|NRTIs, in particular, d4T and ddI (alone and 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: generalized fatigue, weakness, and myalgias;
vague abdominal pain, weight loss, unexplained nausea or vomiting;
Patients may present with acute multi-organ failure (such as fulminant hepatic, pancreatic, and respiratory failure).
|Chronic, asymptomatic mild hyperlactatemia (2.1–5.0 mmol/L):
Adults: 15%–35% of adults receiving NRTI therapy for longer than 6 months
Symptomatic severe hyperlactatemia (>5.0 mmol/L):
Symptomatic lactic acidosis/hepatic steatosis:
Rare in all age groups (1.3–11 episodes per 1,000 person-years), but associated with a high fatality rate (33%–58%)
- Female gender
- High BMI
- Chronic HCV infection
- African-American race
- Prolonged NRTI use (particularly d4T and ddI)
- Coadministration of ddI with other agents (such as d4T, TDF, RBV, or tetracycline)
- Coadminstration of TDF with metformin
- Overdose of propylene glycol
- CD4 T lymphocyte count <350 cells/mm3
- Acquired riboflavin or thiamine deficiency
- Possibly, pregnancy
- Use of propylene glycol (e.g., as an diluent for LPV/r)
Avoid d4T and ddI in combination.
Monitor for clinical manifestations of lactic acidosis and promptly adjust therapy.
Measurement of serum lactate is not recommended.
Clinical signs or symptoms consistent with lactic acidosis:
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):
Consider replacing ddI and d4T with other ARVs.
As alternative, temporarily discontinue all ARVs while conducting additional diagnostic workup.
Lactate >5.0 mmol/L (confirmed with second test)b or >10.0 mmol/L (any one test):
Discontinue all ARVs. Provide supportive therapy (intravenous fluids; some patients may require sedation and respiratory support to reduce oxygen demand and ensure adequate oxygenation of tissues).
Anecdotal (unproven) supportive therapies: bicarbonate infusions, THAM, high-dose thiamine and riboflavin, oral antioxidants (e.g., L-carnitine, co-enzyme Q, vitamin C).
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.