Lactic
acidosis
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NRTIs, in particular, d4T and ddI (alone and in combination) |
Onset:
1–20 months after starting therapy (median onset 4 months in 1 case series).
Presentation:
Usually insidious onset of a combination of signs and symptoms: generalized fatigue, weakness, and myalgias;
vague abdominal pain, weight loss, unexplained nausea or vomiting;
dyspnea;
peripheral neuropathy.
Patients may present with acute multi-organ failure (such as fulminant hepatic, pancreatic, and respiratory failure).
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Chronic, asymptomatic mild hyperlactatemia (2.1–5.0 mmol/L):
Adults: 15%–35% of adults receiving NRTI therapy for longer than 6 months
Children:
29%–32%
Symptomatic severe hyperlactatemia (>5.0 mmol/L):
Adults:
0.2%–5.7%
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%)
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Adults:
- 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
Pre-term infants:
- Use of propylene glycol (e.g., as an diluent for LPV/r)
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Prevention:
Avoid d4T and ddI in combination.
Monitor for clinical manifestations of lactic acidosis and promptly adjust therapy.
Monitoring:
Asymptomatic:
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.
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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.
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