Antiretroviral Associated Adverse Effects and Management Recommendations for Lactic Acidosis

Adverse Effects	Associated ARVs	Onset/Clinical Manifestations	Estimated Frequency	Risk Factors	Prevention/Monitoring	Management
Lactic Acidosis	NRTIs ZDV Less likely with 3TC, FTC, ABC, TAF, and TDF Other Drugs See the Risk Factors and Prevention/ Monitoring columns for information regarding the toxicity of propylene glycol when LPV/r oral solution is used in neonates.	Onset Generally, after years of exposure A few cases have been reported shortly after initiation in people with underlying live disease. Presentation Lactic acidosis may be clinically asymptomatic. Lactic Acidosis May Also Present With 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 Note: Patients may present with acute multiorgan failure (e.g., fulminant hepatic failure, pancreatic failure, respiratory failure).	3TC, FTC, ABC, TAF, and TDF are less likely to induce clinically significant mitochondrial dysfunction than ZDV.	Adults Female sex High BMI Chronic HCV infection African American race Coadministration of TDF with metformin Overdose of propylene glycol CD4 count <350 cells/mm³ Acquired riboflavin or thiamine deficiency Possible pregnancy Overdose in setting of renal insufficiency (e.g., 3TC) Preterm Infants or Any Neonates Who Have Not Attained a Postmenstrual Age of 42 Weeks and a Postnatal Age of ≥14 Days Exposure to propylene glycol, which is used as a diluent in LPV/r oral solution, because these newborns have a diminished ability to metabolize propylene glycol may lead to accumulation, increasing the risk of adverse events.	Prevention Due to the presence of propylene glycol as a diluent, LPV/r oral solution should not be used in preterm neonates or any neonate who has not attained a postmenstrual age of 42 weeks and a postnatal age of ≥14 days. Monitor for clinical manifestations of lactic acidosis and promptly adjust therapy. Monitoring Asymptomatic Patients Routine measurement of serum lactate is not recommended. Patients With Clinical Signs or Symptoms Consistent With Lactic Acidosis Obtain blood lactate level.^a Additional diagnostic evaluations should include serum bicarbonate, anion gap, and/or arterial blood gas; amylase and lipase; serum albumin; and hepatic transaminases.	For Patients With Lactate 2.1–‍5.0 mmol/L (Confirmed With a Second Test) Consider discontinuing all ARV drugs temporarily while conducting additional diagnostic work-up. For Patients With Lactate >5.0 mmol/L (Confirmed With a Second Test)^b or >10.0 mmol/L (Any One Test) Discontinue all ARV drugs. Provide supportive therapy (e.g., IV fluids; some patients may require sedation and respiratory support to reduce oxygen demand and ensure adequate oxygenation of tissues). Anecdotal (Unproven) Supportive Therapies Administer bicarbonate infusions, THAM, high doses of thiamine and riboflavin, and oral antioxidants (e.g., L-carnitine, co-enzyme Q10, vitamin C). Following the resolution of clinical and laboratory abnormalities, resume therapy either with an NRTI-sparing regimen or a revised NRTI-containing regimen. Institute a revised NRTI-containing regimen with caution, using NRTIs that are less likely to induce mitochondrial dysfunction (ABC, TAF, TDF, FTC, or 3TC). Lactate should be monitored monthly for ≥3 months.
^a Blood for lactate determination should be collected, without prolonged tourniquet application or fist clenching, into a pre-chilled, gray-top, fluoride-oxalate-containing tube and transported on ice to the laboratory to be processed within 4 hours of collection. ^b Management can be initiated before receiving the results of the confirmatory test. Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; BMI = body mass index; CD4 = CD4 T lymphocyte; FTC = emtricitabine; HCV = hepatitis C virus; IV = intravenous; LPV/r = lopinavir/ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; THAM = tris (hydroxymethyl) aminomethane; ZDV = zidovudine

Adverse Effects

Associated ARVs

Onset/Clinical Manifestations

Estimated Frequency

Risk Factors

Prevention/Monitoring

Management

Lactic Acidosis

NRTIs

ZDV
Less likely with 3TC, FTC, ABC, TAF, and TDF

Other Drugs

See the Risk Factors and Prevention/
Monitoring columns for information regarding the toxicity of propylene glycol when LPV/r oral solution is used in neonates.

Onset

Generally, after years of exposure
A few cases have been reported shortly after initiation in people with underlying live disease.

Presentation

Lactic acidosis may be clinically asymptomatic.

Lactic Acidosis May Also Present With 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

Note: Patients may present with acute multiorgan failure (e.g., fulminant hepatic failure, pancreatic failure, respiratory failure).

3TC, FTC, ABC, TAF, and TDF are less likely to induce clinically significant mitochondrial dysfunction than ZDV.

Adults

Female sex
High BMI
Chronic HCV infection
African American race
Coadministration of TDF with metformin
Overdose of propylene glycol
CD4 count <350 cells/mm³
Acquired riboflavin or thiamine deficiency
Possible pregnancy
Overdose in setting of renal insufficiency (e.g., 3TC)

Preterm Infants or Any Neonates Who Have Not Attained a Postmenstrual Age of 42 Weeks and a Postnatal Age of ≥14 Days

Exposure to propylene glycol, which is used as a diluent in LPV/r oral solution, because these newborns have a diminished ability to metabolize propylene glycol may lead to accumulation, increasing the risk of adverse events.

Prevention

Due to the presence of propylene glycol as a diluent, LPV/r oral solution should not be used in preterm neonates or any neonate who has not attained a postmenstrual age of 42 weeks and a postnatal age of ≥14 days.
Monitor for clinical manifestations of lactic acidosis and promptly adjust therapy.

Monitoring

Asymptomatic Patients

Routine measurement of serum lactate is not recommended.

Patients With Clinical Signs or Symptoms Consistent With Lactic Acidosis

Obtain blood lactate level.^a
Additional diagnostic evaluations should include serum bicarbonate, anion gap, and/or arterial blood gas; amylase and lipase; serum albumin; and hepatic transaminases.

For Patients With Lactate 2.1–‍5.0 mmol/L (Confirmed With a Second Test)

Consider discontinuing all ARV drugs temporarily while conducting additional diagnostic work-up.

For Patients With Lactate >5.0 mmol/L (Confirmed With a Second Test)^b or >10.0 mmol/L (Any One Test)

Discontinue all ARV drugs.
Provide supportive therapy (e.g., IV fluids; some patients may require sedation and respiratory support to reduce oxygen demand and ensure adequate oxygenation of tissues).

Anecdotal (Unproven) Supportive Therapies

Administer bicarbonate infusions, THAM, high doses of thiamine and riboflavin, and oral antioxidants (e.g., L-carnitine, co-enzyme Q10, vitamin C).

Following the resolution of clinical and laboratory abnormalities, resume therapy either with an NRTI-sparing regimen or a revised NRTI-containing regimen. Institute a revised NRTI-containing regimen with caution, using NRTIs that are less likely to induce mitochondrial dysfunction (ABC, TAF, TDF, FTC, or 3TC). Lactate should be monitored monthly for ≥3 months.

^a Blood for lactate determination should be collected, without prolonged tourniquet application or fist clenching, into a pre-chilled, gray-top, fluoride-oxalate-containing tube and transported on ice to the laboratory to be processed within 4 hours of collection.

^b Management can be initiated before receiving the results of the confirmatory test.

Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; BMI = body mass index; CD4 = CD4 T lymphocyte; FTC = emtricitabine; HCV = hepatitis C virus; IV = intravenous; LPV/r = lopinavir/ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; THAM = tris (hydroxymethyl) aminomethane; ZDV = zidovudine

References

Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lactic Acidosis