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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:2/12/2014; last reviewed:2/12/2014)

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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
Lactic
Acidosis

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).
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
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)

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; increased incidence with the use of d4T/ddI in combination), but associated with a high fatality rate (33%–58%)

Adults:
  • 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)
Prevention:
  • Avoid d4T and ddI individually and especially in combination in an ARV regimen.
  • 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.

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

References 

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 http://www.ncbi.nlm.nih.gov/pubmed/11850253.
  2. Carr A. Lactic acidemia in infection with human immunodeficiency virus. Clin Infect Dis. Apr 1 2003;36(Suppl 2):S96-S100. Available at http://www.ncbi.nlm.nih.gov/pubmed/12652378.
  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 http://www.ncbi.nlm.nih.gov/pubmed/12824798.
  4. Foster C, Lyall H. HIV and mitochondrial toxicity in children. J Antimicrob Chemother. Jan 2008;61(1):8-12. Available at http://www.ncbi.nlm.nih.gov/pubmed/17999978.
  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 http://www.ncbi.nlm.nih.gov/pubmed/14506367.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21447871.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22126740.
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 http://www.ncbi.nlm.nih.gov/pubmed/16080096.
  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 http://www.ncbi.nlm.nih.gov/pubmed/18337140.
  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 http://www.ncbi.nlm.nih.gov/pubmed/19702629.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21288314.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21599820.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21488705.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22410312.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21494566.
  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 http://www.ncbi.nlm.nih.gov/pubmed/21923929.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22303447.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22658063.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22362155.
  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 http://www.ncbi.nlm.nih.gov/pubmed/23169331.
  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 http://www.ncbi.nlm.nih.gov/pubmed/22540188.
Monitoring and Management
  1. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS. 2001;15(6):795-797. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11371695.
  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 http://www.ncbi.nlm.nih.gov/pubmed/15104873.
  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 http://www.ncbi.nlm.nih.gov/pubmed/12682470.
  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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11712096.
  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 http://www.ncbi.nlm.nih.gov/pubmed/14600521.
  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 http://www.ncbi.nlm.nih.gov/pubmed/19125910.
  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 http://www.ncbi.nlm.nih.gov/pubmed/15319667.
  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 http://www.ncbi.nlm.nih.gov/pubmed/12439201.
  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 http://www.ncbi.nlm.nih.gov/pubmed/16886161.