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The Body Covers: The 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Hyperlactatemia and Lactic Acidosis During Antiretroviral Therapy

October 25, 2001

  • Hyperlactatemia and Lactic Acidosis During Antiretroviral Therapy: Relevance, Reproducibility, Possible Risk Factors
    Presenter: Graeme Moyle, M.D.

While it is clear that lactic acidosis is reflective of problems with mitochondria, raised lactate may occur secondary to increased production, increased release or reduced clearance or utilization of lactate. It remains to be fully established to what extent each of these potential contributors are involved in hyperlactatemia, although reduced hepatic clearance looks most likely to be critical. Elevated lactate is relatively common (8-18.3% above 2-2.5 mmol/L in cross-section and/or partially longitudinal studies) whereas lactic acidosis is rare (0.3-0.4% per patient year). So, is hyperlactatemia part of a spectrum of changes that lead to the potentially serious lactic acidosis?

Several possible explanations arise for this difference. First, elevated lactate may be related to sampling error either due to recent patient activity, tourniquet use or delayed sample processing. The largest reported studies on hyperlactatemia, which have included cohorts of untreated individuals, find that the range of lactate values for these patients lie below 2.5 mmol/L (usually a mean around 1 mmol/L) and have described techniques to limit sampling error.

Patients treated for HIV infection may have increased cellular energy requirements. Elevated basal lipolysis, increased fat turnover, elevated endogenous glucose production and glucose turnover have been reported. Patients with lipodystrophy have raised resting energy expenditure. Lipid and glucose oxidation [see yesterday's report] appear normal, suggesting adequate adipocyte and myocyte mitochondrial function. This explanation is, however, unlikely, as high lactate may be seen even in individuals with low fat mass and without metabolic or morphologic manifestations.

It is more possible that adipocytes and myocytes are releasing lactate into the systemic circulation more readily. Persons on antiretrovirals for prolonged periods commonly have metabolic disturbances, including hyperinsulinemia and glucose intolerance with hyperglycemia. Both hyperinsulinemia and hyperglycemia stimulate increased lactate release from adipocytes in vivo. Again, however, hyperinsulinemia does not appear necessary for hyperlactatemia in treated patients.

Diminished lactate clearance is most likely to be critical to lactate levels. Reduced clearance of lactate generally requires hepatic mitochondrial dysfunction. Hyperlactatemia is not, however, an invariable accompaniment of liver failure, as extrahepatic tissues -- such as the kidney -- and muscle may compensate. Patients with HIV infection may have several reasons for diminished hepatic clearance of lactate: NRTI effects on mitochondria, dyslipidemia and insulin resistance contributing to steatosis, direct toxic effects of some agents (e.g., nevirapine), alcohol use, additional concomitant therapy (particularly NSAIDs, valproate, metformin) and hepatitis B or C co-infection.

This meeting heard a presentation of the largest cross-sectional study reported to date. The study evaluated 1,239 individuals who had been receiving antiretroviral therapy for at least four months and an additional 253 individuals who had never received antiretroviral therapy. Of the 1,239 who had at least one lactate sample, 8.7% had a serum lactate level greater than or equal to 2.5 mmol/L with 9 (0.8%) individuals above 5 mmol/L -- a level considered severe. High lactate was observed in similar frequency with male and female patients and duration of therapy was similar between those individuals with normal and raised lactate values. Overall, the median lactate levels for the population of 1,239 treated patients were 1.4 mmol/L and 1.1 mmol/L among untreated individuals. Five untreated individuals had lactate values above 2.5 mmol/L on a single occasion with one individual having elevated lactate on two consecutive occasions (in both cases <3 mmol/L). Raised lactate had a poor (<40%) predictive value for future raised lactate; however, individuals who went on to have severe hyperlactatemia or acidosis often had modest lactate elevations in the weeks or months prior to the severe event. For the whole population, regimens containing ddI appeared to have an increased relative hazard of a raised lactate, whereas regimens that contained ABC appeared to have a significantly diminished relative hazard of hyperlactatemia.

Rates of hyperlactatemia were highest in individuals receiving the combination of d4T/ddI (17%). The hazard of a high lactate relative to d4T/ddI was significantly lower in individuals receiving the combination of ABC/3TC or d4T/3TC. No significant differences between the relative hazard of hyperlactatemia on d4T/ddI were observed with combinations of AZT/ddI or AZT/3TC. Overall, and in a subset of 312 individuals on first-line therapy, rates of hyperlactatemia were similar when d4T was compared with AZT, the incidence in both groups being dependent on combination with ddI or 3TC. These data all suggest that ddI use -- but not thymidine analog choice -- may be a relevant risk for high lactate. Associations with d4T in previous studies may relate to the relatively more common use of this agent with ddI. This association with ddI rather than d4T would be consistent with the effects of these drugs on hepatocytes in vitro.

Additionally, associations with biochemical parameters were observed with hyperlactatemia. In a multivariate model, hyperlactatemia was associated with higher ALT (liver transaminase) levels and higher glucose levels although the median values were not outside of the normal range. Additionally, hyperlactatemia was associated with a wider anion gap (the balance of sodium and potassium to chloride and bicarbonate reflective of blood acidity). Individuals with an anion gap of 12-18 had a 4.9-fold greater chance of hyperlactatemia than those with an anion gap of less than 12. Furthermore, individuals with an anion gap of greater than 18 had an 8-fold higher chance of having an elevated lactate value than those individuals with an anion gap of less than 12. These data raise the possibility that, at least for some individuals, elevated lactates may be a reflection of a shift in acid balance. However, only four events of lactic acidosis were reported in this population.

Overall, these data suggest that lactate may exist in a spectrum from normal through mild to moderate elevation or "compensated" hyperlactatemia to severe and often "decompensated" hyperlactatemia and acidosis. The risks for shifting from normal to raised but compensated hyperlactatemia may include duration of NRTI therapy, ddI use (at least relative to ABC), hyperglycemia and liver dysfunction. Decompensation to acidosis may require additional triggers including respiratory or other intercurrent infection, alcohol bingeing, or introduction of additional drugs.

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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.