non-AIDS-defining Cancers Research Articles

Tumor Initiation and Progression in People Living on Antiretroviral Therapies

Antiretroviral therapy (ART) has significantly extended the lifespan of people living with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS), thereby transforming the disease into a manageable chronic condition. However, this increased longevity has led to a higher incidence of non-AIDS-defining cancers (NADCs) among this population. In this holistic review, we explore the complex interactions between HIV, ART, and cancer development, focusing on how ART influences tumor initiation and progression in people living with HIV/AIDS (PLWHA). Our findings from this reveal several critical aspects of cancer risk in PLWHA. Firstly, while ART restores immune function, it does not fully normalize it. Chronic immune activation and persistent inflammation continue to be prevalent, creating a conducive environment for oncogenesis. Additionally, PLWHA are more susceptible to persistent infections with oncogenic viruses such as human papillomavirus (HPV) and Epstein–Barr virus (EBV), further increasing cancer risk. Some ART drugs have been implicated in genotoxicity and mitochondrial dysfunction, potentially promoting tumorigenesis. ART-induced metabolic changes, including insulin resistance and dyslipidemia, are also associated with heightened cancer risk. Common NADCs in PLWHA include lung cancer, liver cancer, anal cancer, and Hodgkin lymphoma, each with distinct etiologies linked to both HIV-related and ART-related factors. The interplay between HIV infection, chronic inflammation, immune restoration via ART, and the direct effects of ART drugs creates a unique cancer risk profile in PLWHA. Although ART reduces the incidence of AIDS-defining cancers, it does not confer the same protective effect against NADCs. Persistent HIV-related inflammation and immune activation, despite viral suppression, are key factors in cancer development. Additionally, long-term exposure to ART may introduce new oncogenic risks. These insights highlight the need for integrated cancer screening and prevention strategies tailored to PLWHA. Future research is needed to focus on identifying biomarkers for early cancer detection and developing ART regimens with lower oncogenic potential. Healthcare providers should be vigilant in monitoring PLWHA for cancer and adopt comprehensive screening protocols to mitigate the increased cancer risk associated with ART.

Brief Report: Protease Inhibitors Versus Nonnucleoside Reverse Transcriptase Inhibitors and the Risk of Cancer Among People With HIV

Background: The effect of initial antiretroviral therapy (ART) class on cancer risk in people with HIV (PWH) remains unclear. Setting: A cohort study of 36,322 PWH enrolled (1996–2014) in the North American AIDS Cohort Collaboration on Research and Design. Methods: We followed individuals from ART initiation (protease inhibitor [PI]-based, nonnucleoside reverse transcriptase inhibitor [NNRTI]-based, or integrase strand transfer inhibitor [INSTI]-based) until incident cancer, death, loss-to-follow-up, December 31, 2014, 85 months (intention-to-treat analyses [ITT]), or 30 months (per-protocol [PP] analyses). Cancers were grouped (nonmutually exclusive) as follows: any cancer, AIDS-defining cancers (ADC), non-AIDS-defining cancers (NADC), any infection-related cancer, and common individual cancer types. We estimated adjusted hazard ratios (aHR) comparing cancer risk by ART class using marginal structural models emulating ITT and PP trials. Results: We observed 17,004 PWH (954 cancers) with PI-based (median 6 years follow-up), 17,536 (770 cancers) with NNRTI-based (median 5 years follow-up), and 1782 (29 cancers) with INSTI-based ART (median 2 years follow-up). Analyses with 85-month follow-up indicated no cancer risk differences. In truncated analyses, the risk of ADCs (aHR 1.33; 95% CI: 1.00, 1.77 [PP analysis]) and NADCs (aHR 1.23; 95% CI: 1.00 to 1.51 [ITT analysis]) was higher comparing PIs vs. NNRTIs. Conclusions: Results with longer-term follow-up suggest being on a PI-based versus NNRTI-based ART regimen does not affect cancer risk. We observed shorter-term associations that should be interpreted cautiously and warrant further study. Further research with a longer duration of follow-up that can evaluate INSTIs, the current first-line recommended therapy, is needed to comprehensively characterize the association between ART class and cancer risk.

Nationwide Longitudinal Annual Survey of HIV/AIDS Referral Hospitals in Japan From 1999 to 2021: Trend in Non-AIDS-defining Cancers Among Individuals Infected With HIV-1.

Non-AIDS-defining cancers (NADCs) in patients infected with HIV have recently attracted attention because of the improved survival of this patient population. To obtain accurate data, a longitudinal study is warranted for the nationwide surveillance of the current status and national trend of NADCs in patients infected with HIV in Japan. An annual nationwide surveillance of NADCs in patients infected with HIV-1 in Japan from 1999 to 2021. An annual questionnaire was sent to 378 HIV/AIDS referral hospitals across Japan to collect data (clusters of differentiation 4-positive lymphocytes, time of onset, outcomes, and antiretroviral therapy status) of patients diagnosed with any of the NADCs between 1999 and 2021. The response and case-capture rates for the questionnaires in 2021 were 37.8% and 81.2%, respectively. The number of reported NADC cases subsequently increased since the beginning of this study. Evaluation of the case counts of NADCs demonstrated a high incidence of lung, colorectal, gastric, and liver cancers as the top 4 cancers. Pancreatic cancer (0.63), lung cancer (0.49), and leukemia (0.49) had the highest mortality rates among the NADCs. Trends of NADCs regarding transmission routes were maintained over the years in male individuals who have sex with male individuals compared with heterosexual male individuals and female individuals. We demonstrated an increasing trend in the incidence of NADCs over a period of 23 years in Japan. The current data highlighted the importance of raising awareness regarding cancer management for patients infected with HIV in Japan.

The Trends and Risk Factors of AIDS-Defining Cancers and Non-AIDS-Defining Cancers in Adults Living with and without HIV: A Narrative Review.

People living with HIV (PLHIV) are at a high-risk of developing AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs). This review is aimed at exploring available evidence regarding the trends of ADCs and NADCs and the associated risk factors among adult PLHIV. We conducted a comprehensive search of PubMed, Web of Science, and EBSCO host databases to identify articles published between 2010 and 2023 that reported incidence and mortality rates of cancer, including ADCs and NADCs among PLHIV. We compared trends and rates in PLHIV with HIV-negative adults and further assessed related risk factors. A total of 1886 potentially eligible articles were screened, and of these, 36 were included in this study. More than 50% (n = 20) of these were based in high-income countries. Seventeen studies reported a higher prevalence of NADCs compared to ADCs, with twelve of these conducted in high-income countries. Conversely, eight out of twelve studies reporting a higher prevalence of ADCs versus NADCs were from low-and-middle and upper-middle-income countries. Ten studies indicated a higher incidence of ADCs (6 studies) and NADCs (4 studies) among PLHIV compared to HIV-negative individuals. In contrast, only two studies observed an increase in NADCs among the HIV-negative population. In comparing mortality, seven out of nine studies showed elevated NADC-related deaths compared to ADCs. The main risk factors identified for any cancer, NADCs, and related mortality were advancing age, and longer duration of HIV infection, while lower CD4 cell counts (<200 cells/μl), was associated with both ADC and NADC occurrences. Chronic HIV infection combined with advancing age in PLHIV taking antiretroviral therapy appears to have contributed to increasing cancer burden, particularly the incidence of NADCs and associated mortality. These findings stress the importance of screening for high-risk cancers among PLHIV for early detection and treatment to ensure improved outcomes.

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

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. 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. 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). This study demonstrates that even for PWH on ART therapy, maintaining HIV control is associated with lower risk of both viral and nonviral NADCs.

Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up

PurposeOur aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors.MethodsWe included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004–2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors.ResultsAmong 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use.ConclusionNon-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.

Engaging Resource-Constrained Countries in Research Trials of HIV and Cancer: Lessons from Sub-Saharan Africa and the AIDS Malignancy Consortium

HIV contributes significantly to the global burden of cancer. In developing countries, AIDS-defining cancers predominate due to inconsistent access to antiretroviral therapy (ART). Even though AIDS-defining cancers are now less common in developed countries, the prevalence of non-AIDS-defining cancers (NADCs) has increased due to longer life expectancy in a milieu of chronic immune activation, exposure to oncogenic viruses, lifestyle factors, and environmental variables. In resource-constrained countries with inconsistent access to ART, Kaposi sarcoma, aggressive B-cell lymphomas, and cervical cancer continue to be a large problem. Not only do people living with HIV (PLWH) face higher cancer incidence and mortality, but they also encounter persistent stigmatization and barriers to equitable access to cancer treatment. To bridge this gap, the United States National Cancer Institute (NCI) established the AIDS Malignancy Consortium (AMC) to evaluate novel treatments, preventive strategies, and clinical guidelines for PLWH by conducting both domestic and international research. The AMC also emphasizes the development of robust research infrastructure in resource-limited countries, training of researchers, and fair management of clinical trial specimens. Despite various challenges, the AMC has contributed significant insights to international cancer trials among PLWH, thereby transforming clinical practice in low-resource areas. The high global burden of HIV-associated cancer underscores the need for comprehensive research, improved healthcare access, and greater inclusion of PLWH in cancer clinical trials.

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

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. 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. 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. 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). 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.

Association of CD4 + cell count and HIV viral load with risk of non-AIDS-defining cancers.

HIV-induced immunodeficiency contributes to an increased risk of non-AIDS-defining cancers (NADC). This study aims to identify the most predictive viral load (VL) or CD4 + measures of NADC risk among people with HIV (PWH). Extracted from South Carolina electronic HIV reporting system, we studied adult PWH who were cancer-free at baseline and had at least 6 months of follow-up since HIV diagnosis between January 2005 and December 2020. Using multiple proportional hazards models, risk of NADC was investigated in relation to 12 measures of VL and CD4 + cell count at three different time intervals before NADC diagnosis. The best VL/CD4 + predictor(s) and final model were determined using Akaike's information criterion. Among 10 413 eligible PWH, 449 (4.31%) developed at least one type of NADC. After adjusting for potential confounders, the best predictors of NADC were the proportion of days with viral suppression (hazard ratio [HR]: 0.47 (>25% and ≤50% vs. 0), 95% confidence interval [CI]: [0.28, 0.79]) and proportion of days with low CD4 + cell count (AIC = 7201.35) (HR: 12.28 (>75% vs. = 0), 95% CI: [9.29, 16.23]). VL and CD4 + measures are strongly associated with risk of NADC. In analyses examining three time windows, proportion of days with low CD4 + cell count was the best CD4 + predictor for each time window. However, the best VL predictor varied across time windows. Thus, using the best combination of VL and CD4 + measures for a specific time window should be considered when predicting NADC risk.

Burden of chronic health conditions (CHCs) among people with HIV (PWH) and non-AIDS defining cancers (NADC): A report from the center for AIDS research (CFAR) network of integrated clinical systems (CNICS).

12089 Background: Advances in anti-retroviral therapy (ART) have led to improved life expectancy of PWH and a growing population of PWH who are at an increased risk of NADC. While the risk of CHCs in HIV uninfected cancer survivors is well known, the burden of morbidity (CHCs) borne by PWH-NADC remains unstudied and can adversely influence long-term survival. Methods: We utilized CNICS data for PWH ≥18y from 1995- 2018. CNICS data are harmonized across 8 academic sites, comprising patient-level clinical, morbidity, and outcomes data in the ART era. We included individuals with the five most common NADCs: anal squamous cell cancer, non-small cell lung cancer (NSCLC), prostate cancer, classic Hodgkin lymphoma (cHL), and hepatocellular cancer (HCC). For controls, we conducted a 1:2 matching (age at CNICS entry, year of CNICS entry, sex) for each NADC subgroup to select PWH and no NADC at last follow-up. Comorbidities diagnosed after cohort entry are validated in CNICS and were graded using the Common Terminology Criteria for Adverse Events into grade 1 (mild) through grade 4 (severe/life-threatening). Results: We included 693 PWH-NADC and 1,345 non-cancer PWH controls in this study. The NADC distribution was anal cancer (n = 195, 28%), NSCLC (n = 155, 22%), prostate cancer (n = 144, 21%), cHL (n = 124, 18%), and HCC (n = 75, 11%). Mean age at CNICS entry was 45y for cases and controls (SD: 10.4). At a median follow-up of 12.5y for cases and 9.5y for controls, the prevalence of all-grade and grade ≥3 CHCs was higher in PWH-NADC compared with controls (94% vs. 88%, and 25% vs. 14%, respectively [p &lt; 0.01]). PWH-NADC had a higher prevalence of all-grade HTN (87% vs. 80%), CKD (49% vs. 46%), hyperlipidemia (56% vs. 50%), DM (26% vs. 18%), VTE (4% vs. 1%), MI (12% vs. 5%), and CHF (7% vs. 3%) compared with controls (p-value for all &lt; 0.01). In Cox regression including type of NADC, age at CNICS cohort entry, ART use, race/ethnicity, NADCs were associated with increased risk of new-onset grade 3 or 4 CHCs (HR 2.94, p &lt; 0.01). When examining specific CHCs, all NADCs were associated with increased risk of new-onset grade 3 DM ([anal cancer HR 2.34, HCC HR 5.02, NSCLC HR 3.89, cHL HR 2.77, and prostate cancer HR 1.88], p-value for all &lt; 0.01). Additionally, NSCLC was associated with increased risk of G3-4 MI (HR 2.79, p = 0.04), and prostate cancer with G3-4 CHF (HR 6.19, p &lt; 0.01). Conclusions: In this large multi-institutional study, 25% of PWH-NADC had developed severe/life-threatening CHCs at last follow up. Occurrence of NADC among PWH was associated with increased hazards of developing grade ≥3 morbidities. The specific types of CHCs observed in PWH with NADC subtypes could be used to inform risk-based anticipatory surveillance and risk reduction strategies.

HIV Prevalence and Characteristics Among Patients With AIDS-Defining and Non-AIDS-Defining Cancers in a Tertiary Hospital in Kenya.

Antiretroviral therapy (ART) has resulted in a higher life expectancy of persons living with HIV. This has led to an aging population at risk for both non-AIDS-defining cancers (NADCs) and AIDS-defining cancers (ADCs). HIV testing among patients with cancer in Kenya is not routinely performed, making its prevalence undefined. The aim of our study was to determine the prevalence of HIV and the spectrum of malignancies among HIV-positive and HIV-negative patients with cancer attending a tertiary hospital in Nairobi, Kenya. We conducted a cross-sectional study between February 2021 and September 2021. Patients with a histologic cancer diagnosis were enrolled. Demographic data and HIV- and cancer-related clinical variables were obtained. HIV pretest counseling and consent were done, and testing was performed using a fourth-generation assay. Positive results were confirmed using a third-generation assay. We enrolled 301 patients with cancer; 67.8% (204 of 301) were female; the mean age was 50.7 ± 12.5 years. From our cohort, 10.6% (95% CI, 7.4 to 14.7, n = 32 of 301) of patients were HIV-positive with the prevalence of a new HIV diagnosis of 0.7% (n = 2 of 301). Of the HIV-positive patients, 59.4% (19 of 32) had a NADC. The commonest NADC was breast cancer (18.8%; 6 of 32), whereas non-Hodgkin lymphoma (18.8%; 6 of 32) and cervical cancer (18.8%; 6 of 32) were the most prevalent ADCs among HIV-positive patients. The prevalence of HIV infection among patients with cancer was twice the Kenya national HIV prevalence. NADCs comprised a larger percentage of the cancer burden. Universal opt-out HIV testing of patients attending for cancer care regardless of cancer type may facilitate early recognition of HIV-infected patients and aid in appropriate selection of ART and cancer therapies and preventive strategies.

Changing trends in the incidence and spectrum of cancers between 1990 and 2021 among HIV-infected patients in Busan, Korea

BackgroundLong-term follow-up data on cancer incidence and spectrum among human immunodeficiency virus (HIV)-infected individuals in Korea have been scarce. Material and MethodsThis retrospective cohort study included HIV-infected individuals visiting a tertiary care hospital in Busan, South Korea between 1990 and 2021. The observation was divided into 4 periods. The incidence rate was calculated using direct standardization on age and sex, stratified by calendar period. ResultsOf the 1,297 patients, 92 patients (7.1%) were diagnosed with 97 cancers. Excluding 37 patients with prevalent cancer, 1,260 patients were followed for a total of 8,803.7 person-years (PYs), and 55 patients developed 60 incident cancers including 5 second primary incident cancers. In men, the AIDS-defining cancer (ADC) incidence decreased from 294.7 per 100,000 PYs in 1990–1997 to 124.8 per 100,000 PYs in 2014–2021, while the non-AIDS-defining cancer (NADC) incidence increased from 0 per 100,000 PYs to 316.5 per 100,000 PYs during the same period. The proportion of virus-unrelated NADCs (VU-NADCs) increased from 33.3% in 1998–2005 to 49% in 2014–2021. The proportion of human papillomavirus-associated cancers (HPVACs) has recently increased in both ADCs and NADCs. The median time from HIV diagnosis to their first cancer was 1.48 years for ADCs, 6.11 years for VR-NADCs, 8.3 years for VU-NADCs, and 11.5 years for HPVACs. ConclusionThe incidence of NADCs is increasing with the aging of HIV-infected patients, and thus, it is necessary to promote cancer screening and prevention programs.

Abstract B012: Advanced epigenetic aging in non-AIDS-defining cancer patients living with HIV

Abstract Background. With widespread use of antiretroviral therapy, people with HIV (PWH) are living longer and are now at risk for age-related co-morbidities, including non-AIDS defining cancers (NADCs). Given this epidemiological trend, it is important to understand how prolonged HIV infection may relate to molecular features of aging that can impact cancer risk or outcomes. Methyl groups naturally accumulate on human DNA over time, and methylation patterns can be translated into metrics of accelerated aging. We compared epigenetic measures of aging between PWH receiving treatment for an NADC and matched HIV-uninfected NADC patients at Moffitt Cancer Center in Tampa, Florida. Methods. We identified PWH diagnosed with a non-AIDS defining solid tumor from 2004 to 2021 were identified. To be included, patients needed to have an archived specimen amenable for DNA extraction (whole blood, buffy coat, or PBMC) collected within 1 year of cancer diagnosis. HIV-uninfected matches were identified in a similar manner and matched by tumor site, reported age (+/- 5 years), tumor sequence (primary vs. non-primary), and treatment status. Extracted DNA was assayed using the Illumina MethylationEPIC BeadChip, which incorporates data from 850,000 CpG sites across the genome. Data were translated into a biological age using the epiTOC2 clock, which estimates the number of total number of stem cell divisions, and GrimAge, associated with mortality. Methylation data were also deconvoluted to determine immune cell composition (CD4+ T-cells, CD8+ T-cells, B-cells, neutrophils, natural killer cells, monocytes, basophils, eosinophils). Epigenetic age and immune cell proportions were compared across HIV status using Wilcoxan rank sum testing. Age acceleration was calculated as the difference (residuals from a linear model) in the observed age for PWH and a NADC diagnosis, compared to the predicted age based on HIV-uninfected NADC patients, using both unadjusted and immune-cell adjusted linear models. Results. DNA methylation was assessed in 65 NADC PWH and HIV and 64 HIV-uninfected NADC patients. Epigenetic age assessed using the epiTOC2 and GrimAge clocks was significantly elevated in PWH (p&amp;lt;0.001 and p=0.02, respectively). When methylation data was used to de-convolute immune cell composition, the proportion of CD4+ T-cells and neutrophils was significantly (P&amp;lt;0.05) lower in PWH, while the proportions of memory B-cells and CD8+ T-cells were higher. Epigenetic age was accelerated in PWH compared to HIV-uninfected patients using both epiTOC2 and GrimAge clocks, with the difference in the GrimAge clock remaining significant after adjustment for immune cell composition (P-value&amp;lt;0.01). Conclusions. The results of this study demonstrated age acceleration in PWH with a NADC diagnosis compared to their HIV-uninfected counterparts. As cancer is now the leading cause of non-AIDS death in PWH, research into the prognostic implications of these differences is warranted. Citation Format: Anna E. Coghill, Brittney Dickey, Ryan Putney, Anders Berglund. Advanced epigenetic aging in non-AIDS-defining cancer patients living with HIV [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B012.

Cancer in patients with and without HIV infection in the national cancer registry of Rwanda.

As antiretroviral therapy (ART) has been widely scaled up in Rwanda, life expectancies among people with HIV (PWH) have increased. With increasing viral suppression, AIDS-defining cancers (ADCs) typically decrease; however, as the PWH population ages, non-AIDS-defining cancers (NADCs) will be expected to increase. The aim of this study was to compare cancer diagnoses between PWH and patients without HIV in Rwanda and to describe the changes in the number and types of cancer over time. Retrospective cohort study. Rwanda National Cancer Registry (RNCR) recorded the HIV status, primary site, and morphological description for cancer diagnoses from 2007 to 2018. Descriptive analyses were carried out by cancer group (HIV+ and HIV-). A portion of patients whose HIV status was unknown (63%) were excluded from the present analysis. Among the 20 258 cases registered in the Registry, there were 1048 PWH and 6359 HIV- individuals. The proportion of ADCs were significantly higher in the PWH group compared to those without HIV ( P < 0.001). Among PWH, there was a longitudinal increase in NADCs and a decrease in ADCs ( P < 0.001) over time. Among the ADCs in the PWH group, there was a significant decline in Kaposi sarcoma cases over time. The study demonstrates a decreasing frequency of ADCs driven by declines in Kaposi sarcoma diagnoses and an increased frequency of NADCs among PWH in Rwanda over time. These findings support a need for focusing early detection and management efforts on NADCs, as they begin to play a larger role in the disease processes that affect the aging PWH population.

Incidence and mortality of non-AIDS-defining cancers among people living with HIV: A systematic review and meta-analysis.

SummaryBackgroundNon-AIDS-defining cancers (NADCs) are now becoming a rising cause of morbidity among people living with HIV (PLHIV) in the highly active antiretroviral therapy (HAART) era. We conducted a systematic review and meta-analysis to estimate the summary risk of incidence and mortality of a wide range of NADCs among PLHIV compared with the general population.MethodsThis systematic review and meta-analysis was registered in the PROSPERO (registration number CRD42020222020). We searched PubMed, EMBASE, Cochrane library, and Web of Science for relevant studies published before Jan 24, 2022. Cohort or registry linkage studies comparing the incidence or mortality of individual NADCs in PLHIV with that in the general population were included. Studies simply reporting outcomes of cancer precursor lesions or combined NADCs were excluded. We calculated pooled standardised incidence (SIRs) and standardised mortality ratios (SMRs) and their 95% confidence intervals (CIs) using random-effects models, and used robust variance estimation to account for non-independence in study-level effect sizes.FindingsWe identified 92 publications arising from 46 independent studies including 7 articles out of 7 studies from developing countries. Among the 40 types of NADCs investigated, all of the 20 infection-related NADCs, cancers related with human papillomavirus infection in particular, and half of the 20 non-infection-related NADCs occurred in excess in PLHIV compared with the general population. This risk pattern was consistent in most WHO regions and in both high-income and low-and middle-income countries. The increased SIRs for various NADCs were more evident among PLHIV with advanced immunodeficiency, and was explored by HIV transmission route, and use of HAART. PLHIV had increased mortality for anal cancer (SMR 124·07, 95% CI 27·31-563·72), Hodgkin lymphoma (41·03, 2·91−577·88), liver cancer (8·36, 3·86−18·11), lung cancer (3·95, 1·52-10·26), and skin melanoma (3·95, 1·28−12·2).InterpretationPLHIV had increased incidence and mortality for a wide spectrum of NADCs. Primary prevention and effective treatment for NADCs in this population is urgently needed.FundingNatural Science Foundation of China Excellent Young Scientists Fund, Natural Science Foundation of China International/Regional Research Collaboration Project, National Science and Technology Major Project of China, Sanming Project of Medicine in Shenzhen, High Level Project of Medicine in Longhua, Shenzhen, Shenzhen Science and Technology Innovation Commission Basic Research Program, Special Support Plan for High-Level Talents of Guangdong Province, the Guangzhou Basic Research Program on People's Livelihood Science and Technology, the National Natural Science Foundation of China.

Nationwide population-based incidence of cancer among patients with HIV/AIDS in South Korea

Cancers are the leading cause of death among people living with HIV/AIDS (PLWHA); however, nationwide studies on cancer incidence are limited. We aimed to determine the trends in the incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) among Korean PLWHA. Data from the National Health Insurance Sharing Service from 2004 to 2017 were collected. Age- and sex-adjusted standardized incidence ratios (SIRs) for various cancer types relative to the general population were calculated. Of the 11,737 PLWHA followed-up for 65,052 person-years (PYs), 445 (ADCs, 130 and NADCs, 298) developed cancer. The incidence rate of ADCs decreased, whereas that of NADCs remained unchanged. PLWHA were at an increased risk of ADCs (SIR: 12.6, 95% CI: 10.6–15.0), including Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer, and some NADCs, including anal cancer, lung cancer, liver cancer, and oropharyngeal cancer. Of the 396 patients who received antiretroviral therapy (ART), 215 with optimal adherence had lower incidence rates for ADCs and NADCs than those with non-optimal adherence. The 5-year survival rate of PLWHA with NADCs was 57.8%. Close surveillance and routine screening of cancers and improvement in ART adherence are required to improve the clinical outcomes of PLWHA.

Altered mucosal immunity in HIV-positive colon adenoma: decreased CD4+ T cell infiltration is correlated with nadir but not current CD4+ T cell blood counts.

People living with HIV (PLWH) face greater risks of developing non-AIDS-defining cancers (NADCs) than the general population; however, the underlying mechanisms remain elusive. The tumor microenvironment plays a significant role in the carcinogenesis of colorectal cancer (CRC), an NADC. We studied this carcinogenesis in PLWH by determining inflammatory phenotypes and assessing PD-1/PD-L1 expression in premalignant CRC stages of colon adenomas in HIV-positive and HIV-negative patients. We obtained polyp specimens from 22 HIV-positive and 61 HIV-negative participants treated with colonoscopy and polyp excision. We analyzed adenomas from 33 HIV-positive and 99 HIV-negative patients by immunohistochemistry using anti-CD4, anti-CD8, anti-FoxP3, and anti-CD163 antibodies. Additionally, we analyzed the expression levels of immune checkpoint proteins. We also evaluated the correlation between cell infiltration and blood cell counts. HIV-positive participants had fewer infiltrating CD4+ T cells than HIV-negative participants (p=0.0016). However, no statistical differences were observed in infiltrating CD8+ and FoxP3+ T cells and CD163+ macrophages. Moreover, epithelial cells did not express PD-1 or PD-L1. Notably, CD4+ T cell infiltration correlated with nadir blood CD4+ T cell counts (p< 0.05) but not with current blood CD4+ T cell counts. Immune surveillance dysfunction owing to decreased CD4+ T cell infiltration in colon adenomas might be involved in colon carcinogenesis in HIV-positive individuals. Collectively, since the nadir blood CD4+ T cell count is strongly correlated with CD4+ T cell infiltration, it could facilitate efficient follow-up and enable treatment strategies for HIV-positive patients with colon adenomas.

Prevalence and trend of AIDS-defining cancers and non-AIDS-defining cancers and their association with antiretroviral therapy among people living with HIV in South Carolina: a population-based cohort study

ABSTRACT Monitoring cancer trends and risk is critical as cancer remains a growing problem in persons living with HIV (PLWH). Recent population-based data are limited regarding the cancer trends among PLWH. Our study examined the prevalence and trends in the rate of AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC) and their risk factors in PLWH in South Carolina. Utilizing linked population-based HIV data (2005–2020), time-dependent proportional hazards model was used to identify associated risk predictors of developing cancer in PLWH. Among 11,238 PLWH, 250 individuals developed ADC and 454 developed NADC. The median time from HIV diagnosis to cancer diagnosis was 1.9 years for ADC and 3.8 years for NADC. Individuals who developed ADC or NADC were more likely to be older, male, use substances, have hepatitis infection, hypothyroidism, hypertension, and renal disease. Individuals with viral load >100,000 copies/ml were more likely to develop ADC while those with CD4 count >350 cells/mm3 were less likely to develop ADC or NADC. Our findings suggest that long-term viral suppression may contribute to risk reduction for cancer in PLWH. Early HIV diagnosis along with viral load suppression should be a part of ongoing cancer prevention efforts.

A retrospective study of distribution of HIV associated malignancies among inpatients from 2007 to 2020 in China

HIV-associated malignancies are responsible for morbidity and mortality increasingly in the era of potent antiretroviral therapy. This study aimed to investigate the distribution of HIV-associated malignancies among inpatients, the immunodeficiency and the effect of antiretroviral therapy (ART) on spectrum of HIV-associated malignancies. A total of 438 cases were enrolled from 2007 to 2020 in Beijing Ditan Hospital. Demographic, clinical and laboratory data, managements, and outcomes were collected and analyzed retrospectively. Of 438 cases, 433 were assigned to non-AIDS-defining cancers (NADCs) (n = 200, 45.7%) and AIDS-defining cancers (ADCs) (n = 233, 53.2%), 5 (1.1%) with lymphoma were not specified further. No significant change was observed in the proportion of NADCs and ADCs as time goes on. Of NADCs, lung cancer (n = 38, 19%) was the most common type, followed by thyroid cancer (n = 17, 8.5%). Patients with ADCs had lower CD4 counts(104.5/μL vs. 314/μL), less suppression of HIVRNA(OR 0.23, 95%CI 0.16–0.35) compared to those with NADCs. ART did not affect spectrum of NADCs, but affect that of ADCs (between patients with detectable and undetectable HIVRNA). ADCs remain frequent in China, and NADCs play an important role in morbidity and mortality of HIV positive population.

Impact of an enhanced screening program on the detection of non-AIDS neoplasias in patients with human immunodeficiency virus infection

BackgroundThe incidence of non-AIDS defining cancer (NADC) is higher in people living with HIV (PLWH) than in the general population, and it is already one of the leading causes of death in the HIV-infected population. It is estimated that the situation will be aggravated by the progressive aging of PLWH. Early diagnosis through intensive cancer screening may improve the ability for therapeutic interventions and could be critical in reducing mortality, but it might also increase expenditure and harms associated with adverse events. The aim of this study is to evaluate an enhanced screening program for early diagnosis of cancer in PLWH compared to standard practice. The specific objectives are (1) to compare the frequency of cancer diagnosed at an early stage, (2) to analyze safety of the enhanced program: adverse events and unnecessary interventions, (3) to analyze the cost-utility of the program, and (4) to estimate the overall and site-specific incidence of NADC in PLWH.MethodsWe will conduct a multicenter, non-blinded, randomized, controlled trial, comparing two parallel arms: conventional vs enhanced screening. Data will be recorded in an electronic data collection notebook. Conventional intervention group will follow the standard of care screening in the participating centers, according to the European AIDS Clinical Society recommendations, and the enhanced intervention group will follow an expanded screening aimed to early detection of lung, liver, anal, cervical, breast, prostate, colorectal, and skin cancer. The trial will be conducted within the framework of the Spanish AIDS Research Network Cohort (CoRIS).DiscussionThe trial will evaluate the efficacy, safety, and efficiency of an enhanced screening program for the early diagnosis of cancer in HIV patients compared to standard of care practice. The information provided will be relevant since there are currently no studies on expanded cancer screening strategies in patients with HIV, and available data estimating cost effectiveness or cost-utility of such as programs are scarce. An enhanced program for NADC screening in patients with HIV could lead to early diagnosis and improve the prognosis of these patients, with an acceptable rate of unnecessary interventions, but it is critical to demonstrate that the benefits clearly outweigh the harms, before the strategy could be implemented.Trial registrationClinicalTrials.gov NCT04735445. Registered on 25 June 2019