Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

The association between protease inhibitors and anal cancer outcomes in veterans living with HIV treated with definitive chemoradiation: a retrospective study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. METHODS: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. RESULTS: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p < 0.01). CONCLUSION: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation.

Veteran Women Living With Human Immunodeficiency Virus Have Increased Risk of Human Papillomavirus (HPV)-Associated Genital Tract Cancers.

BACKGROUND: Disparities in access to screening often confound observed differences in human papillomavirus (HPV)-associated female genital tract cancer (FGTC) incidence between women living with human immunodeficiency virus (HIV; WLWH) and their HIV-negative counterparts. We aimed to determine if there have been changes in cancer risk among WLWH during the antiretroviral era in a single-payer health system. METHODS: We retrospectively selected WLWH and HIV-negative controls receiving care between 1999 and 2016 at the US Department of Veterans Affairs (VA) and identified FGTC diagnoses via Cancer Registry and International Classification of Diseases-9/10 codes. We extracted demographic and clinical variables from the VA's Corporate Data Warehouse; evaluated incidence rates (IRs), incidence rate ratios, hazard ratios, and 95% confidence intervals (CIs) for cancer risk; and conducted survival analyses. RESULTS: We identified 1454 WLWH and compared them with 5816 matched HIV-negative controls. More WLWH developed HPV-associated FGTCs (total n = 28 [2.0%]; cervical = 22, vulvovaginal = 4, and anal/rectal = 2) than HIV-negative women (total n = 32 [0.6%]; cervical = 24, vulvovaginal = 5, and anal/rectal = 5) (log rank P < .0001). Cervical cancer IR was >6-fold higher for WLWH (204.2 per 100 000 person-years [py] [95% CI, 83.8-324.7]) than HIV-negative women (IR = 31.2 per 100 000 py [95% CI, 17.9-44.5]). The IRs for vulvovaginal and anal cancers were also higher in WLWH. Overall, WLWH were more likely to develop HPV-associated FGTCs compared with their HIV-negative counterparts (all log rank P values < .0001). CONCLUSIONS: Veteran WLWH are more likely to develop HPV-associated FGTCs despite equal access to health care. Even in single-payer health systems, WLWH continue to require special attention to ensure guideline-based high-risk HPV screening for prevention of FGTCs.

Effect of Body Weight and Other Metabolic Factors on Risk of Non-Small Cell Lung Cancer among Veterans with HIV and a History of Smoking.

Among people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, including dyslipidemia, which can modulate NSCLC risk. In this article, we evaluate which metabolic risk factors are associated with incident risk among PWH who smoke. This is done through a retrospective cohort study, using data of HIV+ veterans who smoke from the nationwide Veterans Affairs (VA) healthcare system. Data on diagnostic codes, medication, and laboratory values of 33,351 veterans were obtained using the VA's Corporate Data Warehouse and Central Cancer Registry. We calculated NSCLC incidence and utilized Cox regression to determine metabolic factors associated with NSCLC risk. HIV+ cohort was 97.4% male; median age = 47 years and 20,050 (60.1%) well-controlled (≥80% follow-up time undetectable viral load). Crude incidence rates were lower in well-controlled PWH (1.46 vs. 2.06/1000 PY). Metabolic factors associated with incident NSCLC risk included lower BMI at HIV diagnosis and cachexia history in both groups, while HDL and triglycerides were significant in non-well-controlled smokers only. Our findings that lower BMI at HIV diagnosis, history of cachexia among individuals with well-controlled HIV, and cachexia presence at diagnosis are associated with increased risk of developing NSCLC in PWH with a history of smoking have important implications.

Incidence and survival for oropharynx and non-oropharynx head and neck cancers among veterans living with HIV.

BACKGROUND: People living with HIV/AIDS (PLWH) have an excess risk for head and neck squamous cell carcinoma (HNSCC) compared to the general U.S. population, but little is known about HIV-specific risk factors associated with the incidence and outcomes HNSCC. We aim to identify clinical and HIV-specific risk factors associated with oropharyngeal and non-oropharyngeal HNSCC incidence and outcomes separately. METHODS: We constructed a retrospective cohort study of 45,052 PLWH aged 18 or above from the national Veteran Affairs (VA) Corporate Data from 1999 to 2015. We extracted demographic data and risk factor information, including history of alcohol abuse, smoking, CD4 count (cells/µl), and percent of follow-up time with undetectable HIV viral load as time-updated variables. We calculated the age-standardized incidence rates of oropharyngeal and non-oropharyngeal HNSCC and estimated adjusted hazard ratios (HR). We also examined overall survival using Kaplan-Meier curves and adjusted HR. RESULTS: The standardized incidence rate of oropharyngeal and non-oropharyngeal HNSCC in this veteran cohort of PLWH is 23.0 (95% confidence intervals (CIs): 17.1-28.9) and 55.4 (95% CI: 46.5-64.3) per 100,000 person-years, respectively. Nadir CD4 count ≤200 was associated with an increased risk of non-oropharyngeal HNSCC (HR: 1.78; 95% CI: 1.31-2.30 vs >200). Five-year overall survival of OPSCC (37.0%) was significantly lower than non-oropharyngeal HNSCC (49.1%). CONCLUSIONS: PLWH who receive care in the VA had higher age-adjusted HNSCC incidence rates than reported in the general population, suggesting that HIV and immunosuppression play a role. Additional studies should be conducted to study the interaction between HPV and HIV.

Stable Incidence and Poor Survival for HIV-Related Burkitt Lymphoma Among the US Veteran Population During the Antiretroviral Era.

BACKGROUND: Despite advances in diagnosis and treatment of both HIV and Burkitt lymphoma (BL), persons living with HIV remain at high risk for BL. We conducted this study to evaluate if there have been any changes in the risk of or survival after BL diagnosis among persons living with HIV during the antiretroviral era. SETTING: Veterans living with HIV (VLWH) and age-matched HIV-negative controls receiving care between 1999 and 2016 were retrospectively identified using Veterans Health Administration electronic medical records. METHODS: We identified BL diagnoses through Veterans Health Administration Cancer Registry review and International Classification of Diseases, Ninth/Tenth Revisions, codes, and we extracted demographic, lifestyle, and clinical variables from electronic medical record. We estimated hazard ratios (HR) and 95% confidence intervals (CIs) for BL risk and survival using Cox proportional models. RESULTS: We identified 45,299 VLWH. Eighty-four developed BL (incidence rate = 21.2 per 100,000 person years; CI: 17.1 to 26.3). Median CD4 count at BL diagnosis was 238 cells per milliliter (SD: 324.74) and increased over time. Survival was truncated in VLWH with BL (P < 0.05). The risk of BL in VLWH was 38% less in blacks compared with whites (HR: 0.620; CI: 0.393 to 0.979; P = 0.0401). VLWH with an undetectable viral load for at least 40% of follow-up were 74% less likely to develop BL (HR: 0.261; CI: 0.143 to 0.478; P < 0.0001) and 86% less likely to die after diagnosis (HR: 0.141; CI: 0.058 to 0.348; P < 0.0001). CONCLUSIONS: BL incidence among VLWH did not improve between 2000 and 2016. Survival after BL diagnosis in VLWH remains dismal as compared with their HIV-negative counterparts, although veterans with prolonged periods of undetectable viral load had improved prognosis.

Risk and Predictors of Esophageal and Stomach Cancers in HIV-Infected Veterans: A Matched Cohort Study.

BACKGROUND: To evaluate the risks of esophageal and stomach carcinomas in people living with HIV (PLWH) compared with the general population and risk factors for these cancers in PLWH. SETTING: Retrospective cohort study in the Veterans Health Administration. METHODS: We compared incidence rates for esophageal and stomach cancers in 44,075 HIV-infected male veterans with those in a matched HIV-uninfected cohort (N = 157,705; 4:1 matched on age and HIV-index date). We used Cox regression models to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with HIV infection and for cancer risk factors in PLWH. RESULTS: In unadjusted models, HIV infection was associated with increased risks of esophageal squamous cell carcinoma (ESCC; HR, 2.21; 95% CI: 1.47 to 3.13) and gastric cardia cancer (HR, 1.69; 95% CI: 1.00 to 2.85) but associated with lower risk of esophageal adenocarcinoma (EAC; HR, 0.48; 95% CI: 0.31 to 0.74). After adjusting for age, race/ethnicity, smoking and alcohol use, HIV infection remained statistically significantly associated with elevated risk for ESCC [adjusted hazard ratio (aHR), 1.58; 95% CI: 1.02 to 2.47], especially among HIV-infected patients with CD4 count ≤200 (aHR, 2.20; 95% CI: 1.35 to 3.60). HIV infection was not associated with risks of EAC (aHR, 0.82; 95% CI: 0.53 to 1.26), gastric cardia (aHR, 0.80; 95% CI: 0.33 to 1.94), or noncardia (aHR, 1.06; 95% CI: 0.61 to 1.84) cancers. Risk factors for these cancers in HIV-infected patients were otherwise similar to those in general population (eg, Helicobacter pylori for gastric noncardia cancer). CONCLUSION: HIV-infected individuals with low CD4 count are at highest risk for ESCC, but HIV infection was not independently associated with EAC or gastric cancer after adjusting for confounders.

Cation-selective pathway of OmpF porin revealed by anomalous X-ray diffraction.

The OmpF porin from the Escherichia coli outer membrane folds into a trimer of beta-barrels, each forming a wide aqueous pore allowing the passage of ions and small solutes. A long loop (L3) carrying multiple acidic residues folds into the beta-barrel pore to form a narrow "constriction zone". A strong and highly conserved charge asymmetry is observed at the constriction zone, with multiple basic residues attached to the wall of the beta-barrel (Lys16, Arg42, Arg82 and Arg132) on one side, and multiple acidic residues of L3 (Asp107, Asp113, Glu117, Asp121, Asp126, Asp127) on the other side. Several computational studies have suggested that a strong transverse electric field could exist at the constriction zone as a result of such charge asymmetry, giving rise to separate permeation pathways for cations and anions. To examine this question, OmpF was expressed, purified and crystallized in the P6(3) space group and two different data sets were obtained at 2.6 A and 3.0 A resolution with K(+) and Rb(+), respectively. The Rb(+)-soaked crystals were collected at the rubidium anomalous wavelength of 0.8149 A and cation positions were determined. A PEG molecule was observed in the pore region for both the K(+) and Rb(+)-soaked crystals, where it interacts with loop L3. The results reveal the separate pathways of anions and cations across the constriction zone of the OmpF pore.

Structure and function of interacting IcmR-IcmQ domains from a type IVb secretion system in Legionella pneumophila.

During infection, Legionella pneumophila creates a replication vacuole within eukaryotic cells and this requires a Type IVb secretion system (T4bSS). IcmQ plays a critical role in the translocase and associates with IcmR. In this paper, we show that the N-terminal domain of IcmQ (Qn) mediates self-dimerization, whereas the C-terminal domain with a basic linker promotes membrane association. In addition, the binding of IcmR to IcmQ prevents self-dimerization and also blocks membrane permeabilization. However, IcmR does not completely block membrane binding by IcmQ. We then determined crystal structures of Qn with the interacting region of IcmR. In this complex, each protein forms an alpha-helical hairpin within a parallel four-helix bundle. The amphipathic nature of helices in Qn suggests two possible models for membrane permeabilization by IcmQ. The Rm-Qn structure also suggests how IcmR-like proteins in other L. pneumophila species may interact with their IcmQ partners.