ABSTRACT
Individuals treated for multidrug-resistant tuberculosis (MDR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss. However, AG ototoxicity has never been conceptually integrated or causally linked to MDR-TB patients' pre-treatment health condition. We sought to develop a framework that examines the relationships between pre-treatment conditions and AG-induced hearing loss among MDR-TB-infected individuals in sub-Saharan Africa. The adverse outcome pathway (AOP) approach was used to develop a framework linking key events (KEs) within a biological pathway that results in adverse outcomes (AO), which are associated with chemical perturbation of a molecular initiating event (MIE). This AOP describes pathways initiating from AG accumulation in hair cells, sound transducers of the inner ear immediately after AG administration. After administration, the drug catalyzes cellular oxidative stress due to overproduction of reactive oxygen species. Since oxidative stress inhibits mitochondrial protein synthesis, hair cells undergo apoptotic cell death, resulting in irreversible hearing loss (AO). We identified the following pre-treatment conditions that worsen the causal linkage between MIE and AO: HIV, malnutrition, aging, noise, smoking, and alcohol use. The KEs are: (1) nephrotoxicity, pre-existing hearing loss, and hypoalbuminemia that catalyzes AG accumulation; (2) immunodeficiency and antioxidant deficiency that trigger oxidative stress pathways; and (3) co-administration of mitochondrial toxic drugs that hinder mitochondrial protein synthesis, causing apoptosis. This AOP clearly warrants the development of personalized interventions for patients undergoing MDR-TB treatment. Such interventions (i.e., choosing less ototoxic drugs, scheduling frequent monitoring, modifying nutritional status, avoiding poly-pharmacy) will be required to limit the burden of AG ototoxicity.
Subject(s)
Aminoglycosides/adverse effects , Antitubercular Agents/adverse effects , Ototoxicity/etiology , Tuberculosis, Multidrug-Resistant/drug therapy , Adverse Outcome Pathways , Africa South of the Sahara , Aminoglycosides/administration & dosage , Antitubercular Agents/administration & dosage , Apoptosis/drug effects , Hair Cells, Auditory/drug effects , Hair Cells, Auditory/pathology , Hearing Loss/chemically induced , Hearing Loss/physiopathology , Humans , Ototoxicity/physiopathology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND & AIMS: Malnutrition is common in Sub-Saharan Africa, weakening the immune function of persons living with HIV infection (PLWH). Being malnourished at the initiation of antiretroviral therapy (ART) leads to higher risk of early mortality and reduced quality of life. Thus, introduction of protein-energy-fortified macronutrient supplements at ART initiation may improve HIV treatment outcomes. This review aimed to evaluate the effectiveness of macronutrient interventions. METHODS: This systematic review and meta-analysis included 15 studies conducted from 2000 to 2015 among Sub-Saharan African adults. RESULTS: Six randomized controlled trials and 4 retrospective cohort studies provided data eligible for a meta-analysis. Supplementation significantly increased the overall standardized mean difference (SMD) between baseline and follow-up data in weight (SMD = 0.382, p < .001), BMI (SMD = 0.799, p < .001); fat-free mass (SMD = 0.154, p = .009); and CD4 count (SMD = 0.428, p < .001). CONCLUSION: Protein-energy-fortified macronutrient supplementation at ART initiation may positively influence nutritional status and immunologic response in PLWH in Sub-Saharan Africa.