the potential to be an effective tool to aid in early detection of NPC. The synthesized research also collectively suggests that incorporation of antibody against multiple EBV targets, as well as efforts to optimize assay output, can improve the ability of EBV serological markers to detect NPC. Finally, recent data from the only randomized trial provide preliminary evidence that screening using anti-EBV immunoglobulin A (IgA) antibody may achieve the goal of reducing mortality from NPC. Conclusions: Late diagnosis is one of the reasons for poor survival after an NPC diagnosis. In high-risk areas, early diagnosis aided by EBV antibody could therefore improve survival.

Methylation of HPV16 and EPB41L3 in oral gargles and the detection of early and late oropharyngeal cancer.

As oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) increases in men, the need for a screening test to diagnose OPC early is crucial. While HPV-associated OPC has a favorable prognosis, recurrence is likely, and metastatic OPC is often incurable regardless of HPV status. Our previous study of pretreatment, male OPC cases (n = 101) and age- and smoking-matched controls (n = 101) found methylation of the host EPB41L3 tumor suppressor gene and HPV16 in the oral gargle was correlated with these biomarkers in the tumor. Methylation of these genes in the oral gargle was significantly (p < 0.0001) higher among cases compared to controls. To further study the utility of HPV16/EPB41L3 methylation, we expanded the sample size and specifically increased the number of early OPC cases (T1-T2, N0-N1; small tumors with a single ipsilateral node <3 cm) to evaluate these biomarkers in early and late OPC. This study included 228 OPC cases, 92 of which were early cases and frequency matched to 142 healthy controls. In logistic regression, the AUC for HPV16/EPB41L3 methylation for all OPC cases was 0.82. Among early and late OPC cases, the AUC was 0.78 and 0.85, respectively. For early cases, 76% sensitivity was achieved, replicating results from our prior study, with a specificity of 65%, indicating room for improvement. The ability of HPV16/EPB41L3 methylation to distinguish OPC from healthy controls highlights its utility as a potential biomarker for OPC. However, the inability to predict early OPC better than late stage OPC indicates the need for additional biomarkers to improve screening performance.

Patient-Reported Outcomes in Cancer Patients with HIV.

Elevated cancer-specific mortality in PWH has been demonstrated for non-AIDS-defining malignancies. However, additional clinical endpoints of interest, including patient-reported outcomes (PROs), have not been systematically examined in PWH and cancer. We evaluated differences in patient-reported symptomology between cancer patients with versus without HIV using data from 12,529 patients at the Moffitt Cancer Center, including 55 with HIV. The symptoms were assessed using the Edmonton Symptom Assessment Scale (ESAS), which asks patients to rank 12 symptoms on a scale of 1−10, with scores ≥7 considered severe. The responses across all questions were summed to create a composite score. Vital status through t July 2021 was determined through linkage to the electronic health record. PWH reported a higher composite ESAS score on average (44.4) compared to HIV-uninfected cancer patients (30.7, p-value < 0.01). In zero-inflated negative binomial regression models adjusted for cancer site, sex, and race, the composite ESAS scores and the count of severe symptoms were 1.41 times (95% CI: 1.13−1.77) and 1.45 times (95% CI: 1.09−1.93) higher, respectively, in cancer patients with HIV. Among PWH, higher ESAS scores were associated with mortality (p-value = 0.02). This is the first demonstration of uniquely poor PROs in PWH and cancer and suggests that patient symptom monitoring to improve clinical endpoints deserves further study.

Oral secretory leukocyte protease inhibitor (SLPI): Associations with oropharyngeal cancer and treatment outcome.

BACKGROUND: Rates of oropharyngeal cancer (OPC) associated with alcohol & tobacco use have decreased, while human papillomavirus (HPV) associated OPC has increased among men in the US. Secretory leukocyte protease inhibitor (SLPI), detectable in a variety of secretions, has been implicated in cancers of the head and neck, associated with tumor progression and anti-viral activity. Using the recently verified oral gargle specimen, this study aimed to assess the association of salivary SLPI expression with risk of OPC and response to treatment. METHODS: A case-control study design compared levels of salivary SLPI among OPC cases to age and tobacco smoking matched healthy controls. Oral HPV DNA and SLPI was quantified from oral gargle specimens. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations of oral SLPI and risk of OPC and treatment outcomes. RESULTS: In crude and adjusted analyses of 96 OPC cases and 97 age- and smoking-matched controls, OPC was not significantly associated with oral gargle SLPI levels. Among cases, oral SLPI was associated with tonsillectomy (p = 0.018) and among controls oral SLPI was associated with HPV in the oral gargle (p = 0.008). Higher concentrations of SLPI was significantly associated with increased odds of incomplete treatment response (T2: OR: 12.39; 95% CI: 1.44-106.72; T3: OR: 9.86; 95% CI: 1.13-85.90) among all cases, but not among P16+ cases. CONCLUSIONS: Salivary SLPI was not associated with OPC risk but was associated with higher odds of an incomplete treatment response.

Nanoformulation of CCL21 greatly increases its effectiveness as an immunotherapy for neuroblastoma.

Neuroblastoma is the most commonly diagnosed extracranial solid tumor in children. The patients with aggressive metastatic disease or refractory/relapsed neuroblastoma currently face a dismally low chance of survival. Thus, there is a great need for more effective therapies for this illness. In previous studies, we, as well as others, showed that the immune cell chemoattractant C-C motif chemokine ligand 21 (CCL21) is effective as an intratumoral therapy able to slow the growth of cancers. In this current study, we developed and tested an injectable, slow-release, uniform, and optimally loaded alginate nanoformulation of CCL21 as a means to provide prolonged intratumoral treatment. The alginate-nanoformulated CCL21, when injected intratumorally into mice bearing neuroblastoma lesions, significantly prolonged survival and decreased the tumor growth rate compared to CCL21 alone, empty nanoparticles, or buffer. Notably, we also observed complete tumor clearance and subsequent full protection against tumor rechallenge in 33% of nanoformulated CCL21-treated mice. Greater intratumoral presence of nanoformulated CCL21, compared to free CCL21, at days 1 and 2 after treatment ended was confirmed through fluorescent labeling and tracking. Nanoformulated CCL21-treated tumors exhibited a general pattern of prolonged increases in anti-tumor cytokines and relatively lower levels of pro-tumor cytokines in comparison to tumors treated with CCL21 alone or buffer only. Thus, this novel nanoformulation of CCL21 is an effective treatment for neuroblastoma, and may have potential for the delivery of CCL21 to other types of solid tumors in the future and as a slow-release delivery modality for other immunotherapies.