State of the science and future directions for research on HIV and cancer: Summary of a joint workshop sponsored by IARC and NCI.

An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.

The AIDS and Cancer Specimen Resource (ACSR): HIV malignancy specimens and data available at no cost.

The goal of the AIDS and Cancer Specimen Resource (ACSR) is to play a major role in the advancement of HIV/AIDS cancer-related research/treatment by providing richly annotated biospecimens and data to researchers at no cost. The ACSR acquires, stores, and equitably distributes these samples and associated clinical data to investigators conducting HIV/AIDS-related research, at no costs. Currently, it is the only biorepository of human biospecimens from people with HIV and cancer available to eligible researchers globally who are studying HIV associated malignancies.This review describes the history and organizational structure of the ACSR, its types of specimens in its inventory, and the process of requesting specimens. In addition, the review provides an overview of research that was performed over the last 5 years with its support and gives a summary of important new findings acquired by this research into the development of cancers in people with HIV, including both Aids-related and non-Aids-related malignancies.

Biorepository best practices for research and clinical investigations.

Translational research requires good quality specimens to ensure the integrity of research results. Clinical research must rely not only on quality specimens, but as well on clinical annotation for consistent, accurate and verifiable scientific and clinical outcomes. In laboratory research performed on a specimen by a single investigator, quality control is easily maintained. In a multi-site clinical research network, the numerous steps for biospecimens from procurement through transport, processing, storage and ultimately testing requires strict standardization of operational workflows and procedures. The practices of a central biorepository can inform and contribute to best practices regarding clinical research specimen integrity for multi-site clinical research.

A Plan for Emergency Shutdown and Reopening for a Consortium of Biobanks.

Background: The AIDS and Cancer Specimen Resource (ACSR) is a network of four regional biospecimen repositories and a technical core in the United States and South Africa. Its mission is to acquire, store, and distribute HIV-associated malignancy specimens and related clinical data to support translational research. At the outset of the COVID-19 pandemic, it became apparent that existing ACSR Standard Operating Procedures (SOPs) were not sufficient to ensure long-term maintenance and integrity of inventories during periods of extended shutdown. The ACSR needed an administrative SOP for situations pertaining to epidemics/pandemics. The ACSR Quality Working Group (QWG), comprised of representatives from each of the five ACSR sites and an external member who directs a large university medical center biorepository, addressed the issue. Methods: To understand the individual problems the sites faced, questions were developed to query each of the six QWG sites' contingency plans to cover this type of emergency, the amount of work allowed onsite and by whom, the challenges sites experienced, and the lessons learned to assist with future similar situations, while remaining consistent with the existing IRB protocols. Results: Reported challenges spanned all activities of classical biobanks and differed within the geographical locations of the sites and the local COVID-19 infection rate. Review of the responses to the questions revealed that the general shutdown of society external to the biorepositories presented them with a homogeneous collection of problems, limitations, and needs. This led to creating an SOP that addresses planning for pandemic emergencies, scaling down of activities, shutting down, and reopening plans. Conclusions: The ACSR QWG sites now have a structured response SOP for their sites, including guidance on how to develop and implement an emergency shutdown and reopening plan. The complete SOP is publicly available on the ACSR website.

Collaborating with a Graduate Marketing Class to Boost Awareness of the AIDS and Cancer Specimen Resource.

The AIDS and Cancer Specimen Resource (ACSR) was built and maintained to support research into cancers in individuals infected with the HIV by providing specimens at no charge. Numerous methods to reach investigators about this resource have been used, but the possibility of underusage of the resource has been a concern. Using a commercial marketing firm to raise awareness was not a possibility for the ACSR. However, a unique academic interdisciplinary collaboration was developed with a marketing communications course using primary and secondary marketing research and experiential learning applied to the ACSR. The cross disciplinary approach promoted greater understanding of the intersection between medical research, biobanking, and business. The collaboration resulted in new strategies to improve the visibility of the ACSR by focusing on its social media presence, creating a database of potential new users, enhancing the ACSR website, and making domain name changes. Lessons learned from this exercise should have general applicability across the field of biorepositories.

Fit for genomic and proteomic purposes: Sampling the fitness of nucleic acid and protein derivatives from formalin fixed paraffin embedded tissue.

The demand for nucleic acid and protein derivatives from formalin-fixed paraffin-embedded (FFPE) tissue has greatly increased due to advances in extraction and purification methods, making these derivatives available for numerous genomic and proteomic platforms. Previously, DNA, RNA, microRNA (miRNA), or protein derived from FFPE tissue blocks were considered "unfit" for such platforms, as the process of tissue immobilization by FFPE resulted in cross-linked, fragmented, and chemically modified macromolecules. We conducted a systematic examination of nucleic acids and proteins co-extracted from 118 FFPE blocks sampled from the AIDS and Cancer Specimen Resource (ACSR) at The George Washington University after stratification by storage duration and the three most common tumor tissue types at the ACSR (adenocarcinoma, squamous cell carcinoma, and papillary carcinoma). DNA, RNA, miRNA, and protein could be co-extracted from 98% of the FFPE blocks sampled, with DNA and miRNA "fit" for diverse genomic purposes including sequencing. While RNA was the most labile of the FFPE derivatives, especially when assessed by RNA integrity number (RIN), it was still "fit" for genomic methods that use smaller sequence lengths, e.g., quantitative PCR. While more than half of the protein derivatives were fit for proteomic purposes, our analyses indicated a significant interaction effect on the absorbance values for proteins derived from FFPE, implying that storage duration may affect protein derivatives differently by tumor tissue type. The mean absorbance value for proteins derived from more recently stored FFPE was greater than protein derived from older FFPE, with the exception of adenocarcinoma tissue. Finally, the fitness of one type of derivative was weakly associated with the fitness of derivatives co-extracted from the same FFPE block. The current study used several novel quality assurance approaches and metrics to show that archival FFPE tissue blocks are a valuable resource for contemporary genomic and proteomic platforms.

High frequency of identical clonal immunoglobulin DNA in pre-treatment tumor and plasma from untreated patients with HIV-associated lymphoma: prospective multicenter trial of the AIDS malignancies consortium (AMC 064).

Patients with HIV are at increased risk for developing B-cell lymphomas likely due in part to chronic antigen stimulation leading to clonal immunoglobulin (Ig) gene rearrangements. Next-generation sequencing (NGS)-based identification of circulating Ig clonotypes has not been well-characterized in HIV-related lymphomas. The AIDS Malignancies Consortium (AMC) enrolled 51 untreated patients with HIV-related B-cell lymphomas and analyzed paired tumor/plasma specimens for Ig clonotypes using an NGS approach (AMC064, NCT00981097). Lymphoma-specific clonotypes (>5% frequency) were identified in 83% (33/40) of tumor specimens. Results from paired tumor/plasma specimens showed identical circulating clonotypes in the plasma from 97% (32/33) of patients. High International Prognostic Index (IPI) scores of 3-4 among patients with B-cell lymphoma correlated with higher lymphoma molecules/million diploid genomes in the plasma compared with lower IPI scores of 0-2, median 77335 vs. 6876, p = .005. Further studies are merited to determine whether plasma clonal Ig DNA is prognostic in HIV-related lymphomas.

A biobank to support HIV malignancy research for sub-Saharan Africa.

Sub-Saharan Africa has one of the highest incidences of infection with HIV globally, but more people in this region are living longer owing to increased access to antiretroviral therapy. However, along with increased care and treatment, this population is expected to have an increase in HIV-associated cancers, as is being seen in the USA and other developed countries. To support translational research in HIV-associated cancers, Stellenbosch University in Cape Town, South Africa, was funded to house the state-of-the-art AIDS and Cancer Specimen Resource Sub-Saharan Africa Regional Biorepository (SSA RBR) to proactively obtain, manage and process biospecimens and associated clinical data representing both AIDS-defining and non-AIDS-defining cancers for research. The SSA RBR furthermore functions as the biorepository for AIDS Malignancy Consortium sub-Saharan clinical trial activities in this region. Although the site had much experience with cryopreservation and storage of specimens, capacity building revolving around operations under International Society for Environmental and Biological Resources/National Cancer Institute best practices took place in such areas as custodianship v. ownership, data sharing and facilities management. The process from selection until launch took 14 months.

Serum biomarkers of immune activation and subsequent risk of non-hodgkin B-cell lymphoma among HIV-infected women.

BACKGROUND: There is increasing evidence that chronic immune activation predisposes to non-Hodgkin lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the United States who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined. METHODS: We conducted a nested case-control study within the Women's Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3 to 5 years, 1 to 3 years, and 0 to 1 year before AIDS-NHL diagnosis (n = 22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4(+) T-cell count, and study follow-up time (n = 78). ORs and 95% confidence intervals (CI) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models. RESULTS: Elevated levels of sCD27 (OR = 7.21; 95% CI, 2.62-19.88), sCD30 (OR = 2.64; 95% CI, 1.24-5.64), and CXCL13 (OR = 2.56; 95% CI, 1.32-4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a two to three-fold increased risk of AIDS-NHL in certain subgroups, whereas elevated interleukin 6 was associated with a two-fold increased risk in the 0 to 1 year time-window, only. CONCLUSIONS: These findings support the hypothesis that chronic B-cell activation contributes to the development of AIDS-NHL in women. IMPACT: Soluble CD23 (sCD23), sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL.

The AIDS and Cancer Specimen Resource.

The AIDS and Cancer Specimen Resource (ACSR) is a cooperative agreement among the United States National Cancer Institute (NCI) (Office of the Director, Office of HIV and AIDS Malignancy (OHAM)) and regional US consortia, University of California, San Francisco (West Coast), George Washington University (East Coast), and The Ohio State University (Mid-Region). The ACSR's main objective is to collect, preserve, and disperse HIV-related tissues and biologic fluids along with clinical data to qualified investigators with a focus on HIV/AIDS-related malignancies. The ACSR biorepository has more than 265,000 human HIV-positive and control samples available from 39 processing types, 16 specimen types, and 52 anatomical site types. These HIV-infected biological fluids and tissues are made available to funded approved investigators at no fee. Technical support such as HIV DNA identification in tissues and tissue microarray (TMA) blocks are available to assist approved investigators. Research needs may be filled through ACSR cooperative arrangements when not met by currently banked material. Those participating with the ACSR are expected to share their research findings with the scientific community. Some 117 abstract/poster and podium reports at national and international scientific meetings and 94 publications have been contributed to the scientific literature (as of 2010). Investigators can browse the ACSR Internet site at http://acsr.ucsf.edu for biospecimens to support their scientific initiatives, including basic, translational, biomarker discovery, and molecular epidemiology studies.

HIV as a risk factor for lung cancer in women: data from the Women's Interagency HIV Study.

PURPOSE: Prior reports of an increased risk of lung cancer in HIV-infected individuals have not always included control groups, nor considered other risk factors such as tobacco exposure. We sought to determine the role of HIV infection and highly active antiretroviral therapy (HAART) on lung cancer incidence in 2,651 HIV-infected and 898 HIV-uninfected women from the Women's Interagency HIV Study (WIHS). METHODS: A prospective study of the incidence rates of lung cancer was conducted, with cases identified through medical records, death certificates, and state cancer registries. Standardized incidence ratios (SIRs) were calculated to compare lung cancer incidence among HIV-infected and uninfected WIHS participants, with population-based expectations using the Surveillance, Epidemiology, and End Results registry. Behavioral characteristics in the WIHS were compared to US women by age and race adjusting the population-based data from the National Health and Nutritional Examination Survey (NHANES) III. RESULTS: Incidence rates of lung cancer were similar among HIV-infected and uninfected WIHS women. Lung cancer SIRs were increased in both HIV-infected and -uninfected women compared with population expectations, but did not differ by HIV status. Among HIV-infected women, lung cancer incidence rates were similar in pre-HAART and HAART eras. All WIHS women with lung cancer were smokers; the risk of lung cancer increased with cumulative tobacco exposure. WIHS women were statistically more likely to smoke than US women studied in NHANES III. CONCLUSION: HIV infection is strongly associated with smoking behaviors that increase lung cancer risk. The role of HIV itself remains to be clarified.

Live birth patterns among human immunodeficiency virus-infected women before and after the availability of highly active antiretroviral therapy.

OBJECTIVE: The objective of the study was to investigate the relationship between human immunodeficiency virus (HIV) infection and childbearing before and after the availability of highly active antiretroviral therapy (HAART). METHODS: Enrollment in the Women's Interagency HIV study took place in 1994-1995 (pre-HAART era) and again in 2001-2002 (HAART era). Live birth rates prior to enrollment were compared between treatment era cohorts for HIV-infected and HIV-uninfected women aged 15-44 years using Poisson regression. For HIV-infected women, we included live births between HIV diagnosis date and study entry; the HAART era cohort included only women diagnosed with HIV in 1996 and afterward. RESULTS: Among HIV-infected women, the HAART era live birth rate was 150% higher than in the pre-HAART era (P = .001) vs a 5% increase among HIV-uninfected women. The rate of increase in live birth rate was higher for women > or = 35 years old (vs younger than 25 years, P = .02), and with more than a high school education (vs. less than high school, P = .05). CONCLUSION: The availability of effective therapeutic interventions has had a profound impact on child-bearing among HIV-infected women.

The AIDS and Cancer Specimen Resource: role in HIV/AIDS scientific discovery.

The AIDS Cancer and Specimen Resource (ACSR) supports scientific discovery in the area of HIV/AIDS-associated malignancies. The ACSR was established as a cooperative agreement between the NCI (Office of the Director, Division of Cancer Treatment and Diagnosis) and regional consortia, University of California, San Francisco (West Coast), George Washington University (East Coast) and Ohio State University (Mid-Region) to collect, preserve and disperse HIV-related tissues and biologic fluids and controls along with clinical data to qualified investigators. The available biological samples with clinical data and the application process are described on the ACSR web site. The ACSR tissue bank has more than 100,000 human HIV positive specimens that represent different processing (43), specimen (15), and anatomical site (50) types. The ACSR provides special biospecimen collections and prepares speciality items, e.g., tissue microarrays (TMA), DNA libraries. Requests have been greatest for Kaposi's sarcoma (32%) and non-Hodgkin's lymphoma (26%). Dispersed requests include 83% tissue (frozen and paraffin embedded), 18% plasma/serum and 9% other. ACSR also provides tissue microarrays of, e.g., Kaposi's sarcoma and non-Hodgkin's lymphoma, for biomarker assays and has developed collaborations with other groups that provide access to additional AIDS-related malignancy specimens. ACSR members and associates have completed 63 podium and poster presentations. Investigators have submitted 125 letters of intent requests. Discoveries using ACSR have been reported in 61 scientific publications in notable journals with an average impact factor of 7. The ACSR promotes the scientific exploration of the relationship between HIV/AIDS and malignancy by participation at national and international scientific meetings, contact with investigators who have productive research in this area and identifying, collecting, preserving, enhancing, and dispersing HIV/AIDS-related malignancy specimens to funded, approved researchers at no fee. Scientific discovery has been advanced by this unique biorepository. Investigators are encouraged to browse the ACSR Internet site for materials to enhance their own scientific initiatives.

The cooperative prostate cancer tissue resource: a specimen and data resource for cancer researchers.

PURPOSE: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a National Cancer Institute-supported tissue bank that provides large numbers of clinically annotated prostate cancer specimens to investigators. This communication describes the CPCTR to investigators interested in obtaining prostate cancer tissue samples. EXPERIMENTAL DESIGN: The CPCTR, through its four participating institutions, has collected specimens and clinical data for prostate cancer cases diagnosed from 1989 onward. These specimens include paraffin blocks and frozen tissue from radical prostatectomy specimens and paraffin blocks from prostate needle biopsies. Standardized histopathological characterization and clinical data extraction are performed for all cases. Information on histopathology, demography (including ethnicity), laboratory data (prostate-specific antigen values), and clinical outcome related to prostate cancer are entered into the CPCTR database for all cases. Materials in the CPCTR are available in multiple tissue formats, including tissue microarray sections, paraffin-embedded tissue sections, serum, and frozen tissue specimens. These are available for research purposes following an application process that is described on the CPCTR web site (www.prostatetissues.org). RESULTS: The CPCTR currently (as of October 2003) contains 5135 prostate cancer cases including 4723 radical prostatectomy cases. Frozen tissues, in some instances including patient serum samples, are available for 1226 cases. Biochemical recurrence data allow identification of cases with residual disease, cases with recurrence, and recurrence-free cases. CONCLUSIONS: The CPCTR offers large numbers of highly characterized prostate cancer tissue specimens, including tissue microarrays, with associated clinical data for biomarker studies. Interested investigators are encouraged to apply for use of this material (www.prostatetissues.org).

Changes in sexual behavior among HIV-infected women after initiation of HAART.

OBJECTIVES: We assessed the association between initiation of highly active antiretroviral treatment (HAART) regimens and sexual risk behaviors among HIVinfected women. METHODS: We analyzed data from 724 women who initiated HAART between January 1996 and January 2001 and who had pre-HAART viral loads at or above 400 copies per milliliter. RESULTS: Sexually active women were less likely (odds ratio [OR] = 0.79) to report 2 or more partners during a 6-month period after HAART initiation than before HAART initiation. However, the risk for unprotected sex was higher after HAART initiation than before HAART initiation among all sexually active women (both those who reported 2 or more partners [OR = 1.84] and those who reported 1 partner [OR = 1.22]). CONCLUSIONS: Sexual risk behaviors are associated with receipt of therapy but not with therapeutic response, indicating a risk for transmission among female HAART recipients.

Cancer risk among participants in the women's interagency HIV study.

BACKGROUND: The HIV epidemic has been associated with an increased incidence of specific cancers. However, less is known about cancers occurring in HIV-infected women than men. METHODS: To determine the risk of cancer among HIV-infected and at-risk HIV-uninfected women, cancer incidence data from the Women's Interagency HIV Study (WIHS) were compared with data from the population-based United States Surveillance, Epidemiology, and End Results (SEER) registry. Age- and race-adjusted standardized incidence ratios (SIRs) were computed and exact statistical tests were used to measure significance. RESULTS: Among the 1950 women participants (1554 HIV infected, 391 HIV uninfected, and 5 HIV seroconverters), 48 cancers were diagnosed during study follow-up. Among HIV-infected women, significantly (P < 0.05) increased incidence rates were observed for all cancer types (SIR = 1.9), Kaposi sarcoma (SIR = 213.5), non-Hodgkin lymphoma (NHL) (SIR = 19.0), and lung cancer (SIR = 6.3) when compared with SEER rates. Lung cancer incidence was also elevated (P = 0.07) among the HIV-uninfected women (SIR = 6.9), when compared with SEER rates, and was similar to the SIR for HIV-infected women. While the incidence rate of NHL among HIV-infected women was significantly lower during the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era (relative risk = 0.15, P = 0.005), the incidence of NHL among HIV-infected WIHS participants remained significantly higher than in the US population (SIR = 6.4, 95% CI = 1.3-15.5). CONCLUSION: In the HAART era, the higher rates of cancer among HIV-infected women, coupled with increased life expectancy, should lead to more intensive cancer screening and prevention efforts in this population.

Low incidence of invasive cervical cancer among HIV-infected US women in a prevention program.

OBJECTIVE: To measure the incidence of invasive cervical cancer (ICC) in US women infected with HIV. DESIGN: Multicenter prospective cohort study, conducted between October 1994, and September 2001. SETTING: HIV research centers operating as six urban consortia in the Women's Interagency HIV Study. SUBJECTS: A total of 2131 women (462 HIV seronegative, 1661 HIV seropositive, and eight seroconverters). Women with a history of hysterectomy or of cervical cancer at baseline evaluation were excluded. INTERVENTION: Cervical cytology obtained at 6-month intervals, with a colposcopy referral threshold of atypia, followed by individualized treatment. MAIN OUTCOME MEASURE: ICC diagnoses obtained from study databases and regional cancer registries and confirmed by a gynecologic pathologist. RESULTS: No incident ICC were observed in HIV seronegative women during 2375 woman-years of observation. During 8260 woman-years of observation, eight putative incident cases of cervical cancer were identified in HIV seropositive women, but only one was confirmed, yielding an incidence rate of 1.2/10 000 woman-years (95% confidence interval, 0.3-6.7/10 000 woman-years). The difference in incidence between HIV seropositive and seronegative women was not significant (P = 1.0). CONCLUSION: ICC is uncommon in HIV-infected US women participating in a regular prevention program.

Prevalence and correlates of highly active antiretroviral therapy switching in the Women's Interagency HIV Study.

OBJECTIVE: The purpose of this study was to describe the variability in highly active antiretroviral therapy (HAART) regimens over time, the extent to which individuals switch, and the characteristics of those who are switching. METHODS: We evaluated data collected between 1994 and 2000 from 1056 HIV-positive women enrolled in the Women's Interagency HIV Study (WIHS) who reported initiating HAART. We described the variability and prevalence of changes in HAART regimens between semiannual visits, estimated time to switch using Kaplan-Meier methods, investigated factors associated with a first switch using Cox proportional hazards models, and compared disease markers among women switching or remaining on unchanged HAART regimens. RESULTS: We demonstrated a 13-fold increase in the number of unique HAART regimens reported since mid-1996 and showed that the amount of time spent on the first, second, or third regimen is similar, with an 8-month median time to switching or discontinuing the initial HAART regimen. Women who switched had a lower mean CD4 cell count and were more likely to have HIV RNA levels greater than 400 copies/mL. Overall, the percentage of women switching decreased over the course of follow-up (to 37% in September 2000), although the percentage discontinuing therapy altogether increased 2-fold. CONCLUSION: Our findings on the relatively high rate of HAART switching emphasize the complexity of managing and evaluating these therapies.

Use of mammographic screening by HIV-infected women in the Women's Interagency HIV Study (WIHS).

BACKGROUND: Although HIV-positive women may be less likely than women in general to receive mammography due to socioeconomic disadvantage, HIV diagnosis may increase opportunities for medical interactions which encourage mammography. METHODS: HIV-positive (2,059) and HIV-negative (569) Women's Interagency HIV Study (WIHS) participants reported ever/never history of mammography at baseline (in 1994, 1995) and, at each 6-month follow-up visit, if they had been screened since their last visit. National Health Interview Survey (NHIS) data for 1994 were used to compare WIHS participants to U.S. women. Factors independently related to mammography were determined using logistic regression for baseline data and proportional hazards for follow-up data. Results were adjusted for age. RESULTS: Among women > or =40, fewer WIHS women, regardless of HIV status, reported screening than U.S. women (67% HIV-positive, 62% HIV-negative, 79% NHIS; P < 0.0001). First-time screening while on study was associated with being HIV-positive [rate ratio (95% confidence interval) = 1.6 (1.1, 2.3)]. Factors independently associated with screening were related to health care access and usage. CONCLUSIONS: WIHS women, a disadvantaged population, reported less mammography than the general population. HIV-positive women reported more screening than HIV-negative women, possibly because of greater opportunity to interact with the health care system.