Oral HPV Infection and Head and Neck Squamous Cell Carcinoma in HIV-infected and HIV-uninfected Individuals

Background: Oral HPV infection is etiologically associated with a subset of Head and Neck Squamous Cell Carcinomas (HNSCCs). However, the natural history and risk factors of this infection are largely unexplored particularly in high risk groups such as HIV-infected individuals. Objectives: This dissertation aims to examine the natural history and risk factors for oral HPV infection and HPV-related HNSCC in HIV-infected and HIV-uninfected individuals. Methods: We utilized three different longitudinal studies involving HIV-infected individuals. We semi-annually collected oral rinse samples (in the first and second studies) and anal swabs (in the first study) and analyzed them for 37 different HPV DNA types utilizing the Roche Linear array. In the third study, HNSCCs were validated through chart review or through cancer registry-linkage. In each study, we collected information on biologic and behavior risk factors. We analyzed data utilizing 1) Kaplan-Meier survival analysis, 2) Wei-Lin-Weissfeld regression, and 3) Mixed effects Poisson regression. Results: Study 1: Among HIV-infected individuals, the prevalence (84% vs. 28%), incidence (aHR=4.7, 95%CI=3.6-6.2) and persistence (aHR=1.5, 95%CI=1.2-1.9) were all significantly higher for anal versus oral HPV infections, respectively. Study 2: While 28% of HIV-infected and at risk HIV-uninfected participants had at least one type-specific incident oral HPV infection within 24 months, only 7% of incident oral HPV infections were persistently detected for two or more years. Oral sex and immunosuppression were associated with increased risk of oral HPV infection, while male gender, older age, and current cigarette smoking were associated with increased persistence. Study 3: HPV-related HNSCC is three times more common in HIV-infected individuals compared to the general population. HNSCC was associated with reduced CD4 measured prior to cancer diagnosis. Conclusion: Oral HPV infection is regularly detected in HIV-infected individuals, but commonly clears and HPV-related HNSCC is only modestly elevated in HIV-infected individuals compared to the general population. Older age, gender/sexual orientation, cigarette smoking, and oral sexual behaviors all appear to impact the natural history of oral HPV. HIV-related immunosuppression appears to have the strongest impact in the acquisition or re-activation of oral HPV, but may have a modest role throughout the oral carcinogenesis process

Effect of HPV on head and neck cancer patient survival, by region and tumor site: A comparison of 1362 cases across three continents

Objectives: To explore whether HPV-related biomarkers predict oropharyngeal squamous cell cancer (OPSCC) survival similarly across different global regions, and to explore their prognostic utility among non-oropharyngeal (non-OP) head and neck cancers. Methods: Data from 1362 head and neck SCC (HNSCC) diagnosed 2002–2011 was used from epidemiologic studies in: Brazil (GENCAPO study, n = 388), U.S. (CHANCE study, n = 472), and Europe (ARCAGE study, n = 502). Tumors were centrally tested for p16INK4a and HPV16 DNA (by PCR). Risk of mortality was examined using Cox proportional hazard models. Results: There were 517 OPSCC and 845 non-OP HNSCC. Cases were primarily male (81%), ever smokers (91%), with median age of 58 years and median follow-up of 3.1 years (IQR = 1.4–5.9). Among OPSCC, the risk of mortality was significantly lower among 184 HPV-related (i.e., p16+/HPV16+) compared to 333 HPV-unrelated (p16- and/or HPV16-) cases (HR = 0.25, 95%CI = 0.18–0.34). Mortality was reduced among HPV-related OPSCC cases from the U.S., Europe, and Brazil (each p ⩽ 0.01) and after adjustment, remained significantly reduced (aHR = 0.34, 95%CI = 0.24–0.49). Among non-OP HNSCC, neither p16 (aHR = 0.83, 95%CI = 0.60–1.14), HPV16 DNA (aHR = 1.20, 95%CI = 0.89–1.63), or p16+/HPV16+ (aHR = 0.59, 95%CI = 0.32–1.08) was a significantly predictor of mortality. When interaction was tested, the effect of HPV16/p16 was significantly different in OPSCC than non-OP HNSCC (p-interaction = 0.02). Conclusion: HPV-related OPSCCs had similar survival benefits across these three regions. Prognostic utility of HPV among non-OP HNSCC is limited so tumor HPV/p16 testing should not be routinely done among non-OP HNSCC

HPV vaccination initiation after the routine-recommended ages of 11–12 in the United States

Background: Since 2006, routine HPV vaccination has been recommended for females aged 11–12 in the US. However not much is known about the extent of and factors associated with HPV vaccination after the ages of 11–12. Methods: Provider-verified data on 8710 females aged 13–17 were analyzed from the 2013 NIS-Teen survey. 2013 Data was utilized since it was the first year one can fully evaluate the age at vaccination through age 17 for females who could receive the HPV vaccine at age 11. Results: Among HPV vaccinated females who were 17 in 2013, 47% (95% CI=43–50%) received their first dose after age 12, and 24% (95% CI=21–26%) received their first dose after age 14. The HPV vaccine was more likely to be initiated later than the meningococcal and Tdap vaccines (p<0.05), and later HPV vaccine initiation was more common among those having a more highly educated mother and those not receiving a check-up/well visit between the ages of 11 and 12 in adjusted analyses (p-values<0.05). Females initiating the HPV vaccine late were more likely to not receive three doses (RR=1.90, 95% CI=1.76–2.04). Conclusions: HPV vaccination is commonly initiated after the age of 12 in the US, which could limit the vaccine׳s population-level effectiveness. Keywords: HPV vaccines, Late initiation, Vaccination, NIS-Tee

An evaluation of the effect of the OxyContin® reformulation on unintentional fatal and non-fatal overdose

Objectives: OxyContin® was reformulated with a polyethylene oxide matrix in August 2010 to reduce the potential for intravenous abuse and for abuse by insufflation. The objective of this study was to evaluate the impact of OxyContin’s reformulation on overdose risk for individuals dispensed OxyContin in comparison to those dispensed other opioids under regular care. Methods: Three national insurance databases with National Death Index linkage identified OD in individuals with any dispensing of OxyContin or a primary comparator opioid (ER morphine, transdermal fentanyl, or methadone) between July 2008 through September 2015. A difference-in-differences design was used to compare the pre-post reformulation changes in OD rates for OxyContin versus comparators. Results: 297,836 individuals were dispensed OxyContin and 659,673 individuals were dispensed a primary comparator across the three databases. Overall, there was little or no difference in the temporal change in OD incidence in comparators versus OxyContin (Medicaid: adjusted ratio-of-rate-ratios (aRoRs) ranging from 0.90 to 1.05; MarketScan/HIRD: aRoR ranging from 1.10 to 1.22). However, restriction to person-time without concomitant opioid use revealed a modestly greater reduction in OD incidence over time during OxyContin use, as the aRoRs comparing the primary comparators to OxyContin ranged from 1.06 to 1.30 in Medicaid and from 1.64 to 1.85 in MarketScan/HIRD. Discussion: This study did not detect an overall effect of the OxyContin reformulation on OD in insured patients under regular medical care. There is a suggestion of a modestly reduced OxyContin-associated OD risk following the reformulation but only in commercially-insured individuals receiving single-opioid regimens

HPV16 E6 seropositivity among cancer-free men with oral, anal or genital HPV16 infection

Antibodies against the Human papillomavirus 16 (HPV16) E6 oncoprotein appear years prior to clinical diagnosis of anal and oropharyngeal cancer, but whether they develop around the time of HPV infection is unclear. Serum samples from 173 cancer-free men from the Human Papillomavirus Infection in Men (HIM) Study were tested for HPV antibodies and DNA. HPV16 E6 seropositivity was low among men with oral HPV16-infection (1/28; 3.6%, 95%CI=0.0–18.4%), anal HPV16-infection (1/61; 1.6%, 95%CI=0.0–8.8%), and 24-month persistent genital HPV16-infection (1/84; 1.2%, 0.0–6.5%). This suggests E6 seroconversion may not occur around the time of oral, anal, or genital HPV16 acquisition. Keywords: HPV, HPV16 E6 seropositivity, Oropharyngeal cancer, Anal cancer, Penile cance

Post-Authorization Safety Studies of Acute Liver Injury and Severe Complications of Urinary Tract Infection in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting

INTRODUCTION: At the time of dapagliflozin\u27s approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. OBJECTIVE: To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012-February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. RESULTS: In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59-1.24) and for sUTI was 0.76 (0.60-0.96) in females and 0.74 (0.56-1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. CONCLUSIONS: These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs