Medicine and Health Sciences Commons^™

Optimizing Antiretroviral Therapy With Modern Rifapentine Containing Tb Treatment, Anthony T. Podany

Theses & Dissertations

In the past decade there has been a multitude of phase 3 clinical trials targeting treatment shortening for tuberculosis (TB). The synthetic rifamycin derivative rifapentine (RPT) has been at the forefront of many of the treatment shortening approaches. RPT possesses greater potency and a longer pharmacokinetic (PK) half-life (t_1/2) as compared with the long used rifamycin, rifampin (RIF). For TB preventative treatment, a 3-month, once weekly regimen of RPT and isoniazid (INH; 3HP) was shown to be as effective as 9-months of daily INH therapy in the PREVENT TB trial. Similarly, a 4-week course of daily RPT and …

Neurocognitive Impairment In People Living With Human Immunodeficiency Virus (Hiv): Risk Factors And Mortality, Zaeema Naveed

Theses & Dissertations

Despite the widespread use of combination antiretroviral therapy (cART), HIV-associated neurocognitive impairment (NCI) persists in people living with HIV (PLWH) with clinical and public health implications. Studies have generated inconsistent results regarding etiological factors for NCI in PLWH and a brief user-friendly predictive tool is desirable in clinical practice to assess the probability of having NCI in PLWH. Furthermore, factors associated with clinically meaningful decline in neurocognitive status and survival disadvantage for patients with NCI are understudied in the post-cART era. The goal of this dissertation was to investigate factors associated with baseline NCI and neurocognitive decline and the association …

Neural Oscillatory Activity Serving Sensorimotor Control Is Regulated By The Mitochondrial Redox Environment In Health And Disease, Rachel Spooner

Theses & Dissertations

Despite effective regimens of combination antiretroviral therapy, individuals with HIV are still at higher risk for developing forms of cognitive impairment, with one of the most common behavioral abnormalities to manifest being motor dysfunction. This is an important consideration, as deficits in motor control likely contribute to higher-order cognitive impairments, which together, lead to functional dependencies in the ever-growing aging population of HIV-infected adults. While the neuroanatomical bases of motor dysfunction have recently been illuminated in people living with HIV (PLWH), there remains an open question regarding the molecular processes supporting the circuit-level neuronal dynamics that potentially serve these behavioral …

Development Of Long-Acting Antiviral Drug Nanoformulations, Denise Cobb

Theses & Dissertations

Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, opportunities to improve its profile abound. ART is limited by putative viral reservoir penetrance, emergence of viral mutations, inherent toxicities, and regimen non-adherence. These highlight the need improved drug delivery schemes. Previously, our lab has demonstrated that targeting mononuclear phagocytes for antiretroviral drug delivery extends drug half-life and improves penetrance into viral reservoirs, addressing these limitations of ART. Herein, we developed synthetic and biologic antiretroviral (ARV) drug nanocarriers improve the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ARVs through …

Multimodal Neuroimaging Of Hiv And Aging, Brandon Lew

Theses & Dissertations

HIV infection remains a significant contributor to disease burden, and with the success of antiretroviral therapies, the population of people with HIV is aging. A growing literature suggests a relationship between HIV-infection and a profile of age advancement, most notably in molecular studies of epigenetics. However, despite the widely-known high prevalence of HIV-related brain atrophy, functional deficits, and HIV-associated neurocognitive disorder (HAND), epigenetic age advancement has not been linked to HIV-related changes in neuroimaging metrics.

We applied three neuroimaging methods, structural MRI, resting state functional MRI, and resting state MEG, to study the brain structure and function of 121 virally-suppressed …

Burden And Risk Of Non-Aids Defining Cancers In Hiv-Infected Persons Receiving Antiretroviral Therapy, Brittney L. Dickey

Theses & Dissertations

The burden of cancers not previously associated with an HIV infection, called non-AIDS defining cancers (NADCs), have increased in the years since highly active anti-retroviral therapy has been introduced. The studies in this dissertation attempted to quantify this burden via incidence and mortality compared to the general population. Further, an assessment of risk factors and creation of a predictive risk model, a nomogram, were utilized to better understand how factors associated with demographics, lifestyle, and immune response affected risk for an NADC diagnosis once therapy was initiated and HIV better controlled. Standardized incidence and mortality ratios showed that burden of …

Factors Associated With Substance Use Among Adolescents Living With Hiv In Kenya, Wambui Kagucia

Theses & Dissertations

Background: Substance use is rife in our society and adolescents (10-19 years) do face this problem during this vulnerable period of growth and development. Use of substances is known to be associated with poor health choices and risky sexual behaviour. Since the advent of antiretroviral therapy (ART), significant progress has been made with reduced rates of mother to child transmission (MTCT) and a general downward global trend in acquired immunodeficiency disease (AIDS) related mortalities. However, human immunodeficiency virus (HIV)/AIDS is still a leading cause of mortality in adolescents living in Sub Saharan Africa, with an upward trend in new HIV …

Evaluation Of Immune-Modulating Therapies For Parkinson's Disease, Katherine E. Olson

Theses & Dissertations

Parkinson’s disease (PD) is the second most common neurodegenerative

disorder, second only to Alzheimer’s disease (AD). It is characterized by a

progressive loss of dopaminergic neurons along the nigrostriatal axis and the

formation of proteinaceous inclusions of alpha-synuclein (α-syn). Secondary to

the loss of dopaminergic neurons is a progression in motor and non-motor

symptoms. Motor symptoms are characterized by slowness in movement,

stiffness and tremor. Non-motor symptoms include depression, constipation,

sleep abnormalities and loss of sense of smell. The cause of disease remains

incompletely understood. However, age, genetics, environment, viral infection,

and interplay between the innate and adaptive immune system …

Synthesis And Development Of Long-Acting Abacavir Prodrug Nanoformulations, Dhirender Singh

Theses & Dissertations

Over the past decade, work from our laboratory has demonstrated the potential of targeted nanoformulated antiretroviral therapy (nanoART) to produce sustained high plasma and tissue drug concentrations for weeks following a single intramuscular (IM) administration that can suppress ongoing viral replication and mitigate dose associated viral resistance. While progress has occurred towards developing long-acting nanoformulations for protease and nonnucleoside reverse transcriptase (RT) inhibitors, development of nanoformulations of hydrophilic nucleoside RT inhibitor drugs have remained elusive. Abacavir (ABC); a hydrophilic molecule exhibited limited utilities to develop into long-acting nanoformulation platform. Furthermore, inefficient conversion of ABC to its biological active metabolites; carbovir …

Sonographic Estimation Of The Prevalence Of Hepatic Steatosis In Hiv Monoinfected Patients At Aga Khan University Nairobi., Bernadette Wambui Muthee

Theses & Dissertations

Introduction: Human immunodeficiency virus disease (HIV) is a worldwide health problem. It is estimated that 38.6 million people are infected with HIV globally. It has remained endemic in the African continent for close to 20 years and is a long term developmental challenge in Africa which bears 69 % of the HIV/AIDS global burden.

The introduction of highly active antiretroviral therapy (HAART) has caused dramatic improvement in prognosis of HIV disease. Consequently, this has resulted in substantial reduction in Acquired Immune Deficiency Syndrome (AIDS) related morbidity and mortality. In contrast, this has been accompanied by an upsurge in liver- related …

Ccr5 And The Blood Brain Barrier During Hiv-1 Infection And Cell-Cell Communications, Shawna M. Woollard

Theses & Dissertations

Human Immunodeficiency Virus (HIV-1) infection often results in blood-brain barrier (BBB) dysfunction and central nervous system (CNS) impairment. Since most viral strains that cross the BBB and enter the CNS are macrophage-tropic and use the C-C chemokine receptor type-5 (CCR5) to enter and infect target cells, we hypothesized that CCR5 plays a major role in monocytes-endothelial interactions and HIV-induced BBB dysfunction. Because the cytoskeleton is responsible for cellular morphology and motility, we further hypothesized that HIV-induced monocyte-endothelial interactions and transendothelial migration involve cytoskeletal changes and that CCR5 blockers would also affect these changes. To this end we used two small …

Respiratory Function Amongst Asymptomatic Hiv Positive And Hiv Negative Clients At Aga Khan University Hospital, Nairobi, Noah Kipkemei Murbiy

Theses & Dissertations

Background: Spirometry is used to asses respiratory function abnormalities. This is usually in reference to a validated normal range unique to a particular gender, race, age, weight and height. Majority of persons are usually asymptomatic until the expected FEV1 has decreased by 50%. Early intervention on the abnormalities even in this asymptomatic group has been shown to retard the rate of pulmonary deterioration. An unpublished audit at the Aga Khan University Hospital, Nairobi, revealed that majority of newly diagnosed HIV positive persons were admitted at the Critical Care Units with a pulmonary cause which later resulted in poor outcomes. This …

The Prevalence And Factors Associated With Nonadherence With Arv Treatment And Cotrimoxazole Preventive Therapy Among Hiv Infected Adolescents Attending Out-Patient Hiv Clinics In Kenya, Reson Marima

Theses & Dissertations

Background: There is an increase in the burden of HIV infected adolescents, both those perinatally infected as well as those acquiring HIV during adolescence. Female adolescents continue to be at the highest risk for acquiring HIV; in many Southern African countries, they have a three fold risk of acquiring HIV compared to their male counterparts. Adherence to treatment among adolescents has been shown to range between 30-70%, which is unacceptably low for antiretroviral therapy (ART). Psychosocial wellbeing and social support have been shown to be possible contributing factors to adherence to ART. This relationship has not been previously evaluated …

The Influence Of Antiretroviral Therapy On Qtc Interval Amongst Hiv Patients At Aga Khan University Hospital, Nairobi, Jay Shavadia

Theses & Dissertations

Aim: To determine the influence of antiretroviral (ARV) therapy on the QT_C interval amongst HIV-infected patients.

Design: Prospective Comparative survey of two population samples

Patients and Setting: One hundred and thirty ARV naïve and one hundred and thirty treated HIV-positive patients selected from in and out patient departments of Aga Khan University Hospital underwent clinical evaluation and 12 lead resting ECG between August 2008 and March 2009.

Methodology: Eligible HIV-positive patients were conveniently sampled and had a 12-lead electrocardiogram (ECG) performed to determine the QTinterval, corrected for the heart rate by the Bazzet formula. Analysis was then performed to …