|NRTIs, in particular, d4T and ddI (highest risk in combination)
- 1–20 months after starting therapy (median onset 4 months in 1 case series)
Usually Insidious Onset of a Combination of Signs and Symptoms:
Note: Patients may present with acute multi-organ failure (such as fulminant hepatic, pancreatic, and respiratory failure).
- Generalized fatigue, weakness, and myalgias
- Vague abdominal pain, weight loss, unexplained nausea or vomiting
- Peripheral neuropathy
|Chronic, Asymptomatic Mild Hyperlactatemia (2.1–5.0 mmol/L):
Symptomatic Severe Hyperlactatemia (>5.0 mmol/L):
- 15% to 35% of adults receiving NRTI therapy for longer than 6 months
Symptomatic Lactic Acidosis/Hepatic Steatosis:
- Rare in all age groups (1.3–11 episodes per 1000 person-years; increased incidence with the use of d4T/ddI in combination), but associated with a high fatality rate (33% to 58%)
- Female gender
- High BMI
- Chronic HCV infection
- African-American race
- Prolonged NRTI use (particularly d4T and ddI)
- Co-administration of ddI with other agents (e.g., d4T, TDF, RBV, tetracycline)
- Co-administration of TDF with metformin
- Overdose of propylene glycol
- CD4 count <350 cells/mm3
- Acquired riboflavin or thiamine deficiency
- Possibly pregnancy
- Exposure to propylene glycol (e.g., present as a diluent in LPV/r oral solution)
- Avoid d4T and ddI individually and especially in combination in an ARV regimen.
- Monitor for clinical manifestations of lactic acidosis and promptly adjust therapy.
Clinical Signs or Symptoms Consistent with Lactic Acidosis:
- Measurement of serum lactate is not recommended.
- Obtain blood lactate level;a additional diagnostic evaluations should include serum bicarbonate and anion gap and/or arterial blood gas, amylase and lipase, serum albumin, and hepatic transaminases.
|Lactate 2.1–5.0 mmol/L (Confirmed with Second Test):
Lactate >5.0 mmol/L (Confirmed with Second Test)b or >10.0 mmol/L (Any 1 Test):
- Consider replacing ddI and d4T with other ARVs.
- As an alternative, temporarily discontinue all ARVs while conducting additional diagnostic workup.
Anecdotal (Unproven) Supportive Therapies:
- Discontinue all ARVs.
- Provide supportive therapy (IV fluids; some patients may require sedation and respiratory support to reduce oxygen demand and ensure adequate oxygenation of tissues).
Following resolution of clinical and laboratory abnormalities, resume therapy, either with an NRTI-sparing regimen or a revised NRTI-containing regimen instituted with caution, using NRTIs less likely to inhibit mitochondria (ABC or TDF preferred; possibly FTC or 3TC),and monthly monitoring of lactate for at least 3 months.
- Bicarbonate infusions, THAM, high-dose thiamine and riboflavin, oral antioxidants (e.g., L-carnitine, co-enzyme Q10, vitamin C).