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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Lactic Acidosis

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

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Table 11g. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Lactic Acidosis
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management

NRTIs, in particular, d4T and ddI (highest risk in combination) Onset
  • 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
  • Dyspnea
  • Peripheral neuropathy
Note: 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)

  • 15%–35% of adults receiving NRTI therapy for longer than 6 months
  • 29%–32%
Symptomatic Severe Hyperlactatemia (>5.0 mmol/L)

  • 0.2%–5.7%
Symptomatic Lactic Acidosis/
Hepatic Steatosis
  • Rare in all age groups (1.3–11 episodes per 1,000 person-years; increased incidence with the use of d4T/ddI in combination), 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)
  • 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 
Preterm Infants
  • Use of propylene glycol (e.g., as an diluent for LPV/r)
  • Avoid d4T and ddI individually and especially in combination in an ARV regimen.
  • 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 1 Test):
  • 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).
Anecdotal (Unproven) Supportive Therapies
  • Bicarbonate infusions, THAM, high-dose thiamine and riboflavin, oral antioxidants (e.g., L-carnitine, co-enzyme Q10, 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.
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 the results of the confirmatory test.

Key to Acronyms: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; BMI = body mass index; CD4 = CD4 T lymphocyte; d4T = stavudine; ddI = didanosine; FTC = emtricitabine; HCV = hepatitis C virus; IV: intravenous; LPV/r = ritonavir-boosted lopinavir; NRTI = nucleoside reverse transcriptase inhibitor; RBV = ribavirin; TDF = tenofovir disoproxil fumarate; THAM = tris(hydroxymethyl)aminomethane


General Reviews

  1. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. Mar 2002;46(3):716-723. Available at
  2. Carr A. Lactic acidemia in infection with human immunodeficiency virus. Clin Infect Dis. Apr 1 2003;36(Suppl 2):S96-S100. Available at
  3. Desai N, Mathur M, Weedon J. Lactate levels in children with HIV/AIDS on highly active antiretroviral therapy. AIDS. Jul 4 2003;17(10):1565-1568. Available at
  4. Foster C, Lyall H. HIV and mitochondrial toxicity in children. J Antimicrob Chemother. Jan 2008;61(1):8-12. Available at
  5. Noguera A, Fortuny C, Sanchez E, et al. Hyperlactatemia in human immunodeficiency virus-infected children receiving antiretroviral treatment. Pediatr Infect Dis J. Sep 2003;22(9):778-782. Available at
  6. Arenas-Pinto A, Grant A, Bhaskaran K, et al. Risk factors for fatality in HIV-infected patients with dideoxynucleoside-induced severe hyperlactataemia or lactic acidosis. Antivir Ther. 2011;16(2):219-226. Available at
  7. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr. Mar 1 2012;59(3):274-280. Available at
Risk Factors
  1. mhof A, Ledergerber B, Gunthard HF, Haupts S, Weber R, Swiss HIVCS. Risk factors for and outcome of hyperlactatemia in HIV-infected persons: is there a need for routine lactate monitoring? Clin Infect Dis. Sep 1 2005;41(5):721-728. Available at
  2. Manosuthi W, Prasithsirikul W, Chumpathat N, et al. Risk factors for mortality in symptomatic hyperlactatemia among HIV-infected patients receiving antiretroviral therapy in a resource-limited setting. Int J Infect Dis. Nov 2008;12(6):582-586. Available at
  3. Osler M, Stead D, Rebe K, Meintjes G, Boulle A. Risk factors for and clinical characteristics of severe hyperlactataemia in patients receiving antiretroviral therapy: a case-control study. HIV Med. Feb 2010;11(2):121-129. Available at
  4. Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. Lactic acidosis after concomitant treatment with metformin and tenofovir in a patient with HIV infection. J Ren Care. Mar 2011;37(1):25-29. Available at
  5. Boxwell DC, K.; et al. Neonatal Toxicity of Kaletra Oral Solution—LPV, Ethanol, or Propylene Glycol? Abstract #708. Paper presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston MA. 2011. 
  6. Feeney ER, Chazallon C, O'Brien N, et al. Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial). HIV Med. Nov 2011;12(10):602-609. Available at
  7. Leung L, Wilson D, Manini AF. Fatal toxicity from symptomatic hyperlactataemia: a retrospective cohort study of factors implicated with long-term nucleoside reverse transcriptase inhibitor use in a South African hospital. Drug Saf. Jun 1 2011;34(6):521-527. Available at
  8. Maskew M, Westreich D, Fox MP, Maotoe T, Sanne IM. Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating HAART in South Africa. J Int AIDS Soc. 2012;15(1):13. Available at
  9. Matthews LT, Giddy J, Ghebremichael M, et al. A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy. PLoS One. 2011;6(4):e18736. Available at
  10. Menezes CN, Maskew M, Sanne I, Crowther NJ, Raal FJ. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infect Dis. 2011;11:244. Available at
  11. Phan V, Thai S, Choun K, Lynen L, van Griensven J. Incidence of treatment-limiting toxicity with stavudine-based antiretroviral therapy in Cambodia: a retrospective cohort study. PLoS One. 2012;7(1):e30647. Available at
  12. Dragovic G, Jevtovic D. The role of nucleoside reverse transcriptase inhibitors usage in the incidence of hyperlactatemia and lactic acidosis in HIV/AIDS patients. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Jun 2012;66(4):308-311. Available at
  13. Moren C, Noguera-Julian A, Garrabou G, et al. Mitochondrial evolution in HIV-infected children receiving first- or second-generation nucleoside analogues. J Acquir Immune Defic Syndr. Jun 1 2012;60(2):111-116. Available at
  14. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS. Mar 13 2013;27(5):781-785. Available at
  15. Wester CW, Eden SK, Shepherd BE, et al. Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination antiretroviral therapy-treated adults in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses. Aug 2012;28(8):759-765. Available at
Monitoring and Management
  1. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS. 2001;15(6):795-797. Available at
  2. Carter RW, Singh J, Archambault C, Arrieta A. Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to L-carnitine in a pediatric HIV-positive patient. AIDS Patient Care STDS. Mar 2004;18(3):131-134. Available at
  3. Claessens YE, Cariou A, Monchi M, et al. Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Critical care medicine. Apr 2003;31(4):1042-1047. Available at
  4. Delgado J, Harris M, Tesiorowski A, Montaner JS. Symptomatic elevations of lactic acid and their response to treatment manipulation in human immunodeficiency virus-infected persons: a case series. Clin Infect Dis. 2001;33(12):2072-2074. Available at
  5. Lonergan JT, Barber RE, Mathews WC. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. AIDS. Nov 21 2003;17(17):2495-2499. Available at
  6. Marfo K, Garala M, Kvetan V, Gasperino J. Use of Tris-hydroxymethyl aminomethane in severe lactic acidosis due to highly active antiretroviral therapy: a case report. Journal of clinical pharmacy and therapeutics. Feb 2009;34(1):119-123. Available at
  7. McComsey G, Lonergan JT. Mitochondrial dysfunction: patient monitoring and toxicity management. J Acquir Immune Defic Syndr. Sep 1 2004;37 Suppl 1:S30-35. Available at
  8. Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr. Nov 1 2002;31(3):257-275. Available at
  9. Wohl DA, McComsey G, Tebas P, et al. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis. Sep 1 2006;43(5):645-653. Available at

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