Date of Award

January 2020

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Elijah Paintsil

Abstract

Background: Though antiretroviral therapy (ART) regimens have become progressively less toxic, ART-associated toxicity is still pervasive. Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor (INSTI), a class of antiretrovirals that are generally well-tolerated by patients. However, in the clinic there are reports of unexpectedly high rates of toxicity in cohorts of pregnant women such as neural tube defects, and in older patients’ adverse effects such as neuropsychiatric disorders. We hypothesized that these adverse effects could be due to DTG-induced mitochondrial toxicity in the central nervous system.

Methods: Human neuroblastoma cells were treated with ART regimens that are currently considered standard of care for HIV management. The cells were passaged every 4 days with standard growth media. Neuroblastoma cells were exposed to 1X or 4X-Cmax of tenofovir, emtricitabine, and DTG in single or in combination for 24 hours. We harvested the cells after 24 hours of treatment to determine the effect of treatment on cell growth, mitochondrial protein presence, mitochondrial expression levels, and NMDA receptor protein levels.

Results: Our preliminary results indicate that DTG has a potentially appreciable effect on both mitochondrial function and cholesterol biosynthesis. ATP synthase expression levels appears to be relatively unaffected by treatments while expression levels for the other mitochondrial complexes appear to be decreased from DTG treatment compared to other single treatments.

Conclusion: Though DTG in clinical trials has been demonstrated to be a potent treatment for HIV viral load, have a high resistance barrier, and low interaction potential, there is still much to be understood in terms of toxicity mechanisms. Our study indicates that the clinical safety profile of DTG and DTG-combination therapies need to be further evaluated.

Comments

This is an Open Access Thesis.

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