Health economic evaluation to inform strategies for HIV treatment and prevention

HIV treatment has advanced remarkably since 1996, with the advent of highly active antiretroviral therapy (HAART). HAART stops HIV replication and, as a result, the virus is reduced to undetectable levels. This allows immune reconstitution to take place, leading to long-term disease remission and prolonged survival.

The BC Centre for Excellence in HIV/AIDS (BC-CfE) has demonstrated that HAART renders HIV undetectable in sexual fluids and can dramatically reduce HIV transmission. As a result, the BC-CfE is engaged in a number of HIV “treatment as prevention” initiatives aimed at expanding HIV testing and treatment within BC and internationally to decrease HIV-related morbidity and mortality, as well as HIV transmission.

Dr. Bohdan Nosyk’s research is focused on cost-effectiveness analysis of treatment as prevention strategies to inform the most effective allocation of scarce health resources. The initial objective of this proposal is to construct a mathematical cohort simulation model to determine the cost-effectiveness of HAART scale-up in terms of the total costs accumulated, quality adjusted life years, and HIV incidence in BC from 1996 to 2010. A series of statistical and econometric analyses are required to estimate the relevant clinical and economic parameters needed to populate the simulation model. These analyses will be facilitated by the availability of linked administrative datasets and prospectively collected longitudinal data of HAART utilization, duration, and health outcomes at the population level in BC. The analyses will be stratified by HIV acquisition risk factor. This model will be used to predict the potential impact and cost-effectiveness of future policy changes in BC and internationally.

Family planning health services research

Unplanned pregnancy is a problem in BC, especially among vulnerable populations who face stark economic, education-related, and work consequences. Women in BC spend almost 30 years trying to avoid pregnancy, compared with an average of less than three years spent pregnant or trying to conceive. Current surveys indicate that few women use highly effective contraception methods. Half of all pregnancies are unplanned and almost a third of BC women have an abortion. BC has Canada’s second highest abortion rate, and without the recent rate declines seen nationally. Moreover, vulnerable populations are overrepresented among those with unplanned pregnancies and especially among those seeking abortion.

Dr. Wendy Norman’s research program will develop evidence to support improvements to family planning access, quality of care, and health policy. This research will involve innovation end-users (health professionals, health system leaders, and an advisory board of citizens) in problem identification, prioritization, and research design leading to facilitated uptake of solutions. Norman’s research utilizes content expertise, collaborations, and trust established over decades as a respected and effective physician leader in this field. This program builds on more than $1.3 million dollars of project-based funding already in place and infrastructure support from research institutes, hospitals, and the University of British Columbia. Research partnerships have been established with all relevant health service organizations and health decision leaders in BC and are now forming with those across Canada.

This innovative program of research and capacity-building will transform health service delivery of family planning in BC and throughout Canada. Women, especially among vulnerable populations, will experience improved access to high quality family planning via. equity-enhancing strategies within BC’s evolving health-care system.

Effects of antiretroviral therapy (ART) program design on the HIV epidemic in sub-Saharan Africa

Access to antiretroviral therapy (ART) for HIV infection has dramatically increased in recent years. More than eight million people worldwide are now being treated, the majority of whom reside in sub-Saharan Africa. The success of ART roll-out has been possible through large increases in funding, but has been facilitated by the promotion of the “public health approach” to implementing ART in resource-limited settings. The public health approach is characterized by simplified drug formularies and standardized treatment monitoring, which does not insist on laboratory tests that are commonly used for ART management in industrialized countries.

In regions of the world where ART became widely available in the mid 1990s, such as British Columbia, ART expansion was associated with dramatic declines in HIV-related mortality and HIV transmission. However, the population-level impact of ART programs in Sub-Saharan Africa remains to be seen. Dr. David Moore’s program of research will examine how health policies regarding the design and implementation ART treatment programs in Uganda, a low-income country with a generalized HIV epidemic can potentially affect the future shape of the epidemic there.

HIV adaptation to immune selection pressures: historic trends and future implications

HIV has tremendous capacity to mutate and evolve due to the body’s immune response. However, the extent to which the virus has adapted to its human hosts over the course of the pandemic remains poorly understood. Repeated cycles of immune selection and transmission may allow the accumulation of key “escape mutations” — changes in the viral genome that help HIV evade the body’s defences. If immune targets in the HIV genome were disappearing over time due to the accumulation of these mutations, our ability to generate natural and vaccine-induced protective immune responses would diminish as the epidemic progresses.

Furthermore, the extent to which immune escape has influenced HIV pathogenesis remains unknown. Studies investigating the evolution of HIV virulence have largely focused on population-level trends in clinical markers over time, but few have addressed this issue using biological assessments of replication capacity or viral protein function.

Dr. Zabrina Brumme’s research team will undertake the first large-scale investigation of immune-driven HIV evolution and its implications over the 30-year history of the epidemic in North America. Host and viral genetic sequences from 1979 to the present will be analyzed to characterize the extent of population-level HIV adaptation over the epidemic’s course. Functional assessments of viral replication capacity and protein function will be performed to determine whether HIV is evolving towards increased virulence, gradual attenuation, or simply adapting to changing host-pathogen pressures over time.

With this study, Brumme is poised to answer two key questions of HIV biomedical research, namely, to what extent the virus has adapted to its hosts since AIDS was first recognized, and what implications this has for the future of the epidemic. Results have the potential to significantly advance HIV vaccine research.

Understanding tumor microenvironment interactions in lymphoid cancers: Translation into improved treatment outcome prediction and development of personalized therapies

Malignant lymphomas are the fifth most frequent cancer in humans, affecting patients of all ages. Despite generally effective treatments, a significant number of patients still die from the progressive disease. Interactions of the malignant cells with cells of the tumor microenvironment are increasingly recognized to play a pivotal role in the development of many lymphoma subtypes. However, the clinical potential of an improved understanding of microenvironment-related biology remains largely untapped.

Dr. Christian Steidl’s research focuses on B-cell lymphomas; in particular on the two related subtypes — Hodgkin lymphoma and primary mediastinal B-cell lymphoma — that often affect adolescents and young adults. This study will investigate tumor microenvironment interactions as therapeutic targets in B-cell lymphomas. Steidl’s team will seek to elucidate the underlying pathobiology of the tumor microenvironment, and macrophage interactions in particular, to identify novel drug targets and pave the way for the design of innovative clinical trials.

The study will also identify outcome predictors and resistance mechanisms of childhood and adult Hodgkin lymphoma. Molecular treatment outcome predictors will be developed using genomics approaches. Better outcome prediction using biological markers will identify patients at high risk and allow for personalized treatment approaches for children and adults suffering from relapsed Hodgkin lymphoma. Specifically, the recent emergence of novel targeted therapies holds the promise to overcome this high risk using these therapies to augment or replace existing therapies.

Finally, this research will define the mutational landscape of Hodgkin lymphoma and primary mediastinal B-cell lymphoma. This will involve the complete characterization of mutations by next-generation sequencing approaches. Preliminary data indicate that somatic mutations in both diseases are critically deregulating molecular pathways that might be targetable by novel therapeutic approaches. These studies will aim to transform novel findings into meaningful advances in clinical hematology.

Training parents as friendship coaches for children with Attention-Deficit/Hyperactivity Disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) is a syndrome marked by inattention and/or hyperactivity/impulsivity that affects 5-8 percent of Canadian youth. It makes up the most frequent referral for children’s mental health services and is associated with considerable psychosocial morbidity. A significant aspect of the impairment in ADHD is the difficulty these children face in getting along with peers. More than half of children with this condition are severely disliked by their peers or do not have a single friend. Peer problems result in loneliness and sadness for children with ADHD, and heighten the risk for future school failure, drug abuse, and delinquency. Treatments for the core symptoms of ADHD are ineffective at changing peers’ liking of children with ADHD, and if existing treatments do not also improve peer relationship problems, children with ADHD remain likely to experience poor health outcomes. These findings underscore the importance of developing adjunctive treatments capable of addressing the peer problems faced by children with ADHD.

Dr. Amori Mikami’s research focuses on the development, efficacy testing, and knowledge translation of novel psychosocial interventions for peer problems in children with ADHD. She proposes to expand upon an innovative intervention: training parents to improve the peer relationships of their children with ADHD. This is known as parental friendship coaching (PFC). Supported by the National Institute of Mental Health, Mikami created the PFC intervention and demonstrated in a randomized trial of 62 children with ADHD that PFC appeared effective relative to a no-treatment control group.

Mikami is following up on these promising preliminary results with a more definitive test of PFC and a better study of the mechanisms behind treatment efficacy. She will compare PFC against an active attention control intervention (to ensure the incremental value of the PFC techniques beyond social support and therapist time), involve 150 children from two diverse areas in Canada, follow up with participants eight months post-intervention, and use a thorough battery to measure outcomes, mediators, and moderators. Future studies will focus on disseminating new knowledge about PFC and peer problems to practitioners.

Manipulating the trajectory of the human fetal, newborn & infant immune system

Millions of newborns and infants die each year from infectious diseases. Many of these deaths are preventable, and analysis of the immune development of children can help define paths for medical intervention that may save lives.

Dr. Tobias Kollmann’s research team is conducting the first global comparison of immune development in cohorts of children from different countries. This project will compare the immune development of children born in Vancouver to those born in South Africa, Mozambique, Ecuador and Belgium. Preliminary research has found striking qualitative and quantitative differences in children’s immune development that appear to be directly related to their genetic make-up as well as the particular environment to which they are exposed. Kollmann’s team is dissecting the cause-effect relationship for the role of host genetics and studying the environmental factors that direct the developmental path of the innate and adaptive immune responses. Analysis of these genetic and environmental factors will potentially reveal pathways that direct future efforts to treat and prevent infectious diseases.

Kollmann’s team is already developing a platform that will help deliver targeted vaccinations to protect newborns. Using genetically altered strains of Listeria monocytogenes, the vaccine will induce a desired immune response only in specific cells and then disappear without harming the child. Preliminary data suggest this goal is within reach, and Kollmann’s team is working in partnership with industry to design and test a Listeria-based vaccination for newborns. Through this work, safe yet effective methods will be identified to prevent millions of newborn and infant deaths due to infectious diseases.

Psycho-social predictors of physical activity in community-dwelling and vulnerable seniors: Linking daily life processes with long-term health outcomes

Canada is an aging society, and the proportion of Canadians older than 65 is estimated to double within the next 10 years. It is well known that aging is associated with declining health, but there is also tremendous variability in aging outcomes. While physical activity can reduce the risk of many age-related diseases, such as cardiovascular disease and diabetes, Canadian seniors have low rates of physical activity.

Dr. Christiane Hoppmann’s research takes an innovative approach to examining key psychological factors, such as goals and planning, that may explain why some seniors are successful at implementing physical activity into their daily lives while others remain physically inactive. There is also recognition that the translation of physical activity goals into action demands cognitive and emotional resources that become increasingly limited with aging. For example, seniors with memory failures and fear of falling may encounter more difficulties engaging in physical activity. Hoppmann’s team will conduct an in-depth investigation of the psychological determinants of daily physical activity using a design called time-sampling. This method, which involves seniors completing a diary of their physical activities, memory, and emotions several times a day, will allow an examination of daily fluctuations across domains of functioning. Physical activity will also be assessed using portable electronic devices worn on the hip called accelerometers. Hoppmann’s team will also conduct one- and two-year follow-up assessments to link daily physical activity with long-term physical and mental health.

This research constitutes an important step to better understanding the psychological determinants of physical activity in seniors and their impact on physical and mental health. Findings will inform novel interventions (e.g. targeting goals and emotion-regulation) to promote healthy aging in community-dwelling and particularly vulnerable seniors in Canada.

Adaptive stress response signaling driving treatment resistance and metastasis in cancer

Cancer deaths are driven by two key biological processes: metastasis and treatment resistance. Although these processes are extensively studied as unrelated occurrences, evidence of shared signaling networks suggests common genetic or adaptive events. These pathways will change a therapy-responsive tumour to a resistant and lethal tumour. This occurs in prostate cancer where strategies used to kill tumours induce adaptive responses promoting the emergence of treatment-resistant tumours prone to metastasize. There is limited study of linkages between metastasis and treatment resistance, and Dr. Amina Zoubeidi’s research program will address an important knowledge gap in our understanding of aggressive tumour behavior in prostate cancer. The hope is that this research will translate into novel therapeutic development for prostate and other human cancers.

Zoubeidi’s work will be facilitated by her recent development of novel cell lines and xenograft models of prostate cancer that are resistant to a new generation of the AR pathway inhibitor drugs MDV3100 and abiraterone. These drugs, while recently introduced as therapeutics for patients with castration-resistant prostate cancer, offer survival gains of only four months and promote MDV- or abi-resistance. Zoubeidi has observed that MDV-resistant tumours metastasize whereas the castration-resistant tumours from which they were derived are non-metastatic. These observations suggest that tumours acquire metastatic traits in parallel with drug resistance.

Zoubeidi’s research program will focus on identifying common molecular mechanisms that elicit both metastasis and resistance to this new generation of prostate cancer drugs. Because tumour invasion and resistance dictate treatment outcome, pathways identified with this approach will represent relevant targets that can be inhibited singularly or jointly as more effective therapy. The research program is organized under three themes: the role of sustained AR activation in these processes; mechanisms associated with acquired EMT and their abilities to elicit treatment resistance; and the emergence of cancer cell “stem-ness” as a common mechanism driving treatment resistance and metastasis.

Mechanistic and experimental evolution studies of metallo-beta-lactamases

Pathogenic bacteria, such as P. aeruginosa, E. coli, and K. pneumonia, can cause serious infectious diseases such as pneumonia, urinary tract infections, and diarrhea. These bacteria are becoming resistant to many of our commonly used antibiotics and have been spreading rapidly over the past decade. Antibiotic-resistant bacteria are a serious threat to Canadian and global health, and new strategies are needed to combat them.

Groups of enzymes called beta-lactamases confer antibiotic resistance to the bacteria by allowing them to destroy beta-lactam antibiotics such as penicillin. Moreover, ongoing changes in bacterial beta-lactamase genes in nature are producing more potent enzymes to destroy our newest antibiotics.

Dr. Nobuhiko Tokuriki’s research will study the ways that beta-lactamase enzymes change. His team will combine experiments in the laboratory to identify mechanisms of change with detailed studies of enzyme function so they can develop ways to block their activity. The information obtained in this research will ultimately be used to develop novel, persistent, and sustainable antibiotics and inhibitors against pathogenic bacteria.