National Institutes of Health Campus
Bethesda, Maryland

BACKGROUND

The AIDS Malignancies Working Group (AMWG) was initially convened in response to emerging opportunities in research on HIV/AIDS-related malignancies and the rapid development of tools for pursuing crucial questions. AMWG represents a spectrum of disciplines with an interest in AIDS malignancies and those conducting research relevant to these cancers. This meeting of the internal NIH component of the AMWG was convened in response to the rapid rise of AIDS in developing countries and the anticipated increase in cancers. The meeting was intended to be an information gathering session to discuss relevant international issues and to identify additional agenda items in preparation for a larger meeting that includes researchers outside of the NIH. The participants heard updates from the extramural and intramural programs regarding their areas of research with an international component, and from the Fogarty International Center. After the presentations, a roundtable discussion was held to highlight the issues relevant to conducting and supporting research in AIDS malignancies in the international arena after which the comments were synthesized into a group consensus of action items.

MEETING OBJECTIVES AND OPENING REMARKS

Dr. Jodi Black welcomed the participants and after introductions around the table pointed to several opportunities for conducting research in AIDS-malignancies by establishing collaborations with investigators internationally; in essence by using the global lab. In her opening remarks she stated that although the AIDS epidemic is apparently under control in industrialized nations, the incidence of HIV/AIDS in developing countries is rapidly increasing, and transmission continues to occur in industrialized nations albeit at a much lower frequency. The WHO and UNAIDS estimated 44,000 new cases of HIV in North America in 1999, compared to 3.8 million in Sub-Saharan Africa. Given the increase in heterosexual transmission and a false sense of control in the younger generation, there may be increased risk for HIV transmission in the U.S. Therefore, complications of HIV including malignancies will continue to require management for some time. Several obstacles to AIDS malignancy research in the U.S. were identified at previous AMWG meetings and included the following:

1. A lack of global surveillance of AIDS and cancer. The WHO is developing guidelines for governments to improve the reliability of the evidence about the incidence and severity of AIDS-related malignancies in all HIV-infected populations. This effort may result in a reliable source of global surveillance information;
2. Low prevalence of some malignancies in the U.S. It was noted that HHV-8 and Kaposi's sarcoma, and HPV and high-grade cervical cancer are not prevalent in the U.S. but are highly prevalent in Africa. International collaborations would help facilitate studies of the natural history of these diseases, virus transmission, and the contribution of factors other than immunosuppresion that contribute to the establishment and maintenance of disease;
3. Lack of specimens. Access to samples from longitudinal studies and rare AIDS-associated malignancies is needed. Well- characterized, banked samples would be useful for development and validation of diagnostics and may facilitate the discovery of novel infectious agents involved in cancer. Is there a willingness of the international community, and funding available, to train and encourage health care workers to participate in specimen collection and processing for the NCI-sponsored AIDS and Cancer Specimen Bank (ACSB)?

To set the stage for the roundtable discussion, Dr. Black asked the participants to consider several issues while they listened to the remainder of the presentations:

1. Identify gaps in our current knowledge, what are the questions;
2. Consider research opportunities. In addition to research in NHL, KS and PCNL, should we be investigating anal cancer, lung cancer and breast cancer in the context of HIV infection;
3. How can we facilitate NCI's role in stimulating/coordinating research in AIDS malignancies;
4. Can we utilize the global lab to better understand the nature of AIDS malignancies and develop treatment? Identify existing mechanisms for international research and can they be used as a foundation for increasing collaborations;
5. Additional agenda items in preparation for a larger meeting including researchers outside the NIH, to take place in May.

PRESENTATIONS
Extramural Program

Dr. Vaurice Starks, Analytic Epidemiology Research Branch (AERB), Division of Cancer Control and Population Sciences

Dr. Sandra Melnick's portfolio supports etiologic epidemiologic research on the role of infectious agents in cancer occurring as a result of acquired immunodeficiency. The total budget for AIDS research in the Division of Cancer Control and Population Sciences is approximately 11 million dollars, nearly all of which is part of the research portfolio of the Analytic Epidemiology Research Branch (AERB ). The Division of Cancer Control and Population Sciences currently supports about 29 AIDS-related grants. Some of Dr. Melnick's grants are R01 grants awarded in response to a PA for research on the epidemiology of AIDS-related cancers. Of the 29 total AIDS grants, 5 are international studies, with a budget of approximately 3 million dollars. The international AIDS related grants represent 17% of the total AIDS grants, and 11% of the total active grants in AERB's portfolio (AERB currently has 324 active grants with a total budget of 101 million dollars). The AIDS related grants that have international components are investigator-initiated, and are supported by the RO1/UO1/PO1/R29 mechanisms. The international AIDS studies include descriptive, analytic and molecular epidemiology of cancer outcomes associated with the Human T-cell Lymphotropic Virus I/II; Epstein-Barr Virus (EBV); Human Herpesvirus-8 (HHV8)/ Kaposi's Sarcoma associated Herpesvirus (KSHV); Human Papillomavirus (HPV); and Hepatitis B and C viruses. While most of the international studies are in sub-Saharan Africa, a few are in Japan and China. Currently, the AERB/DCCPS portfolio has no research funded in India, Southeast Asia or Thailand.

The Division of Cancer Control and Population Sciences is re-issuing a program announcement entitled the Molecular Epidemiology of HIV-Associated Cancers. The portfolio also includes co-funding for a trans-NIH program announcement for studies of HIV pathogenesis in women (PA-97-105), co-funding for the NIAID-sponsored natural history studies of HIV infection in women and men, and supplemental funding for an NICHD grant to study AZT mutagenicity among infants born to HIV-infected mothers.

The following are titles of some of the grants with international relevance that are supported by AERB:

Natural History of Cervical Neoplasia in HIV-1 and HIV-2, Dakar, Senegal
Epidemiology and Biology of HIV and Cervical Neoplasia, Dakar, Senegal
Epidemiology and Sexual Transmission of HHV-8 in Malawi, Lilongwe, Malawi
Kaposi's Sarcoma and Human Herpesvirus in Africa, Lusaka, Zambia
HPV and cervix neoplasia - a case control, Uppsala, Sweden
Molecular epidemiology of persistent HPV infection, Sao Paulo, Brazil
Molecular epidemiology of hepatocellular carcinoma, Shanghai (Haimen City), China and Senegal, West Africa
Malignant complications of chronic HCV, Cairo, Egypt
Determinants of the sevular increase in non-hodgkin's lymphoma, Copenhagen, Denmark
Natural history of HTLV-1 and HCV infection, Miyazaki, Japan

Dr. Ken Cremer, Biological Carcinogenesis Branch, Division of Cancer Biology

Dr. Cremer's portfolio supports basic research on viral oncology and AIDS-associated malignancies, the underpinning for translational and clinical research. Dr. John Finerty's portfolio supports research hematologic malignancies with special emphasis on those occurring as a result of congenital, iatrogenic or acquired immunodeficiencies. The total budget for AIDS research in the Division of Cancer Biology branch is approximately 70 million dollars, divided between the Biological Carcinogenesis Branch (approximately 35 million for virology and other biologic agents) and the Cancer Immunology Branch (approximately 35 million dollars for AIDS related cancer immunology). The Division of Cancer Biology supports about 280 basic research AIDS related grants. Some of Dr. Cremer's grants are RO1 grants awarded in response to RFAs and PAs for research on AIDS-associated cancers and relevant animal models, and the remainder are unsolicited grants. None of these basic virology grants focuses entirely on international studies, although a few have some international components or collaborators. The virology grants are concentrated on understanding the basic molecular biology of HHV-8/KSHV, gene structure, expression and function, immunological responses to virus infection including antibody and T-cell responses, mechanisms of viral oncogenesis, viral and disease pathogenesis, and the development of animal models of viral pathogenesis and oncogenesis. Last year Dr. Cremer organized and hosted a workshop, "Sensitivity and Specificity of Assays for the Detection of KSHV/HHV-8," which focused on the exchange of information about current serologic and PCR methods to detect the KSHV/HHV-8 virus in human tissue and fluid samples. Much of the information exchanged was from non-NCI supported and international studies. Dr. Finerty's AIDS immunology grants focus on the role of cytokines, B and T cell ontogeny, lymphocyte activation and deactivation, the effect of somatic mutation on lymphomagenesis, immunodeficiencies, antigen receptors on B and T cell, and transgenic animals.

At this point a discussion occurred regarding the difficulty in obtaining state department clearance, the unequal geographic distribution of NCI funded studies and issues involving OPRR and single project assurance initiative problems.

Dr. John Finerty, Cancer Immunology Branch, Division of Cancer Biology

There are no direct international AIDS directed grants in Dr. Finerty's portfolio, however his branch supports research in CD4 restoration and basic lymphocyte research which is considered relevant to AIDS related studies. The Branch supports basic immunology research related to dendritic cells, antigen presenting cells, T and B cell ontogeny, chronic lymphoproliferative disease, role of the thymus in aging, pediatric cancer, follicular lymphomas, leukemia, and immunodeficiences.

HAART does not restore immune competency and that can be documented in several publications. This leaves the patient immune deficient because of a lack of T cells. Thus, HAART while keeping viral loads to a minimum does not allow the immune system to reconstitute itself by supplying more T cells. Recent studies have indicated that in order to maintain TOTAL T cell number i.e. homeostasis, the "immune system" does not "care" which T cell subset - CD4 or CD8 - are used to keep total T cell numbers at par.

Individuals with immunodeficiency due to congenital, iatrogenic, or acquired causes are at high risk of developing lymphomas. This risk is well known to be dramatically increased in HIV+ patients. Several NCI-sponsored research studies suggests that Skewing of B cells subsets, and a decrease in VH3 seems to coincide with progression to AIDS.

Intramural Program

Dr. Robert Biggar, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics

The primary focus of the Viral Epidemiology Branch is to study the viral etiology of cancer. Their scope includes the spectrum of all cancer-causing viruses, but they have particular expertise in HIV and HTLV based on studies that date back to the early 1980s. Most of the international involvement is based on investigator-driven long-term collaborations. Sites have included Europe, Africa and South America (Brazil). One example is the European long-term hemophilia cohort (since 1984), which includes Austria, Germany, Switzerland, Italy and Greece. There is also a similar cohort study of gay men in Denmark. The relevant information about cancer from their cohort studies has been integrated with Valerie Beral's AIDS epidemiology data (The International Collaboration on HIV and Cancer). They have contributed information about cancer risk from about 3000 people to the 30,000 in the Beral database on cancer risk in HIV-infected cohorts studied long-term.

This cohort meta-analysis study complements VEB's National AIDS and Cancer Match Registry study, which now includes cancer information for 309,000 people with AIDS. They have gathered information about the types of cancers occurring in AIDS patients and are now in the analytic phase of the study. Several manuscripts are in preparation or submitted, including studies of cancer in children, HPV-related cancers and T cell lymphomas. Although the vast majority of the rise in lymphomas is of B cell origin, Dr. Biggar noted that T cell lymphomas are also statistically increased in the AIDS setting.

Studies on HHV-8/KSHV are primarily conducted overseas. A recent collaboration involves a case-control study of HHV-8 and KS in Italy (Sicily and Rome) looking at environmental factors and their relationship to the development of KS in HHV-8 positive people. Another study involves KS research in Zaire and Botswana, looking at HHV-8 prevalence and strain types. A paper describing the endemic nature of HHV-8 in Brazilian Amerindians, and the discovery of an additional viral subtype (E) is in press in the Journal of Infectious Diseases.

On the genetic side, they have preliminary data suggesting that there is genomic instability in KS samples from Africa and Europe. Such data would confirm that KS is a true cancer. Abnormalities have been shown in chromosomes by loss of heterozygosity studies and as point mutations by microsatellite formation. These results are consistent with earlier work showing Kaposi's sarcoma to be a clonal tumor with metastatic potential.
The group is also involved in research on HTLV-1 and its relationship to T-cell lymphomas, ATLL, childhood dermatitis and tropical spastic paraparesis. The HTLV association with ATLL is striking, and understanding the genesis may provide substantial insights into how viruses cause cancer. In this area, they are focusing on early life infections, through studies in Jamaica.

A question was asked about the existence of AIDS and or Cancer registries around the world. Dr. Biggar pointed out that there are registries in many areas, and the results of the better registries are summarized in the IARC book Cancer in Five Continents However, the quality of the registry differs greatly between countries and the data presented can be misleading. The best registries are from countries where there is little AIDS. Australia has good AIDS and cancer registries but relatively little AIDS, for example. Furthermore, in the areas where there is a lot of AIDS (e.g., Africa), AIDS registration is nearly non-existent, so doing good linkage studies is impossible. Unfortunately, many of the Third World registries will not be very helpful in clarifying cancer risks in persons with AIDS. Among the best prospects for good studies is a cancer registry in Johannesburg, where AIDS is frequent and cancer registration fairly sophisticated.

Dr. Doug Lowy, Papillomaviruses and cancer: global aspects, Division of Basic Sciences

Dr. Lowy gave a comprehensive, but concise overview of cancer in the HPV setting. The proportion of cancers attributable to HPV is as follows: Cervical cancer, 100%; anal cancer, 86%; cancer of the vulva, 30%; cancer of the penis, 25%; cancer of the oropharynx, 50%; cancer of the larynx, 10%; cancer of the oral cavity, 10%. The percentage of all cancers attributable to HPV in females is greater than 20% in the Pacific Islands, south-central Asia, sub-Saharan Africa and tropical Latin America compared to north America where it is under 5%.

There is an increased persistence of HPV in HIV+ patients in both the anus and the cervix and a higher proportion of low-grade lesions; however, there does not seem to be an increase in cervical cancer in the AIDS arena. This might be due to patients dying prior to the development of high grade lesions. The recurrence rate of cervical dysplasia is higher in HIV+ women than in HIV- women. Long term renal transplant patients have a higher risk of anal and cervical cancer.

An HPV vaccine based on virus-like particles (VLPs) elicited neutralizing titers around 10,000 in healthy volunteers. A prophylactic vaccine efficacy trial is being proposed in Guanacaste, Costa Rica, where a long-term NCI sponsored natural history study was conducted, and there is a high incidence of cervical cancer. The study design consists of 3 arms: placebo, HPV16 L1 VLPs, and HPV16 L1/L2-E7-E2 chimeric VLPs; multiple endpoints: HPV16 DNA, LSIL, or HSIL; and will require 10,000 women and 3 - 4 years. HIV is not prevalent in Costa Rica. There is no immunogenicity data about the vaccine in the HIV setting.

Suggestions:

1. Increase investigations of anal cancer in the HIV setting. Dr. Joel Palefsky at University of California, San Francisco, may be able to provide more in depth suggestions for the types of questions that might be addressed in an international setting;
2. Develop a screening program in high prevalence countries that includes therapy. Dr. Mark Schiffman in DCEG may have some suggestions. The self-administered HPV test may be useful in the international arena;
3. Strengthen maternal-fetal transmission studies. This may help establish and maintain infrastructure and then simultaneous samples could be obtained for a variety of studies;
4. In addition to vaccines, antivirals could be developed through an applied research program. Antiviral development is usually supported through NIAID;

Other investigators working on HPV internationally include: Nancy Kiviat in Senegal; Anne Willoughby in NICHD; Jim Lipton at NIDCR is co funding studies with the Fogarty International Center at the University of Washington (Joan Kreiss and Nancy Kiviat), and John Greenspan at UCSF; and Bill Blattner at the University of Maryland.

Dr. Bhatia noted that India has a high incidence of cervical cancer and existing infrastructure for both basic science and prevention studies.

Dr. Ken Bridbord, The Fogarty International Center (FIC), NIH

The FIC supports $1.25 million for applications in competing supplements. The AIDS International Training and Research Program (AITRP) was discussed and Dr. Bridbord asked if NCI would make a financial commitment if the request for supplements were expanded to include AIDS malignancies. Subsequent to this meeting, NCI did agree to participate in the AITRP. Several handouts were distributed describing The HIV-AIDS and Related Illnesses Collaboration Award (AIDS-FIRCA) and the AITRP. The AIDS-FIRCA is ongoing, every 4 months. The AITRP has 2 windows of competition such that over a 5-year period it opens up twice. If the budget expands and additional needs develop the possibility of increasing the number of openings exists.

AROUND THE TABLE COMMENTS

Dr. Mike Dean is interested in molecular epidemiology which requires clinical research with an epidemiological design. He would be open to bringing people over to train and to expand on existing infrastructure.

Dr. Kishor Bhatia worked on lymphoid neoplasias with Dr. Ian Magrath in the Lymphoma Biology Section for the past 10 years. They helped set up a clinical trials consortium in India and completed 2 phases of a trial which helped answer both clinical and biological questions. This program was expanded into the International Network for Cancer Treatment and Research (INCTR), which is co-sponsored by NCI and WHO and its headquarters is located in Brussels. The purpose of the INCTR is to help build the capacity for cancer research in developing countries. At present they are concentrating on aspects of lymphoid neoplasia and viral epidemiology. 

Dr. Robert Biggar suggested exploiting the current technology for genomic research. The biggest gap is the lack of viably preserved cells for genomic analysis. There are also international communication problems, therefore it's best to target simple and expedient interventions that will be viewed as helpful in foreign countries. We need to work on reconfiguring current administrative obstacles such as multiple IRB approvals for single studies. He also feels small-scale studies are suffering due to US legalese and the cost of shipping samples due to extensive regulations.

Dr. Doug Lowy suggested increasing our understanding of the incidence of anal cancers in HIV. Provide screening and follow-up. This may best be done in an emerging versus a poorer country. Develop animal models for vaccine and antiviral testing. Antivirals may effect a broader spectrum of HPV subtypes.

Dr. Andrew Blauvelt suggested creating a database of international investigators by disease type interests or country. This database would be useful as an initial starting point for contacts, and could include a website of potential international collaborators and their research interests.

Dr. Roy Wu described his program as having a clinical slant. He noted that patient accrual is a problem in the U.S. and this hinders the ability to answer questions. The international community has a larger number of patients with disease but poor infrastructure to facilitate participation in studies. How can we bridge this gap? NIH alone may not be able to help eliminate the obstacles (mostly granting clearance in a timely manner) resulting from OPRR issues and we may need to involve the state department especially now that OPRR is within DHHS. He suggested having a meeting with members of OPRR and the State Department to identify the obstacles and to discuss ways to enhance scientific exchange between the U.S. and developing countries. It will continue to be difficult to participate in good international studies without changing part of the current system of regulations.

Dr. Sandra Bridges suggested inviting the people with knowledge of the existing infrastructure to the next meeting. She can suggest people at NIAID and NICHD who can help. She believes that an observational project looking for HPV frequency and subtype would be a natural addition to several existing studies, ie vaccine studies.

Dr. Vaurice Starks suggested inviting international collaborators to the next meeting to help identify roadblocks specific to their country. Her branch is interested in expanding into areas where there is not yet a presence. How can we bridge areas with infrastructure to areas without? Bridging extramural investigators with intramural investigators may be of some help with funding issues.

Dr. Robert Yarchoan noted that patient accrual is also a problem for his clinical research studies of KS. How can we marry our therapy and infrastructure with the patient population? He is willing to participate in training.

Dr. Ken Bridbord asked how could we build a better base for clinical research? The FIC is beginning to discuss ways to build infrastructure across many disciplines. He suggested putting Hepatitis C virus on the radar screen as Russia might have HCV transmission in association with the risk factors for HIV. He noted that NIDDK and NHLBI might be interested, and to think about the range of issues involving blood safety.

Dr. John Finerty noted that the increase in NHL in this country presents a tremendous opportunity to study this disease. He explained that patients with immune deficiencies are at high risk of lymphomagensis indicating that the immune system plays a role. Thus, there is a need to understand the pathogenesis of lymphomagenesis. However, the CSR review process is not conducive for AIDS lymphoma grant funding. The problem may be that reviewers with expertise in infectious diseases are reviewing AIDS oncology grant applications. It might be helpful if the CSR was more flexible in assigning AIDS oncology related proposals to a clinical oncology or an immunology study section. He recommended that scientists wishing to study NHL-immunology not include AIDS in the title and abstract.

Dr. Ken Cremer suggested including the D43 grantees from FIC in the next meeting because they will be most familiar with the issues relevant to their country. With those grants in place there is a way to put supplemental money in place for certain areas and certain sites. Competing supplements can be issued for pilot studies on a case by case basis without going through a formal study section. He suggested the program directors email their grantees the URL links to FIC program announcements to increase interaction. He also noted that we need to include NHLBI in future meetings.

Since there are possible NIH-wide HCV initiatives in response to Congressional interest, it might be worth while exploring those investigations relevant to HIV and associated malignancies and other complications in patients with long-term exposure to HCV and HIV. Liver disease may become a problem associated with HIV and HCV in long-term survivors. This may be an area worthy of study due to increased longevity of HIV+ population. Dr. Steve Rose (Genetics and Transplantation Branch, NIAID) may be a good contact. NIDA has interest in blood- borne pathogens (HIV, HBV, HCV) in association with IVDU and may be able to contribute (Dr. Steven Gust, Office of AIDS). Additionally, NIDDK would probably be taking the lead on most HCV initiatives (Dr. Serrano).

Dr. Ellen Feigal suggested we also think about the unique scientific questions that can be addressed in the international arena including studies of differences in viral transmission routes and strains in different countries. She noted the value of training investigators in other countries for preparing quality specimens for the AIDS and Cancer Specimen Bank (ACSB). A mechanism for disseminating information about international studies is to expand the AIDS oncology research handbook to include this information. She suggested being cautious about appearing like a SWAT team in the international arena. She also noted that we need to work better across the institutes and integrate those research pockets, via a trans-NIH approach. The next meeting may be one of the same format that includes representatives from other institutes. Utilizing the INCTR was also emphasized.

Additional Comments:

The OAR is interested in international issues and is having a meeting on Feb 14 and 15 to discuss the issues. Linda Reck is the main organizer of the working group meeting.

Assign a developing country to PI's in the AIDS Malignancy Consortium (AMC). This will be discussed at the next AMC meeting. Can we marry the D43 work with the AMC. Blessing existing relationships rather than forcing new ones may work better.

It is less costly to do research in developing countries due to lower salaries. Short-term in country training guarantees the country will benefit, rather than bringing trainees here and risking their refusal to return home. However, building infrastructure requires long term training, therefore, we need to train systems rather than individuals where there is a precommitment to returning home and perhaps sending another individual to continue the knowledge transfer.

SUMMARY AND ACTION ITEMS

Gaps in our knowledge

• We are not able to take full advantage of our current technology with regard to genetic research due to lack of appropriate samples.
• There are gaps in our basic understanding of the natural history of cancer, the basic molecular biology and pathogenesis. This knowledge would facilitate the development of treatment. Basic research studies are increasingly more difficult to get funded through the CSR review process.
• Animal models for vaccine and antiviral studies of HPV are needed.

Research opportunities in developing countries.

• The opportunity to conduct clinical trials where the patient population exists.
• The opportunity to study differences in viral transmission routes, strain variability , and disease presentation.

• Lack of a system to disseminate information about opportunities for international studies to the scientific community.
• Lack of patients for clinical trials
• Administrative obstacles: the requirement for multiple IRB's approvals for a single study, OPRR and SPA, the length of time to get State Department clearance, politics abroad.
• The CSR review process.
• Funding issues.

Existing mechanisms for international research

• The INCTR
• Individual collaborations within existing NIH programs, both intramural and extramural

Action Items

• Develop the Trans-NIH approach to gather information about all NIH-supported international studies, to discuss issues involved in establishing international collaborations, and to identify the existing mechanisms and studies that may have multiple project support potential. Organize another information gathering meeting, prior to the larger meeting planned for May, that includes members from NHLBI, NIAID, OAR, NIDDK, and NIDA .
• Invite foreign collaborators to help identify obstacles within nations
• Develop a database or website with information regarding NIH-supported international studies including information about contacts, resources, and travel awards for the purpose of bringing investigators together.