Hyperlactatemia and Lactic Acidosis During Antiretroviral Therapy: Causes, Management and Possible Ætiologies

Nucleoside analogs represent key components of the antiretroviral combinations used to manage HIV infection. Lactic acidosis represents a rare but clinically important and potentially fatal manifestation of NRTI toxicity. The proposed mechanism for this adverse effect is suggested to be via inhibition of mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA during chronic NRTI therapy may lead to cellular respiratory dysfunction hence both increased production and decreased clearance of lactate. However, NRTI therapy may represent only one of many contributors to lactic acidosis. The development of acidosis may be better seen as a symptom of underlying disorders rather than a disease in itself. In normal conditions the cytosolic (or ‘anærobic’) metabolism of glucose does not produce hydrogen ions (H+). Lactic acidosis is likely only to occur when increases in production and defects in clearance of H+ ions is present, this most likely to be when the mitochondrial function of oxidative phosphorylation is disturbed. Healthy individuals have circulating levels of lactate but maintain normal blood pH. Lactate levels may rise during periods of increased energy needs (such as exercise, hypermetabolic states), hypoxic or hypoperfused states (cardiac, respiratory disease, haemoglobin disorders) when cellular lactate release is increased (such as hyperinsulinæmic states) or when the key tissues involved in clearance (liver, kidneys) dysfunction. However, raised lactate (hyperlactatæmia) does not inevitably lead to acidosis. Indeed, recent surveys of individuals on NRTI therapy indicate hyperlactatæmia to be a relatively common event occurring episodically in 10-20% of individuals whereas acidosis remains rare at less than 0.4% per treatment year. Whilst the treatment of lactic acidosis requires immediate therapy discontinuation and additional supportive measures, the management of hyperlactatæmia initially only requires remeasurement of lactate under controlled resting conditions and careful patient observation.