Formal reasoning on qualitative models of coinfection of HIV and Tuberculosis and HAART therapy.

BACKGROUND: Several diseases, many of which nowadays pandemic, consist of multifactorial pathologies. Paradigmatic examples come from the immune response to pathogens, in which cases the effects of different infections combine together, yielding complex mutual feedback, often a positive one that boosts infection progression in a scenario that can easily become lethal. HIV is one such infection, which weakens the immune system favouring the insurgence of opportunistic infections, amongst which Tuberculosis (TB). The treatment with antiretroviral therapies has shown effective in reducing mortality. An in-depth understanding of complex systems, like the one consisting of HIV, TB and related therapies, is an open great challenge, on the boundaries of bioinformatics, computational and systems biology. RESULTS: We present a simplified formalisation of the highly dynamic system consisting of HIV, TB and related therapies, at the cellular level. The progression of the disease (AIDS) depends hence on interactions between viruses, cells, chemokines, the high mutation rate of viruses, the immune response of individuals and the interaction between drugs and infection dynamics. We first discuss a deterministic model of dual infection (HIV and TB) which is able to capture the long-term dynamics of CD4 T cells, viruses and Tumour Necrosis Factor (TNF). We contrast this model with a stochastic approach which captures intrinsic fluctuations of the biological processes. Furthermore, we also integrate automated reasoning techniques, i.e. probabilistic model checking, in our formal analysis. Beyond numerical simulations, model checking allows general properties (effectiveness of anti-HIV therapies) to be verified against the models by means of an automated procedure. Our work stresses the growing importance and flexibility of model checking techniques in bioinformatics. In this paper we i) describe HIV as a complex case of infectious diseases; ii) provide a number of different formal descriptions that suitably account for aspects of interests; iii) suggest that the integration of different models together with automated reasoning techniques can improve the understanding of infections and therapies through formal analysis methodologies. CONCLUSION: We argue that the described methodology suitably supports the study of viral infections in a formal, automated and expressive manner. We envisage a long-term contribution of this kind of approaches to clinical Bioinformatics and Translational Medicine.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

An integrated modelling approach for R5-X4 mutation and HAART therapy assessment

We have modelled the within-patient evolutionary process during HIV infection using different methodologies. New viral strains arise during the course of HIV infection. These multiple strains of the virus are able to use different coreceptors, in particular the CCR5 and the CXCR4 (R5 and X4 phenotypes, respectively)influence the progression of the disease to the AIDS phase. We present a model of HIV early infection and CTLs response which describes the dynamics of R5 quasispecies, specifying the R5 to X4 switch and effects of immune response. We illustrate dynamics of HIV multiple strains in the presence of multidrug HAART therapy. The HAART combined with X4 strain blocker drugs might help to reduce infectivity and lead to slower progression of disease. On the methodology side, our model represents a paradigm of integrating formal methods and mathematical models as a general framework to study HIV multiple strains during disease progression, and will inch towards providing help in selecting among vaccines and drug therapies. The results presented here are one of the rare cases of methodological cross comparison (stochastic and deterministic) and a novel implementation of model checking in therapy validation

StochKit-FF: Efficient Systems Biology on Multicore Architectures

The stochastic modelling of biological systems is an informative, and in some cases, very adequate technique, which may however result in being more expensive than other modelling approaches, such as differential equations. We present StochKit-FF, a parallel version of StochKit, a reference toolkit for stochastic simulations. StochKit-FF is based on the FastFlow programming toolkit for multicores and exploits the novel concept of selective memory. We experiment StochKit-FF on a model of HIV infection dynamics, with the aim of extracting information from efficiently run experiments, here in terms of average and variance and, on a longer term, of more structured data.Comment: 14 pages + cover pag

Treatment Outcomes and Associated Factors in TB/HIV-Coinfected Patients in Namibia

AbstractHIV and TB have merged into a deadly co-epidemic in Namibia. Currently, though, TB and HIV data at the national, regional, and district level might be underreported and insufficient to understand the full burden and outcome rates of TB and HIV. Targeting the TB outcomes rate among TB/HIV-coinfected individuals is an effective strategy for decreasing future TB burden and furthering the gains in the control of both diseases. The objective of this study was: to assess the outcomes of patients registered for anti-TB treatment in //Karas Region which has the largests burden of TB in Namibia. A 5-year retrospective cohort study was used to evaluate successful (cured, treatment completed) and unsuccessful (death, treatment failure, default, and loss to follow-up) TB treatment outcomes. The epidemiological disease triangle framework served as the theoretical foundation. Health facility records were reviewed for 200 TB/HIV-coinfected patients for the period 2016-2020 in the Keetmanshoop Health District of the //Karas Region. The data were analyzed using chi-square and multivariate logistic regression with 95% confidence interval. At 79.5%, treatment success in the Keetmanshoop Health District was below the \u3e90% recommended target set by the World Health Organization. Conclusion, treatment success outcomes were still below the target set by the WHO (\u3e90%). Geographical location, distance to the health facility, unemployment, and adverse TB medication interaction were associated factors to unsuccessful TB outcome. The study promotes social change by providing actionable management strategies and policies to strengthen the control of TB/HIV programs for the prioritization of TB/HIV- coinfected patients at increased risk of experiencing unsuccessful treatment outcome in the Keetmanshoop District

Structures of risk: lived experiences of multi-syndemic clustering in the greater Boston area

People who experience structural violence are an increased risk for health conditions including HIV and Hepatitis C. Particularly they are at greater risk for experiencing known syndemic interactions between these two chronic infectious diseases. The risks are mediated bio-socially through the ways that structural inequality increases social and biological vulnerability to illness and suffering. Structural inequalities, or experiences of structural violence shape environments of risk; environments of risks increase social and biological vulnerability to the structures of risk promoting syndemic interactions between biological, behavioral, and psychological conditions. The lived experiences of people diagnosed with a combination of HIV, HCV, and mental health conditions (MHC) (e.g., mood disorders and depression) are, however, thus far understudied. Many aspects and consequences of structural violence and social suffering; poverty, homelessness, substance use, lack of access to healthcare, and structural risks for HIV, HCV, MHC and interactions between the three. Through this mixed-methods, primarily qualitative, ethnographic fieldwork with individuals in the Boston area living with HIV, HCV, or both HIV and HCV, or suffering from MHC I ethnographically explore people’s perceptions of their vulnerability to these syndemic interactions. I also investigate their experiences of being at-risk for these conditions. Through this process, I seek to illuminate individuals’ understandings of the impact structures of risk (i.e., substance use, food insecurity and unstable housing) have on lived experiences with HIV/HCV, HIV/MHC, and HCV/MHC syndemics. The perceptions of the lived realities of disease-behavioral-psychological interactions and health consequences are analyzed in the context of substance use. Substance use’s biological and social dimensions have a role in promoting syndemic interactions for each of the syndemics experienced within this population. Therefore, substance use is a syndemogenic factor because of its role as a mediator for environments of risks, and as a structural risk factor in all three of these syndemics. These interactions, and consequential health outcomes, in sufferers’ own words, enrich the landscape of syndemics research, producing a clearer picture regarding the structures of risks affecting this vulnerable group in the greater Boston area

From despair to hope studies in HIV and tuberculosis 1992-2011

Includes abstract. Includes bibliographical references

Effects of Nonadherence to HIV/AIDS Drugs on HIV-Related Comorbidities in Eastern Nigeria

Developing countries like Nigeria continue to have HIV epidemic challenge due to the scarcity of evidence-based information and lack of resources to boost HIV education. The study population, Owerri, is one of the states in Nigeria with a high incidence rate of HIV. The purpose of this phenomenological study was to explore the experiences of people living with HIV/AIDS regarding the effects of nonadherence to HIV/AIDS drugs. The integrated theory of health behavior model provided the framework for the study. I collected, transcribed, and analyzed interview data to identify clusters and themes. Results showed that various factors influenced and (e.g., free drugs, fear, culture, medication side effects, discrimination, relationship/support system, poverty, belief, easy access) contributed to adherence behavior among respondents. People living with HIV/AIDS may be encouraged to adhere to drug treatments because of these research findings. This study contributed to a positive social change in that respondents were excited and open about sharing their fears, challenges, struggles and hope with the anticipation to influence others to be open about their HIV disease

Evidence-based decision support in HIV/TB care: designing treatment, monitoring, and assessment support for care providers

Introduction: HIV and tuberculosis (TB) coinfection, which is a major challenge for healthcare systems worldwide, requires effective strategies to support care providers in applying best clinical evidence in making treatment decisions about the care of individ- ual patients. Clinical decision support (CDS) systems have the potential to facilitate the implementation of evidence-based guidelines in clinical practice. Aim: The aim of this thesis was to explore how a CDS system could be designed to sup- port the adoption of evidence-based guidelines in the treatment of HIV-related TB. Study design: The HIV outpatient clinic at the Karolinska University Hospital, Huddinge, Stockholm, was the setting for a user-centered design approach structured in three phases: contextual analysis (Studies I and II), design (Study III), and evaluation (Study IV). Study I explores care providers’ challenges and requirements; Study II, which describes socio- demographic and clinical characteristics of patients in this setting, analyzes the factors associated with anti-TB treatment success as well as adverse drug reactions; Study III proposes a CDS framework of drug therapy recommendations that is applied to HIV- related TB treatment guidelines; Study IV formatively evaluates the conceptual design of a CDS prototype that is based on the framework developed in Study III. Methods: In Study I, the contextual analysis is based on observations and interviews. Study II analyses patient treatment outcomes in the research setting between the years 1987 to 2010 (inclusive). Study III presents the design that is based on prototyping and guideline modeling. Study IV uses focus groups of physicians and nurses in the evalua- tion of the design. Results: The contextual analysis revealed challenges related to the complexity of HIV- related TB treatment (Studies I and II). Because the care providers thought they lacked sufficient experience with HIVTB drug therapy, they sought improved support tools and structures (Study I). Combined HIV and TB treatment was related to treatment success, but was also associated with adverse drug reactions (Study II). The design phase ap- plied the eviTMA (evidence-based Treatment, Monitoring, and Assessment) framework to model HIV-related TB treatment guidelines. This resulted in a CDS prototype that models alternative drug therapy options, their expected effects, and recommended mon- itoring routines (Study III). The care providers identified several potential benefits of the eviTMA CDS prototype including support for decision making, collaboration, and qual- ity improvement work (Study IV). Identified concerns that need to be addressed in future include the risk of overdependence on CDS, increased workload, and aspects related to the implementation and maintenance of a CDS system (Study IV). Conclusions: The main contribution of this thesis is the eviTMA CDS framework de- signed to support care providers in the adoption of evidence-based drug therapy rec- ommendations. The framework was evaluated in a CDS prototype for HIV-related TB treatment. Application to other conditions was desired by care providers and should be explored in future

Health-Related Quality of Life in the Era of Highly Active Anti-Retroviral Therapy in a United States’ Military Cohort of Individuals Living with Human Immunodeficiency Virus

With the introduction of highly active anti-retroviral therapy (HAART), infection with human immunodeficiency virus (HIV) has evolved from being a progressive fatal illness to a manageable chronic disease. However, the improved control of HIV with HAART is associated with adverse drug effects. Also, as people living with HIV (PLWH) grow older they are faced with greater burden of age-associated diseases, such as diabetes, cardiovascular and renal diseases all of which may affect the quality of life of PLWH. Health-related quality of life (HRQOL) is a patient-centered outcome measure that has the potential to improve care by assessing and monitoring treatment effects, enhancing communication between patient and provider, and tracking changes in functional status over time. The goal of this dissertation was to examine the relationship between HIV-infection, HAART use and HRQOL in a large United States' Military Cohort of individuals living with HIV, the HIV Natural History Study (NHS). In the first study, we examined the baseline factors associated with HRQOL in the NHS. In the second study, we further evaluated predictors of changes in HRQOL over time. In the third study, we examined whether HRQOL measures could be a useful tool in predicting time to hospitalization in our cohortPh.D., Epidemiology -- Drexel University, 201