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.

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.

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.

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.

Characterization of the formation of protein aggregates induced by the inhibition of the ubiquitin proteasome system

Protein aggregation is a pathological feature of a large number of diseases with a strong preponderance in age-related neurodegenerative disorders like Parkinson’s disease. Failure to eliminate aberrant proteins in the cell plays a major role in these pathologies and is often linked to the impairment of the ubiquitin proteasome system, which degrades proteins labeled (or modified) with ubiquitin. The overall goal of Dr. Thibault Mayor’s research is to further define the involvement of the ubiquitin proteasome system in aggregation diseases using proteomic and cell biology approaches.

Mayor’s team has developed a new cellular assay to monitor the formation of aggregates induced by proteasome inhibition. They have identified by mass spectrometry more than 500 proteins that localize in these structures. Using a computational approach, Mayor will determine which features are shared among these proteins to give better insight into the mechanisms leading to aggregation. The UCHL1 enzyme may also be a major player in the aggregation process, and Mayor’s team will use the cell assay and mass spectrometry to further characterize UCHL1 and determine whether other enzymes related to the ubiquitin proteasome system may promote aggregation.

Current treatments for most aggregation diseases are primarily based on symptom management instead of directly treating the cause. Mayor’s work may potentially lead to a better understanding of the aggregation mechanism and identify novel targetable pathways to prevent formation or favor clearance of protein aggregates that could be used for new therapeutics.

Reducing sexual health inequities among vulnerable populations

The men and women who work in Canada’s off-street sex industry are an underserved and poorly understood population that represents the majority of the Canadian sex worker populace. Men and women off-street sex workers experience an array of interrelated factors known to be associated with significant morbidity and mortality including violence and victimization, economic vulnerability, limited access to health services, substance abuse, arrest, exploitation, inconsistent condom use, STI, and HIV.

Dr. Victoria Bungay’s research program seeks to contribute to the growing body of knowledge addressing the intersecting causes and contributing factors that exacerbate vulnerability for health inequities among the men and women who work in the off-street sex industry. This knowledge is critical to informing effective multi-level interventions aimed at protecting sex worker health and safety. Informed by critical perspectives on the connection between health and social issues, the research program will:

  •     Identify and examine how specific health issues (e.g. STI, HIV, violence, exploitation) and social processes (e.g. racism, poverty, heterosexism, sexism) intersect in ways that may compound their effects and exacerbate health inequities.
  •     Generate policy and programming recommendations needed to promote effective service delivery to protect individuals’ sexual health.
  •     Use an integrated approach to knowledge translation to facilitate the translation of this knowledge into social, health and legal policies and programs to protect the health of sex workers.

The research includes a series of ongoing and planned studies that include ethnographic methods, discourse analysis, and mixed-method designs. Bungay employs an integrated approach to knowledge translation that includes collaboration with stakeholders throughout the entire research processes. Her program of research is among the first studies in North America to examine intersections between gender, race, sexuality, and class as influential for male and female sex worker health and safety in the off-street context.

A wearable assistive device for improving quality of life

Mobility of the upper extremities has a significant impact on independence and quality of life. For individuals with neuromuscular disorders due to aging, stroke, injury, or other diseases, the activities of daily living (such as eating and dressing) can be very challenging. However, biomedical robotic technologies offer a promising tool with which to improve the mobility of individuals with impaired upper extremities.

Collaborating with experts in the field of neuromuscular rehabilitation, Dr. Carlo Menon is leading the design and development of a smart assistive medical device that is portable and wearable. The objective is to develop a device that will assist with functional movements and strengthen muscular tone of the weakened or impaired extremities. The device will have potential use for both upper extremity assistance and rehabilitation.

This research will improve the quality of life for individuals with neuromuscular disorders by restoring mobility of the upper extremities. The proposed project will include the following phases: a) interaction with the neuromuscular collaborators to iteratively reformulate the design; b) the engineering design and development of the biomedical robotic device; c) the engineering testing of the device; d) a study of the interactions between the device and both healthy volunteers and individuals with neuromuscular disorders to verify that the device can assist functional movements; e) technology transfer to neuromuscular scientists and clinicians.

Operations research applied to assess different strategies to reduce the public health and economic burdens of HIV/AIDS in British Columbia

Although traditional HIV prevention strategies — behaviour modification, condoms, needle exchange – have been very successful, their effect has reached a plateau since they are not always available, practical, or fully adhered to. In the past five years, research has shown that using antiretroviral therapy (ART) to treat those infected with HIV not only decreases mortality and morbidity but also decreases HIV transmission. Unfortunately, many individuals are still unaware that they are HIV-positive or that they should be on ART, since they have not been linked to our health-care system. These individuals will unnecessarily suffer from their disease and they will incur avoidable hospitalizations, physician visits, and costs.

Dr. Viviane Lima aims to identify different strategies to decrease the public health and economic burdens of HIV in British Columbia (BC). Since individuals living with HIV should follow the same continuum of care from infection until the time of first ART, diminishing the individual and economic burdens of HIV will require a combined effort of different players in our health-care system and the development of a comprehensive strategy to tackle each component in the continuum of care pathway. Lima’s research will employ innovative statistical and mathematical models to analyze these data and compare the potential effects of different complex strategies. This project will create great opportunities for trainees to be supported across a variety of disciplines, further enhancing BC’s competitive advantage in population-health and HIV research. The proposed methodology can also be applied to other diseases, conditions, and settings dealing with similar issues.

Uncovering novel regulators of beta cell genesis, growth and function

To date, the only successful approach for curing type 1 diabetes is to replace the insulin-producing beta cells that have been destroyed by the disease. Pancreas- and islet-cell transplantation are promising therapeutic strategies; however, scarcity of transplantable tissue has limited their widespread use. One way to produce enough beta cells to cure type 1 diabetes is to determine how the cells develop normally within the embryo and apply this knowledge to the regeneration of beta cells in the culture dish or directly in people with diabetes.

Using human and mouse model systems, Dr. Francis Lynn’s research aims to enhance our understanding of normal regulatory pathways that govern pancreas- and insulin-producing pancreatic beta cell genesis and function. The hope is that a greater understanding will enable cell-based approaches for treating and curing diabetes. Lynn’s long-term objective is to understand how regulatory DNA-binding proteins called transcription factors drive beta cell formation and function. This research specifically focuses on one member of the Sox gene family of transcription factors named Sox4. Preliminary data suggest that Sox4 is instrumental in governing both the birth of beta cells and their replication later in life. These observations place Sox4 as a novel and previously unappreciated key regulator of beta cell biology.

Lynn hopes that a thorough characterization of the pathways through which Sox4 regulates beta cell formation and function will inform novel approaches for generation of large numbers of functional beta cells from human embryonic stem cells or induced pluripotent stem cells.

The dynamic interplay between women’s stress and reproductive axes across reproductive transitions: post-partum amenorrhea, the resumption of ovarian cyclicity and early pregnancy

Stress is often cited as having negative effects on women’s health. Most research, however, does not adequately account for the changes in stress physiology women experience as they transition between key reproductive phases (post-partum amenorrhea, resumption of ovarian cyclicity, and pregnancy). Reproductive function is modulated by the HPG (hypothalamic-pituitary-gonadal) axis, while stress response is controlled by the HPA (hypothalamic-pituitary-adrenal) axis. These two axes overlap and interact in manner a that affects both reproductive function and stress.

Dr. Pablo Nepomnaschy’s research focuses on investigating the relationship over time between the HPA and HPG axes. Understanding this relationship is paramount to all research focused on how stress affects women’s health and reproduction and their children’s development. The aims of this research are to: 1) produce the first longitudinal description of stress and reproductive hormones for healthy women as they transition across reproductive phases; 2) study the dynamic interactions between the HPA and HPG axes across those phases; 3) evaluate the role of psychosocial, energetic, and health stressors as modulators of reproductive transitions and the effect these transitions have on the physiologic responses to those stressors; 4) conduct an exploratory pilot study of the effects that peri-conceptional stress has on the development of the HPA axis in children.

Nepomnaschy will use data and bio-specimens from British Columbian and Guatemalan women and children. The socio-economic and ethnic homogeneity of the Guatemalan population provides a unique opportunity for the development of a basic model of the longitudinal relationship between the HPA and HPG axes. Those results will be used to develop studies to investigate stress-related health outcomes for women and children in BC, particularly among disenfranchised groups facing higher risk of stress exposure, such as BC’s Aboriginal population, new immigrants, and the homeless.