Why do NRTIs (Nucleoside Reverse Transcriptase Inhibitors) cause mitochondrial toxicities?

Mechanism of NRTI-Induced Mitochondrial Toxicity

NRTIs cause mitochondrial toxicity primarily by inhibiting DNA polymerase γ, the enzyme responsible for mitochondrial DNA synthesis, leading to impaired mitochondrial function and various clinical manifestations including lactic acidosis and lipodystrophy. 1

Primary Mechanism of Toxicity

• NRTIs are designed to inhibit HIV reverse transcriptase but also inhibit mitochondrial DNA polymerase γ, disrupting mitochondrial DNA synthesis and replication 1
• The inhibition of mitochondrial DNA polymerase γ leads to progressive depletion of mitochondrial DNA, causing dysfunction in the mitochondrial respiratory chain 2
• This mitochondrial dysfunction results in impaired cellular energy production and increased anaerobic metabolism, leading to lactate accumulation 3, 4

Hierarchy of Mitochondrial Toxicity Among NRTIs

• Different NRTIs have varying potentials for inhibiting mitochondrial DNA polymerase γ, with the following hierarchy (from highest to lowest toxicity): zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir 2
• Stavudine and didanosine are associated with the highest risk of severe mitochondrial toxicity, including potentially fatal lactic acidosis 1
• Newer NRTIs like tenofovir and abacavir have lower potential for mitochondrial toxicity as they are not associated with significant inhibition of DNA polymerase γ 1

Additional Mechanisms of Mitochondrial Damage

• Beyond DNA polymerase γ inhibition, NRTIs may also impair other mitochondrial enzymes including adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator 2
• The cumulative effect of these impairments leads to progressive mitochondrial dysfunction over time, explaining why toxicities often appear after prolonged treatment 5
• Chronic HIV infection itself may contribute to mitochondrial dysfunction, potentially creating a synergistic effect with NRTI toxicity 6

Clinical Manifestations of NRTI-Induced Mitochondrial Toxicity

• Lactic acidosis with hepatic steatosis is the most severe manifestation, with a high mortality rate despite its relative rarity (estimated incidence of 1.3 cases/1000 person-years of NRTI exposure) 1
• Other clinical manifestations include peripheral neuropathy, myopathy, cardiomyopathy, pancreatitis, and features of lipodystrophy syndrome 2, 7
• Risk factors for developing severe lactic acidosis include female gender, obesity, pregnancy, and prolonged use of NRTIs 1

Monitoring and Management Considerations

• Early signs of mitochondrial toxicity may include nonspecific symptoms such as fatigue, nausea, abdominal pain, and unexplained weight loss 1, 3
• Laboratory findings may show elevated lactate levels (>5 mmol/L considered abnormal, >10 mmol/L indicating serious toxicity), increased anion gap, and elevated liver enzymes 3, 4
• Management primarily involves discontinuation of the offending NRTIs, with consideration of switching to NRTIs with lower mitochondrial toxicity potential such as tenofovir or abacavir 1, 5
• Severe lactic acidosis requires intensive supportive care including possible mechanical ventilation, bicarbonate infusions, and hemodialysis 1
• Experimental therapies based on the mitochondrial pathophysiology include administration of thiamine and riboflavin, though clinical validation of these approaches is still needed 1, 8

Prevention Strategies

• Using NRTIs with lower mitochondrial toxicity potential (tenofovir, abacavir) rather than those with higher risk (stavudine, didanosine) 1
• Regular monitoring for early signs of mitochondrial toxicity, particularly in patients with risk factors 5
• Avoiding combinations of NRTIs with overlapping toxicity profiles 7
• Consideration of NRTI-sparing regimens in patients with history of mitochondrial toxicity 5