non-AIDS-defining Cancers Research Articles

Risk of cancer in HIV-infected patients in Spain, 2004–2015. The CoRIS cohort study

IntroductionCancer is a leading cause of death in individuals with HIV. MethodsThe incidence of cancer in HIV patients of the CoRIS cohort in the 2004–2009 and 2010–2015 periods has been analysed and compared to the incidence in the Spanish general population, estimated from data of the Spanish Cancer Registry Network. ResultsBetween January 2004 and November 2015, 12,239 patients were included in CoRIS and 338 incident cancer cases were diagnosed. The overall incidence of cancer per 100,000 persons-year (95% CI) was 702.39 (629.51–781.42) with no significant differences between the 2 periods. A 38% of the incident cancer cases were AIDS defining cancers (ADC) and 62% non-AIDS defining cancers (NADC). In the period 2010–2015, there was a significant decrease in the incidence of ADC (standardised incidence ratio [SIR]); 95% CI: 0.38; 0.21–0.66) and NADC predominated. Compared to the general population, the incidence of cancer was double in men with HIV. Higher relative risks were documented (SIR; 95% CI) for Hodgkin's lymphoma in both sexes (males: 8.37, 5.13–14.17; females: 21.83, 2.66–47.79), non-Hodgkin's lymphoma in males (5.30, 2.86–8.45) and cervical cancer (7.43, 3.15–13.87) and head and neck cancer (3.28, 1.21–5.82) in women. ConclusionsThe overall incidence of cancer in individuals with HIV is higher than in the Spanish general population, and it has remained stable since 2004 with a current predominance of NADC. These data suggest that additional efforts should be made in the prevention and the early detection of cancer in these patients.

HIV infection induces CD44+PD-L1+ tumor initiating cells in AIDS associated non-AIDS defining cancers

Abstract The antiretroviral therapy (ART) significantly increased the number of aging HIV patients and the non-AIDS defining cancers (NADC) have become the most frequent co-morbidity and causes of death among HIV patients. The role of HIV infection in cancer initiation and progression is unclear. Tumor initiating cells (TIC) are responsible for chemo-resistance, metastasis and mortality. Our previous work demonstrated that tumor-intrinsic PD-L1 correlate with proportion (%) of TIC and virulence. Supernatants from HIV infected peripheral blood lymphocyte (PBMC) cultures (HIV-sup) significantly increased % TIC (CD44+PD-L1+) in two human tumor cell lines-SCC4 (squamous carcinoma) and HeLa (cervical cancer). HIV single stranded RNA (ssRNA) binds TLR7/8, and leads to immune activation and inflammation. The Cancer Genome Atlas database analyses showed that squamous cancer and cervical adenocarcinoma patients with TLR7/8 amplification had significantly poor overall survival. TLR7 agonist R848 led to significant increase in % TIC, whereas treatment of the cancer cells with HIV-sup in presence of TLR7/8 inhibitor ODN2088 reversed this effect. Similarly, pharmacological inhibition (by ACHP) of TLR7/8 mediated NFkB signaling pathway decreased TIC % two-fold, confirming HIV mediated TLR7/8 signaling has pro-TIC effects. High levels of inflammatory cytokine IFNα correlates with HIV load and persistent infection. Treatment with IFNα led to a significant increase in TIC whereas blocking IFNα-induced JAK signaling by ruxolitinib, in presence of HIV-sup reduced TIC significantly. Thus, our novel data gives insight into HIV induced host-pathogen interactions that lead to TIC prevalence.

Oral oncolytic and antiretroviral therapy administration: dose adjustments, drug interactions, and other considerations for clinical use.

The rise in non-AIDS defining cancers (NADCs) is emerging as a leading cause of death for HIV and cancer patients. To address this, current literature and guidelines suggest the continuation of antiretroviral therapy (ART) with oral oncolytic agents to prevent adverse complications associated with HIV disease progression. However, such an approach has the potential for drug–drug interactions and adverse events for patients on such therapy. Further, recommendations on how to adjust these medications, when used concomitantly, are limited. As such, our purpose is to evaluate existing literature through such means as drug databases (e.g. Micromedex, Lexi-Comp, etc.) and package inserts along with PubMed/Medline, Embase, and Google Scholar databases to develop a reference tool for providers to utilize when there is a decision to treat a patient with ART and oral oncolytic agents concurrently. Our findings suggest that there are many drug interactions that should be taken into consideration with dual therapy. Metabolism is a key determinant of dose adjustment, and many oncolytic agents and ART agents must have their dose adjusted as such. Most notably, several tyrosine kinase inhibitors require dose increases when used with non-nucleoside reverse transcriptase inhibitors (NNRTIs) but must be decreased when used concomitantly with protease inhibitors (PIs) and cobicistat. Further findings suggest that certain agents should not be used together, which include, but are not limited to, such combinations as bosutinib with NNRTIs, cobicistat, or PIs; idelalisib with maraviroc or PIs; neratinib with NNRTIs, cobicistat, or PIs; and venetoclax with NNRTIs. Overall, the most prominent oncolytic drug interactions were discovered when such agents were used concomitantly with PIs, cobicistat-boosted elvitegravir, or NNRTIs. Future studies are necessary to further evaluate the use of these agents together in disease therapy to generate absolute evidence of such findings. However, from the studies evaluated, much evidence exists to suggest that concomitant therapy is not without drug interactions. As such, clinical decisions regarding concomitant therapy should be evaluated in which the risk and benefit of dual therapy are assessed. Dose adjustments must be made accordingly and in consultation with both HIV and oncology clinicians and pharmacists to reduce the risk for adverse outcomes and disease progression for those with cancer and HIV/AIDS.

Breast cancer in women living with HIV.

With the introduction of HAART, the life expectancy of the patients infected with HIV almost approached that of the general population. The incidence of certain HIV-Associated cancers as Kaposi Sarcoma (KS) and Non-Hodgkin Lymphoma (NHL) decreased, while an increase in Non-AIDS-Defining cancers (NADCs) has been documented. HIV infection is a risk factor for numerous cancers in PLWH. Breast cancer is the most common cancer worldwide among all women. The association between HIV infection and breast cancer has not been thoroughly investigated: when compared to the general population, people living with HIV/AIDS (PLWHA) have a similar or slightly lower risk of breast cancer. Screening tests are essential weapons to fight cancer burden and more effective therapeutic and preventive strategies are needed, especially among PLWHA. Further and more comprehensive studies are needed to better characterize breast cancer among PLWH.

Riesgo de cáncer en personas con VIH en España, 2004-2015. Estudio de la cohorte CoRIS

IntroductionCancer is a leading cause of death in individuals with HIV. MethodsThe incidence of cancer in HIV patients of the CoRIS cohort in the 2004-2009 and 2010-2015 periods has been analysed and compared to the incidence in the Spanish general population, estimated from data of the Spanish Cancer Registry Network. ResultsBetween January 2004 and November 2015, 12,239 patients were included in CoRIS and 338 incident cancer cases were diagnosed. The overall incidence of cancer per 100,000 persons-year (95% CI) was 702.39 (629.51-781.42) with no significant differences between the 2periods. A 38% of the incident cancer cases were AIDS defining cancers (ADC) and 62% non-AIDS defining cancers (NADC). In the period 2010-2015, there was a significant decrease in the incidence of ADC (standardised incidence ratio [SIR]); 95% CI: 0.38; 0.21-0.66) and NADC predominated. Compared to the general population, the incidence of cancer was double in men with HIV. Higher relative risks were documented (SIR; 95% CI) for Hodgkin's lymphoma in both sexes (males: 8.37, 5.13-14.17; females: 21.83, 2.66-47.79), non-Hodgkin's lymphoma in males (5.30, 2.86-8.45) and cervical cancer (7.43, 3.15-13.87) and head and neck cancer (3.28, 1.21-5.82) in women. ConclusionsThe overall incidence of cancer in individuals with HIV is higher than in the Spanish general population, and it has remained stable since 2004 with a current predominance of NADC. These data suggest that additional efforts should be made in the prevention and the early detection of cancer in these patients.

Editorial Commentary: Challenge of Non–AIDS-Defining Cancers (NADCs), Focusing on Trans Activation Response Element (TAR) RNA Embedding Exosomes

Editorial Commentary: Challenge of Non–AIDS-Defining Cancers (NADCs), Focusing on Trans Activation Response Element (TAR) RNA Embedding Exosomes

High Cancer Burden Among Antiretroviral Therapy Users in Malawi: A Record Linkage Study of Observational Human Immunodeficiency Virus Cohorts and Cancer Registry Data.

With antiretroviral therapy (ART), AIDS-defining cancer incidence has declined and non-AIDS-defining cancers (NADCs) are now more frequent among human immunodeficiency virus (HIV)-infected populations in high-income countries. In sub-Saharan Africa, limited epidemiological data describe cancer burden among ART users. We used probabilistic algorithms to link cases from the population-based cancer registry with electronic medical records supporting ART delivery in Malawi's 2 largest HIV cohorts from 2000-2010. Age-adjusted cancer incidence rates (IRs) and 95% confidence intervals were estimated by cancer site, early vs late incidence periods (4-24 and >24 months after ART start), and World Health Organization (WHO) stage among naive ART initiators enrolled for at least 90 days. We identified 4346 cancers among 28 576 persons. Most people initiated ART at advanced WHO stages 3 or 4 (60%); 12% of patients had prevalent malignancies at ART initiation, which were predominantly AIDS-defining eligibility criteria for initiating ART. Kaposi sarcoma (KS) had the highest IR (634.7 per 100 000 person-years) followed by cervical cancer (36.6). KS incidence was highest during the early period 4-24 months after ART initiation. NADCs accounted for 6% of new cancers. Under historical ART guidelines, NADCs were observed at low rates and were eclipsed by high KS and cervical cancer burden. Cancer burden among Malawian ART users does not yet mirror that in high-income countries. Integrated cancer screening and management in HIV clinics, especially for KS and cervical cancer, remain important priorities in the current Malawi context.

Increased risk of non-AIDS-defining cancers in Asian HIV-infected patients: a long-term cohort study

BackgroundData on the long-term risks of non-AIDS defining cancers (NADCs) are limited, especially in Asians. The incidence of NADCs may correlate with the epidemiological trend of cancers or oncogenic infection in each country, and thus the target cancers would be different between Western and Asian countries. We aimed to elucidate the incidence of NADCs and its predictive factors in Asian HIV-infected patients.MethodsSubjects were HIV-infected patients (n = 1001) periodically followed-up for 9 years on average. NADCs were diagnosed by histopathology and/ or imaging findings. Standardized incidence ratios (SIR) were calculated as the ratio of the observed to expected number of NADCs for comparison with an age-and sex-matched general population. Cox’s proportional hazards model was used to estimate hazard ratios (HR).ResultsDuring the median follow-up of 9 years, the 10-year cumulative incidence of NADCs was 6.4%.At NADC diagnosis, half of patients presented at age 40–59 years and with advanced tumor stage. Compared with the age-and sex-matched general population, HIV-infected patients are at increased risk for liver cancer (SIR, 4.7), colon cancer (SIR, 2.1), and stomach cancer (SIR, 1.8). In multivariate analysis, a predictive model for NADCs was developed that included age group (40–49, 50–59, 60–69, and ≥ 70 years), smoker, HIV infection through blood transmission, and injection drug use (IDU), and HBV co-infection. The c-statistic for the NADCs predictive model was 0.8 (95%CI, 0.8–0.9, P < 0.001). The higher 10-year incidence rate of NADCs was associated with increasing prediction score.ConclusionsLiver and colon cancer risk was elevated in Asian HIV-infected individuals, similar to in Western populations, whereas stomach cancer risk was characteristically elevated in Asian populations. Half of Asian NADC patients were aged 40–59 years and had advanced-stage disease at diagnosis. Periodic cancer screening may be warranted for high-risk subpopulations with smoking habit, HIV infection through blood transmission or IDU, and HBV co-infection, and screening should be started over 40 years of age.

Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA

People living with HIV/AIDS on antiretroviral therapy have increased risk of non-AIDS-defining cancers (NADCs). However, the underlying mechanism for development and progression of certain NADCs remains obscure. Here we show that exosomes released from HIV-infected T cells and those purified from blood of HIV-positive patients stimulate proliferation, migration and invasion of oral/oropharyngeal and lung cancer cells. The HIV transactivation response (TAR) element RNA in HIV-infected T-cell exosomes is responsible for promoting cancer cell proliferation and inducing expression of proto-oncogenes and Toll-like receptor 3 (TLR3)-inducible genes. These effects depend on the loop/bulge region of the molecule. HIV-infected T-cell exosomes rapidly enter recipient cells through epidermal growth factor receptor (EGFR) and stimulate ERK1/2 phosphorylation via the EGFR/TLR3 axis. Thus, our findings indicate that TAR RNA-containing exosomes from HIV-infected T cells promote growth and progression of particular NADCs through activation of the ERK cascade in an EGFR/TLR3-dependent manner.

Epidemiological trends and therapeutic challenges of malignancies in adult HIV-1-infected patients receiving combination antiretroviral therapy in a tertiary hospital from Romania: An observational retrospective study

BackgroundMalignancies have become a leading cause of morbidity and mortality in people living with HIV (PLHIV). The primary endpoint of our study was to describe the epidemiology of acquired immunodeficiency syndrome (AIDS)-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Epidemiological disparities, mortality predictors and survival analysis within the two groups of patients were key secondary endpoints. MethodsWe retrospectively evaluated all adult PLHIV with histopathologically proven cancers registered from 2010 to 2016 in the “Matei Balș” National Institute for Infectious Diseases, Bucharest, Romania. Results110 eligible patients have been included in the study. The incidence of ADCs decreased from 1.6% in 2010 to 0.3% in 2016, unlike NADCs which remained fairly stable over time (0.3%). The higher CD4 count and lower HIV-RNA level at the cancer diagnosis were associated with prolonged survival in ADCs group, but not in NADCs group. The mean CD4 count was 449/mm3 to survivors and 92/mm3 to non-survivors (p=0.017). The mean level of HIV-RNA was 64,671 copies/mL to survivors and 1,760,345 copies/mL to non-survivors (p=0.002). ConclusionsA good therapeutic control of HIV infection at the diagnosis of ADCs was associated with better survival, emphasizing the key role of the effective cART in the management of HIV-associated cancers.

Human immunodeficiency virus infection in breast cancer patients: The prevalence thereof and its effect on breast cancer characteristics at Dr. George Mukhari Academic Hospital Breast Clinic, Ga-Rankuwa, South Africa.

BackgroundSince the advent of highly active anti-retroviral therapy, improved immune functioning and prolonged survival of Human immunodeficiency virus (HIV)-positive patients has been accompanied by an increased incidence of non-AIDS-defining cancers (NADC). Breast cancer is the most prevalent NADC among HIV-positive women. However, data regarding the interaction between these two diagnoses remain limited.ObjectivesTo determine the effect of HIV status on the presentation of breast cancer patients at Dr. George Mukhari Academic Hospital (DGMAH).MethodsThe age, gender, HIV status, CD4 count and tumour node metastases stage at presentation were recorded from the files of patients with histologically proven breast carcinoma, who had presented to the breast clinic at DGMAH from 01 January 2013 to 30 November 2017. Histological subtypes and molecular markers were retrieved from the National Health Laboratory Service. Prevalence of HIV among breast cancer patients was calculated. Cross-tabulations compared the variables between HIV-positive and HIV-negative groups. Statistical significance was assessed using Fisher’s Exact Test.ResultsHIV status was determined in 129 breast cancer patients. Eighty (62.02%) were HIV-negative and 49 (37.98%) were HIV-positive. All patients were female. The mean age at presentation with breast cancer in the HIV-positive group was approximately 10 years younger, compared to the entire population and to the HIV-negative group (p < 0.0001). No further statistically significant associations were observed concerning HIV status and other variables.ConclusionHIV-positive women present with breast cancer at a significantly younger mean age. Breast cancer screening protocols may need to be adjusted accordingly in such patients.

Body Mass Index and the Risk of Serious Non-AIDS Events and All-Cause Mortality in Treated HIV-Positive Individuals: D:A:D Cohort Analysis

The relationship between body mass index (BMI) [weight (kg)/height (m)] and serious non-AIDS events is not well understood. We followed D:A:D study participants on antiretroviral therapy from their first BMI measurement to the first occurrence of the endpoint or end of follow-up (N = 41,149 followed for 295,147 person-years). The endpoints were cardiovascular disease (CVD); diabetes; non-AIDS-defining cancers (NADCs) and BMI-NADCs (cancers known to be associated with BMI in general population); and all-cause mortality. Using Poisson regression models, we analyzed BMI as time-updated, lagged by 1 year, and categorized at: 18.5, 23, 25, 27.5, and 30 kg/m. Participants were largely male (73%) with the mean age of 40 years (SD 9.7) and baseline median BMI of 23.3 (interquartile range: 21.2-25.7). Overall, BMI showed a statistically significant J-shaped relationship with the risk of all outcomes except diabetes. The relative risk (RR) for the BMI of <18.5 and >30 (95% confidence interval) compared with 23-25, respectively, was as follows: CVD: 1.46 (1.15-1.84) and 1.31 (1.03-1.67); NADCs: 1.78 (1.39-2.28) and 1.17 (0.88-1.54); and "BMI-NADCs": 1.29 (0.66-2.55) and 1.92 (1.10-3.36). For all-cause mortality, there was an interaction by sex (P < 0.001): RR in males: 2.47 (2.12-2.89) and 1.21 (0.97-1.50); and in females: 1.60 (1.30-1.98) and 1.02 (0.74-1.42). RR remained around 1 for intermediate categories of BMI. The risk of diabetes linearly increased with increasing BMI (P < 0.001). Risk of CVD, a range of cancers, and all-cause mortality increased at low BMI (<18.5) and then tended to increase only at BMI > 30 with a relatively low risk at BMI of 23-25 and 25-30. High BMI was also associated with risk of diabetes.

Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials.

This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.

Abstract LB-160: Incidence of non-AIDS-defining cancers over time in the post-ART era

Abstract Background: In the current era of potent antiretroviral therapy (ART), complications and mortality from HIV/AIDS have declined dramatically. ART increasingly allows persons with HIV-infection (PWH) to live longer, but also increases lifetime risk of age-associated chronic diseases such as cancer. Furthermore, the interplay of HIV, immune dysfunction, ART use, aging, and other traditional chronic disease risk factors is under-studied in the context of specific non-AIDS-defining cancers (NADCs). These cancers represent a public health problem that will grow increasingly urgent as HIV-infected individuals age. Descriptive epidemiology of these cancers (compared to Kaposi's sarcoma [KS] and non-Hodgkin's lymphoma [NHL], the most common AIDS-defining cancers [ADCs]), and its changes with the evolution of ART over time, are necessary to address this issue. Methods: This study used longitudinally collected data from the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) which captures clinical, sociodemographic, and behavioral data on over 32,000 PWH in care at eight US treatment sites. We included patients who enrolled in CNICS from 2000 through 2014, were not diagnosed with cancer prior to enrollment, and were followed at a CNICS site for at least 180 days. We used linear regression to calculate cancer type-specific time trends, and poisson regression to calculate incidence densities for all cancers, NADCs, and ADCs. Poisson models were adjusted for: age in 2000 (study baseline), nadir CD4 count, any ART use, and hepatitis C virus co-infection. Age and nadir CD4 were standardized to the population mean prior to Poisson regression. Results: We observed significant changes over time in the incidence rates of colorectal, oropharyngeal, and prostate cancers as well as KS, NHL, and melanoma. From 2000-2014 we observed increases in the incidence densities of colorectal (10.4 to 38.6 cases per 100,000 person-years), oropharyngeal (10.4 to 29.0), and prostate cancers (10.4 to 87.1). Over the same period, we observed decreases in the incidence densities of KS (251.5 to 68.2 cases per 100,000 person-years) and NHL (250.5 to 126.1). The adjusted all-cancer incidence density decreased from 728.6.3 (per 100,000 person-years) in 2000-1 to 518.1 in 2013-4. For ADCs the adjusted incidence density decreased from 224.2 in 2000-1 to 115.5 in 2013-4, while for NADCs the adjusted incidence density increased from 286.7 in 2000-1 to 358.6 in 2013-4. Conclusion: Changes in the incidence densities of NADCs from 2000-2014 reflect the increasing efficacy of ART. PWH are living longer, with reduced incidence of AIDS-defining cancers and increased incidence of age-related NADCs such as colorectal and prostate cancer. These findings support the continued need to study cancer among PWH to better understand their unique risk factors, including the potential influence of immune recovery and ART on specific NADC risk. Citation Format: Brian Thomas Joyce, Elizabeth Hibler, Christopher Matthews, Richard Moore, Joseph Eron, Kenneth Mayer, Mari Kitahata, Michael Saag, Lifang Hou, Chad Achenbach. Incidence of non-AIDS-defining cancers over time in the post-ART era [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-160.

Risk for cancer among people living with AIDS, 1997-2012: the São Paulo AIDS-cancer linkage study.

Previous studies have reported an increased risk for certain types of cancer in the HIV-infected population. The aim of this study was to assess the risk for cancer in people with AIDS (PWA) in comparison with the general population in São Paulo (Brazil), between 1997 and 2012. A population-based registry linkage study was carried out to assess the risk for cancer, using a standardized incidence ratio (SIR) approach. A total of 480 102 person-years, of which 337 941 (70.4%) person-years were men, were included in the analysis. Around 2074 cancer cases were diagnosed among PWA, of which 51.0% were non-AIDS-defining cancers (NADC). The risk for AIDS-defining cancers and NADC in the male population with AIDS was significantly higher than that in the general population (SIR=27.74 and 1.87, respectively), as it was in the female population with AIDS compared with the general population (SIR=8.71 and 1.44, respectively). Most virus-related NADC occurred at elevated rates among PWA: anal cancer (SIR=33.02 in men and 11.21 in women), liver (SIR=4.35 in men and 4.84 in women), vulva and vagina (SIR=6.78 in women) and Hodgkin lymphoma (SIR=5.84 in men and 2.71 in women). Lung (SIR=2.24 in men and 2.60 in women) and central nervous system (SIR=1.92 in men and 3.48 in women) cancers also occurred at increased rates. Cancer burden among PWA in São Paulo was similar to that described in high-income countries such as the USA and Italy following the introduction of the highly active antiretroviral therapy. As coinfection with oncogenic viruses disproportionally affects this population, virus-related cancers accounted for a great share of excessive cases.

Cancer in children and adolescents with AIDS in the city of São Paulo: A population-based linkage study

Introduction Previous studies revealed an elevated risk of cancer in children and adolescents with AIDS. However, there is limited population-based data from developing countries. The objective of the present study was to describe the cancer spectrum in children and adolescents with AIDS in the City of Sao Paulo from 1997 to 2012. Methods It is a population-based registry linkage study using the databases of the Population-based Cancer Registry of Sao Paulo (1997–2012) and of the Sistema de Informacao de Agravos de Notificacao (SINAN)/Information System on Disease Notification (1984–2013). Children and adolescents with AIDS and cancer have been identified by means of a probabilistic record linkage process between the aforementioned databases. We calculated crude and age-standardized incidence rates (world standard population, 0–19 years) per million. To assess trends, we calculated the annual percent change (APC) and its 95% confidence intervals (95% CI) using Joinpoint software. To compare risk of cancer in children with AIDS to that of the general pediatric population of Sao Paulo, we estimated the standardized incidence ratio (SIR) and respective 95% CIs. Analysis were stratified by AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). Results We identified 24 cases of cancer in patients with AIDS aged Conclusion To our knowledge, this is the first population-based study to describe cancer spectrum in children and adolescents with AIDS in Brazil. ADCs still account for an important share of cancer cases in this pediatric population. Between 1997 and 2012, there has been a reduction in the incidence of all cancers, driven by the decrease in the incidence of ADCs because of wide use of antiretroviral therapy. The finding of the present study is in line with previous research conducted in the United States, Spain and Italy. However, children and adolescents with AIDS remain at increased risk for developing ADCs as well as HL in comparison to the general population.

Abstract 5060: Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA

Abstract Background: Residual and persistent HIV replication plays key roles in the development and progression of non-AIDS-defining cancers (NADCs), including head and neck as well as lung cancers. However, the underlying mechanisms remain elusive. HIV-infected T cells produce immunologically active exosomes to influence intercellular communication and regulate immune response at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. We investigated the role of exosomes derived from HIV-infected T cells in growth and progression of head and neck cancer (HNC) and lung cancer cells. Methods: Exosomes were isolated from conditioned media of HIV-1-infected J1.1 cells and non-infected control Jurkat cells using the ultracentrifugation protocol. Exosomes were validated by western blotting for tetraspanins (CD9, CD63 and CD81) and transmission electron microscope. The acetyl-CoA acetylcholinesterase (AChE) enzyme activity was used to quantify exosomes. HNC cells UM-SCC-104, TR146, HSC3, SCC9 and lung cancer cells NCI-H1299, NCI-H1437 were treated with exosomes for cell growth, migration and gene expression in vitro and in vivo. Exosome HIV RNA was determined by quantitative RT-PCR. Results: Exosomes isolated from HIV-1-infected T cells, but not those from normal control T cells, significantly stimulated HNC and lung cancer cell proliferation, migration and invasion in vitro. Exosomes purified from plasma of HIV-positive individuals also stimulated proliferation of cancer cells. HNC and lung cancer cells co-inoculation with exosomes from HIV-1-infected T cells into nude mice promoted tumor growth compared to those from non-HIV control T cells. Mechanistically, we found that the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosomes from HIV-1-infected T cells, enhanced cancer cell proliferation and stimulated EGF- and TLR3-inducible gene expression. The TAR RNA mutant with nucleotide replacements in the loop/bulge region failed to induce gene expression. Moreover, co-transfection of the TAR RNA aptamer blocked induction of gene expression induced by HIV-positive T-cell exosomes. Conclusion: HIV TAR RNA-containing exosomes derived from HIV-1-infected T cells promote growth and progression of NADCs through interaction with EGFR and TLR3. Citation Format: Lechuang chen, Zhimin Feng, Hong Yue, Scott Sieg, Bingcheng Wang, Alex Y. Huang, Ge Jin. Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5060.

Association of Viral Suppression With Lower AIDS-Defining and Non-AIDS-Defining Cancer Incidence in HIV-Infected Veterans: A Prospective Cohort Study.

Viral suppression is a primary marker of HIV treatment success. Persons with HIV are at increased risk for AIDS-defining cancer (ADC) and several types of non-AIDS-defining cancer (NADC), some of which are caused by oncogenic viruses. To determine whether viral suppression is associated with decreased cancer risk. Prospective cohort. Department of Veterans Affairs. HIV-positive veterans (n= 42441) and demographically matched uninfected veterans (n= 104712) from 1999 to 2015. Standardized cancer incidence rates and Poisson regression rate ratios (RRs; HIV-positive vs. uninfected persons) by viral suppression status (unsuppressed: person-time with HIV RNA levels ≥500 copies/mL; early suppression: initial 2 years with HIV RNA levels <500 copies/mL; long-term suppression: person-time after early suppression with HIV RNA levels <500 copies/mL). Cancer incidence for HIV-positive versus uninfected persons was highest for unsuppressed persons (RR, 2.35 [95% CI, 2.19 to 2.51]), lower among persons with early suppression (RR, 1.99 [CI, 1.87 to 2.12]), and lowest among persons with long-term suppression (RR, 1.52 [CI, 1.44 to 1.61]). This trend was strongest for ADC (unsuppressed: RR, 22.73 [CI, 19.01 to 27.19]; early suppression: RR, 9.48 [CI, 7.78 to 11.55]; long-term suppression: RR, 2.22 [CI, 1.69 to 2.93]), much weaker for NADC caused by viruses (unsuppressed: RR, 3.82 [CI, 3.24 to 4.49]; early suppression: RR, 3.42 [CI, 2.95 to 3.97]; long-term suppression: RR, 3.17 [CI, 2.78 to 3.62]), and absent for NADC not caused by viruses. Lower viral suppression thresholds, duration of long-term suppression, and effects of CD4+ and CD8+ T-cell counts were not thoroughly evaluated. Antiretroviral therapy resulting in long-term viral suppression may contribute to cancer prevention, to a greater degree for ADC than for NADC. Patients with long-term viral suppression still had excess cancer risk. National Cancer Institute and National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.

Are Non-HIV Malignancies Increased in the HIV-Infected Population?

The introduction of antiretroviral therapy (ART) has revolutionized HIV infection management, resulting in improved outcomes and survival for people living with HIV (PLWH). However, as PLWH are living longer and aging, non-AIDS-defining cancers (NADCs) represent a significant source of morbidity and mortality in the HIV-infected population. Here, we review the epidemiology of NADCs in PLWH. Cancer mortality among PLWH is much higher than that among the general population. Up to 10% of deaths among PLWH have been attributed to NADCs. Furthermore, PLWH have an increased risk for specific NADCs, including lung cancer, hepatocellular carcinoma, head and neck cancers, anal cancer, and Hodgkin lymphoma. In the past decade, the incidence rates of AIDS-defining cancers (ADCs) have been decreasing while the incidence rates of NADCs have been increasing. In particular, the incidence of specific NADCs are changing at different rates. For example through 2010, the incidence rates for anal, liver, and prostate cancers among PLWH had increased, while incidence rates for lung cancer had decreased and incidence rates for colorectal cancer remained relatively stable over time. However, as early ART becomes more prevalent and the percentage of PLWH over 50 increases, these trends may evolve further. Incidence of NADCs should be expected to increase further as the PLWH population continues to age. Screening and prevention for these cancers among the HIV-infected population should be emphasized.

Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America

BackgroundThis study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort.MethodsDemographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer ≤ 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type.ResultsAmong 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range [IQR]: 32–47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio [aHR] = 1.63, p = 0.02), age (aHR = 1.02 per year, p = 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year, p = 0.01).ConclusionADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV.