JAIDS Journal of Acquired Immune Deficiency Syndromes:
Brief Report: Clinical Science
Absence of Sustained Hyperlactatemia in HIV-Infected Patients With Risk Factors for Mitochondrial Toxicity
Wohl, David A. MD*; Pilcher, Christopher D. MD*; Evans, Scott PhD†; Revuelta, Manuel MD‡; McComsey, Grace MD§; Yang, Yijun ScD†; Zackin, Robert PhD†; Alston, Beverly MD∥; Welch, Stacey MA¶; Basar, Michael BA#; Kashuba, Angela PharmD**; Kondo, Pualani††; Martinez, Ana RPh‡‡; Giardini, Jeffrey BS§§; Quinn, Joseph RN∥∥; Littles, Melvin AA¶¶; Wingfield, Harry MFA##; Koletar, Susan L. MD***; Adult AIDS Clinical Trials Group A5129 Team
From the *Department of Medicine, University of North Carolina, Chapel Hill, NC; †Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA; ‡Department of Medicine, Beth Israel Medical Center, New York, NY; §Departments of Medicine and Pediatrics, Case Western Reserve University, Cleveland, OH; †Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA; †Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA; ∥Division of AIDS, National Institutes of Health, Bethesda, MD; ¶Social and Scientific Systems, Silver Spring, MD; #Complications Section, Frontier Science and Technology Research Foundation, Amherst, NY; **University of North Carolina School of Pharmacy, Division of Pharmacotherapy, University of North Carolina, Chapel Hill, NC; ††Retrovirology Research Laboratory, University of Hawaii, Honolulu, HI; ‡‡Pharmacology Affairs Branch, Division of AIDS, National Institutes of Health, Bethesda, MD; §§Frontier Science and Technology Research Foundation, Amherst, NY; ∥∥AIDS Clinical Trials Unit, University of Pennsylvania, Philadelphia, PA; ¶¶AIDS Clinical Trials Unit, Mount Sinai School of Medicine, New York, NY; ##AIDS Clinical Trials Unit, University of Alabama, Birmingham, AL; ***Department of Medicine, Ohio State University, Columbus, OH.
Received for publication September 23, 2003; accepted December 10, 2003.
Supported by the National Institute of Allergy and Infectious Diseases, AIDS Clinical Trials Group (grants AI-25868-15, AI-25924, AI-25879, and AI-46370); General Clinical Research Center Program of the Division of Research Resources, National Institutes of Health (grants RR00046 and RR00080); and University of North Carolina Center for AIDS Research Program of the National Institutes of Health (grant 9P30 AI50410).
Reprints: David A. Wohl, 211A West Cameron Avenue, Chapel Hill, NC 27599 (e-mail:email@example.com).
Background: The prevalence of asymptomatic hyperlactatemia among HIV-infected individuals has been reported to be 4% to 36%. This variability may reflect differences in the definition of and risk factors for hyperlactatemia and/or techniques for venous lactate collection.
Methods: We examined the prevalence of elevated venous lactate collected in accordance with Adult AIDS Clinical Trials Group (AACTG) guidelines among HIV-infected and nucleoside analogue–treated subjects with risk factors associated with hyperlactatemia. Sustained hyperlactatemia was defined as 2 consecutive levels ≥1.5 but ≤4 times the upper limit of normal (ULN) within 30 days.
Results: Eighty-three subjects were enrolled. Two thirds had ≥2 risk factors, with 11% having >4 risk factors. The median entry venous lactate level was 1.2 mmol/L (range: 0.7–5.1 mmol/L). Two subjects had a lactate level >1.5 times the ULN: 1 with a value of 2.1 times the ULN at entry and a week 2 level of 1.2 times the ULN and a second subject with a week 2 value of 1.9 times the ULN but an entry level of 1.4 times the ULN. The latter subject developed symptomatic lactic acidosis 3 weeks following study discontinuation.
Conclusions: Sustained asymptomatic hyperlactatemia among subjects with risk factors associated with hyperlactatemia was not observed when venous lactate was measured in a standardized fashion. One case of hyperlactatemia that evolved into symptomatic lactic acidosis was diagnosed soon after the completion of the study, however. Our findings indicate that asymptomatic hyperlactatemia is either very rare or an artifact of collection technique.
Elevations of blood lactate in HIV-infected patients receiving antiretroviral therapy (ART), particularly regimens containing nucleoside analogue reverse transcriptase inhibitors (NRTIs), are well described. 1–7 ART-associated hyperlactatemia may be asymptomatic or symptomatic, which, in the extreme, can progress to life-threatening acidosis. 1–13 Fulminate lactic acidosis is rare among ART-treated patients, with an incidence rate of <1.0 per 100 person-years. 5,14,15 The prevalence of asymptomatic elevations in lactate has been reported to be from 4% to 36% in cross-sectional studies of HIV clinic attendees, however. 14–17 The disparity in the rates of asymptomatic hyperlactatemia seen across cohorts may be attributed to differences in the definition of hyperlactatemia used and the presence of potential risk factors for hyperlactatemia such as ART regimen composition, patient demographics, and comorbidities. Further, venous lactate measurement is vulnerable to artifactual increases, and the techniques employed to minimize falsely elevated results vary from study to study. 18
Although the prevalence of hyperlactatemia in the setting of HIV infection is unclear, a number of risk factors, often in combination, for elevated lactate among such patients have been described. Exposure to NRTIs, especially stavudine (d4T) and didanosine (ddI), peripheral neuropathy, peripheral lipoatrophy, low bone mineral density, obesity, female sex, and pregnancy have been reported to be associated with ART-related hyperlactatemia. 1,19–27
We examined the prevalence of hyperlactatemia in a cohort of NRTI-receiving patients with multiple putative risk factors for and potential signs of elevated blood lactate who were screened for entry into a clinical study of an intervention designed to prevent progression of asymptomatic or mildly symptomatic hyperlactatemia.
AIDS Clinical Trials Group (ACTG) study A5129 was a prospective multicenter study to explore the efficacy of B-vitamin administration in preventing progression of asymptomatic or minimally symptomatic venous hyperlactatemia. The study was designed to be conducted in 2 steps: step I, screening for sustained hyperlactatemia, and step II, vitamin B therapy for subjects with sustained hyperlactatemia. Eligible subjects were enrolled between February 2002 and September 2002 at 3 sites: Beth Israel Medical Center in New York, Case Western Reserve University in Ohio, and the University of North Carolina in North Carolina.
HIV-infected subjects ≥13 years of age on NRTI-containing ART for at least 4 weeks with indications for lactate measurement but without symptoms associated with rapidly progressive hyperlactatemia were eligible to enroll into step I. Subjects must have had at least one of the following indications for lactate measurement: a history of venous or arterial lactate level >1 but <4 times the upper limit of normal (ULN); an anion gap >15 mmol/L within 3 months before entry, serum carbon dioxide (CO2) or bicarbonate (HCO3) <20 mmol/L, creatine kinase (CK) >2 times the ULN, alanine aminotransferase (ALT) >1 and <5 times the ULN, or lactic dehydrogenase (LDH) >2 times the ULN; current use of d4T-containing therapy for at least 6 months; nausea of grade 2 (DAIDS Toxicity Grading Scale), mild abdominal pain or other vague abdominal complaints that do not limit daily activities (grade 1), mild fatigue or weakness (grade 1), anorexia associated with reported loss of <3% total body weight, or mild to moderate peripheral neuropathy (grade 1 or 2) all within 30 days prior to entry; current lipoatrophy; or a clinical diagnosis of osteopenia, osteoporosis, or spontaneous fracture.
During step I, all subjects had venous lactate levels drawn in strict accordance with the AACTG Guidelines for Lactate Collection and Processing. 28 These guidelines specify that venous lactate specimens must be collected without the aid of fist-clenching or use of a tourniquet. If a tourniquet is necessary, it is applied lightly and the lactate level is drawn first. Additionally, subjects are asked to refrain from exercise and alcohol consumption for 24 hours prior to the blood draw. Blood is collected in the appropriate chilled tube and processed within 30 minutes of the draw. At 2 of the study sites, venous lactate specimens were collected in tubes containing sodium fluoride–potassium oxalate (gray top). At the other site (University of North Carolina), tubes containing sodium heparin (green top) were used. For the purpose of this study, sustained hyperlactatemia was defined as 2 consecutive elevated nonexercise venous lactate levels ≥1.5 and ≤4 times the ULN, the second of which must be fasting and measured no more than 30 days after the first. The ULN of venous lactate was 2.4 mmol/L at 1 site and 2.2 mmol/L at the other 2 sites.
The first 34 subjects enrolled had nonfasting venous lactate levels obtained at entry (week 0) and then fasting venous lactate levels collected again within 14 days (week 2). To facilitate enrollment, the protocol was amended in May 2002 to eliminate the second venous lactate collection in cases in which the week 0 lactate was <1.5 or >4 times the ULN. Therefore, the remaining subjects only had a week 2 lactate level obtained if their week 0 level was between 1.5 and 4 times the ULN.
Based on the results of step I of the study, step II was not initiated.
Descriptive statistics are used to describe the study sample. Categoric variables are summarized by frequency counts and percentages. Continuous variables are summarized by displaying descriptive statistics. Confidence intervals are used to estimate population parameters, and graphic methods are used to display lactate data.
From February 2002 to August 2002, 83 subjects were enrolled. Baseline characteristics of the subjects are listed in Table 1. Most of the subjects were male (86%) and nonwhite (65%). All subjects were receiving NRTI antiretroviral agents at baseline and, as expected given the inclusion criteria, most (71%) were receiving d4T at entry or for the 6 months just prior to entry (74%). At study entry, 43 (52%) were taking 3TC, 18 (22%) were taking ddI, and 14 (17%) were taking abacavir; 52 (63%) were receiving a protease inhibitor; and 31 (37%) were receiving a non-NRTI.
Two thirds (67%) of study participants had 2 or more risk factors or signs associated with hyperlactatemia, and 10 (11%) had 4 or more factors. In addition to d4T exposure, risk factors experienced by at least 10% of the cohort included anorexia during the previous 30 days (100%), LDH >2 times the ULN within the 3 months prior to entry (78%), an anion gap >15 mmol/L in the previous 3 months (63%), an ALT level between 1 and 5 times the ULN during the 3 months prior to study entry (17%), lipoatrophy (14%), fatigue (13%), peripheral neuropathy (11%), and mild abdominal pain (10%).
At baseline, the median nonfasting and nonexercise venous lactate level of the cohort obtained using strict adherence to standardized venous lactate collection techniques was 1.2 mmol/L (range: 0.7–5.1 mmol/L). A repeat venous lactate level performed in a nonexercise and fasted state was collected from 34 subjects at week 2; the median lactate value at this time point was 1.1 mmol/L (range: 0.5–4.6 mmol/L). As demonstrated in Figure 1, only 1 subject had a venous lactate level >1.5 times the ULN at baseline, with a value 2.1 times the ULN (5.1 mmol/L). On repeat testing at week 2, the venous lactate level of this subject was 1.2 times the ULN (2.9 mmol/L), although no intervention had been performed. This subject was receiving d4T, efavirenz, and indinavir at study entry, and d4T exposure was the only reported risk factor for hyperlactatemia. Another subject prescribed d4T, abacavir, and lopinavir/ritonavir had a lactate level at entry of 1.4 times the ULN and then 1.9 times the ULN at the week 2 visit. This subject entered the study with >6 months of d4T exposure, fatigue, elevated anion gap, and lipoatrophy. Two other subjects had a single venous lactate measurement of between 1.0 and 1.5 times the ULN. One was taking d4T, ddI, and indinavir, and the other was taking d4T, ddI, nevirapine, and lopinavir/ritonavir. Both had >6 months of d4T therapy prior to study entry, and at baseline, the latter subject reported a history of fatigue, lipoatrophy, and peripheral neuropathy. None of these subjects reported new symptoms associated with hyperlactatemia during the study.
There were no episodes of symptomatic hyperlactatemia or lactic acidosis during the study. Given our data (0 of 83), a 95% confidence interval for the prevalence of hyperlactatemia is (0 [3.54%]). In other words, the true prevalence of hyperlactatemia as defined by this study is likely to be less than 3.54%.
Nevertheless, the subject whose lactate increased from 1.4 to 1.9 times the ULN from entry to week 2 was diagnosed with symptomatic lactic acidosis within 3 weeks of the week 2 final study visit. A review of the medical records of the remaining subjects was conducted at the 3 study sites. No other cases of symptomatic hyperlactatemia or lactic acidosis were detected within the 24 weeks following study discontinuation.
In this study, sustained elevations of blood lactate above 1.5 times the ULN in a cohort of antiretroviral-treated HIV-infected persons with multiple putative risk factors and/or signs of hyperlactatemia were not observed.
Only 2 subjects had a lactate value above 1.5 times the ULN at 1 of the on-study determinations. In 1 case, the entry lactate level of 2.1 times the ULN declined on subsequent testing to 1.2 times the ULN. In the other case, the lactate level was observed to rise from a baseline of 1.4 to 1.9 times the ULN at week 2 in the absence of symptoms. Shortly thereafter, however, the subject became symptomatic with lactic acidosis. This improved on withdrawal of ART and later recurred with reintroduction of therapy. This subject, without symptoms of elevated blood lactate during the 2-week study period, appears to have had evolving hyperlactatemia that progressed to symptomatic lactic acidosis in the 3-week period after the study. A search of the medical records of the remaining subjects failed to document any other cases of symptomatic hyperlactatemia or lactic acidosis within 6 months of subject study discontinuation.
These results suggest that hyperlactatemia, especially sustained hyperlactatemia, is rarer than previously reported even among subjects with risk factors previously associated with lactate elevation. Hyperlactatemia identified in previous studies and in practice may be a result of falsely elevated lactate measurements influenced by the methods and conditions of specimen collection. In this study, we believe that strict adherence to guidelines for the collection and processing of these specimens likely reduced the possibility of such falsely elevated lactate results.
There are potential limitations to our investigation; foremost is the potential for type II error given the size of the cohort studied. If the prevalence of hyperlactatemia above 1.5 times the ULN is at least 5%, however, as suggested in previous cross-sectional studies, there would be greater than a 98% probability that our study should have detected at least a single case. Furthermore, our inclusion criteria were based on published data regarding factors associated with elevated lactate in the setting of antiretroviral exposure and therefore should have led to enrichment of the cohort with cases of hyperlactatemia and an increase in the prevalence beyond that found in nonselected populations. Another possible limitation of our study is the definition of hyperlactatemia that we employed. The defining of hyperlactatemia as 1.5 times the ULN rather than as any level above the ULN was designed to eliminate from the case definition lactate levels that were higher than the laboratory reference ranges but of little or no clinical significance. In this study, only 4 subjects had a venous lactate level above the ULN, the 2 subjects described previously and 2 with single lactate values between 1 and 1.5 times the ULN. Even when applying a stringent definition of hyperlactatemia as any value above the ULN, the prevalence of asymptomatic hyperlactatemia that we observed was lower than those reported in previous cross-sectional studies of populations not selected for risk factors for elevated lactate. 14–16 One study conducted at 1 of the sites participating in this study did find a similar prevalence of elevations of lactate above the ULN with strict adherence to lactate collection guidelines. 17 As with the other previous investigations, this study, unlike our investigation, enrolled subjects without known risk factors for hyperlactatemia. Lastly, although the rigorous blood collection and processing techniques used reduce spurious results, venous lactate collection remains subject to increased variability compared with arterial lactate collection, on which reference ranges are based. Importantly, only 4 subjects had a lactate level less than the ULN, and in 2, the levels were within 0.3 mmol/L of the ULN.
These results indicate that sustained asymptomatic hyperlactatemia is rare when lactate levels are carefully collected. In addition, we conclude that routine screening of lactate levels in asymptomatic ART-receiving patients is not justified.
1. Carr A, Miller J, Law M, et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000; 14(Suppl):F25–F32.
2. Mokrzycki MH, Harris C, May H, et al. Lactic acidosis associated with stavudine administration: a report of five cases. Clin Infect Dis. 2000; 30:198–200.
3. Lonergan JT, Behling C, Pfander H, et al. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis. 2000; 31:162–166.
4. Acosta BS, Grimsley EW. Zidovudine-associated type B lactic acidosis and hepatic steatosis in an HIV-infected patient. South Med J. 1999; 92:421–423.
5. Gérard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic hyperlactataemia: an emergency complication of antiretroviral therapy. AIDS. 2000; 14:2723–2730.
6. Vrovenraets SME, Treskes M, Regez RM, et al. Hyperlactatemia in HIV-infected patients: the role of NRTI treatment [abstract 625]. Presented at the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, February 2001.
7. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001; 15:717–723.
8. Bissuel F, Bruneel F, Habersetzer F, et al. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med. 1994; 235:367–371.
9. Chariot P, Drogou I, de Lacroix-Szmania I, et al. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol. 1999; 30:156–160.
10. Allaouchiche B, Duflo F, Cotte L, et al. Acute pancreatitis with severe lactic acidosis in an HIV-infected patient on didanosine therapy [letter]. J Antimicrob Chemother. 1999; 44:137–138.
11. Sundar K, Suarez M, Banogon PE, et al. Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature. Crit Care Med. 1997; 25:1425–1430.
12. Miller KD, Cameron M, Wood LV, et al. Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann Intern Med. 2000; 133:192–196.
13. Tanaka K, Fukahori S, Jojima H, et al. Fatal lactic acidosis in a patient with acquired immunodeficiency syndrome treated with stavudine, lamivudine and indinavir. Kansenshogaku Zasshi. 1999; 73:1232–1235.
14. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis. 2001; 33:1931–1937.
15. Hocqueloux L, Alberti C, Feugeas J, et al. Prevalence, risk factors and outcome of hyperlactataemia in HIV-infected patients. HIV Med. 2003; 4:18–23.
16. Harris M, Chan KJ, Tesiorowski A, et al. Random venous lactate levels among HIV-positive patients on antiretroviral therapy. J Acquir Immune Defic Syndr. 2002; 31:448–450.
17. McComsey GA, Yau L, Southwell H, et al. Elevated lactate levels are uncommon, even in heavily pretreated HIV-infected subjects [abstract T-710] Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 2002.
18. Gallagher EJ. Rodriguez K. Touger M. Agreement between peripheral venous and arterial lactate levels. Ann Emerg Med. 1997; 29:479–483.
19. Brew B, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV distal symmetrical sensory polyneuropathy [abstract 9]. Presented at the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, February 2001.
20. Verma A, Schein RMH, Jayaweera DT, et al. Fulminant neuropathy and lactic acidosis associated with nucleoside analog therapy. Neurology. 1999; 53:1365–1367.
21. ter Hofstede HJM, de Marie S, Foudraine NA, et al. Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases. Int J STD AIDS. 2000; 11:611–616.
22. Falco V, Rodriguez D, Ribera E, et al. Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature. Clin Infect Dis. 2002; 34: 838–846.
23. Coghlan ME, Sommadossi JP, Jhala NC, et al. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Clin Infect Dis. 2001; 33:1914–1921.
24. Carr A, Miller J, Eisman JA, et al. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS. 2001; 15:703–709.
25. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect. 2002; 78:58–59.
26. Boxwell DE, Styrt BA. Lactic acidosis in patients receiving nucleoside reverse transcriptase inhibitors [abstract 1284]. Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 1999.
27. Bristol-Myers Squibb Company. Healthcare provider important drug warning letter. January 5, 2001.
This article has been cited 11 time(s).
Journal of Infectious Diseases
Toward a pharmacogenetic understanding of nucleotide and nucleoside analogue toxicity
Journal of Infectious Diseases, 194():
Effects of highly active antiretroviral therapy on paediatric metabolite levels
Hiv Medicine, 7(1):
Lancet Infectious Diseases
Symptomatic hyperlactataemia precipitated by the addition of tetracycline to combination antiretroviral therapy
Lancet Infectious Diseases, 6(4):
MitochondrionMitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemiaMitochondrion
PediatricsSerum lactate levels in infants exposed peripartum to antiretroviral agents to prevent mother-to-child transmission of HIV: Agence Nationale de Recherches Sur le SIDA et les Hepatites Virales 1209 Study, Abidjan, Ivory CoastPediatrics
Antimicrobial Agents and ChemotherapyHigh levels of zidovudine (AZT) and its intracellular phosphate metabolites in AZT- and AZT-lamivudine-treated newborns of human immunodeficiency virus-infected mothersAntimicrobial Agents and Chemotherapy
Clinical Infectious Diseases
Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy
Clinical Infectious Diseases, 43(5):
Clinical Infectious DiseasesPregnancy and Optimal Care of HIV-Infected PatientsClinical Infectious Diseases
Scandinavian Journal of Infectious DiseasesLong term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicityScandinavian Journal of Infectious Diseases
Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides
Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy
Antiviral Therapy, 10():
hyperlactatemia; lactate; nucleosides analogues; mitochondrial toxicity
© 2004 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.