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SUPPLEMENT ARTICLE Lactic Acidemia in Infection with Human Immunodeficiency Virus Andrew Carr HIV, Immunology, and Infectious Diseases Clinical Services Unit, St. Vincent’s Hospital, Sydney, Australia Lactic acidosis in patients infected with the human immunodeficiency virus was initially identified as a rare complication of therapy with nucleoside analog reverse transcriptase inhibitors (NRTIs). The only patient group that appears to be at greater risk is pregnant women. More recently, milder elevations in lactate (i.e., lactic acidemia or hyperlactatemia) have been found to be more common and to be associated with numerous illnesses. Mild asymptomatic lactic acidemia is common, but it appears to lead to more severe illness only rarely. This suggests that routine measurement of plasma lactate should be limited to patients with previous acidemia who reinitiate NRTI therapy and to pregnant women. For symptomatic lactic acidemia (generally 15 mmol/L), NRTIs and other antiretroviral therapy should be ceased. Currently, asymptomatic lactic acidemia should not be treated and should not lead to a change in antiretroviral therapy. Lactic acidemia (defined by venous lactate 12.0 mmol/ L) is common to several toxicities associated with nucleoside analog reverse transcriptase inhibitors (NRTIs) and nucleotide analog reverse transcriptase inhibitors that may have a mitochondrial pathogenesis [1]. Virologically active triphosphate forms of NRTIs and nucleotide analog reverse transcriptase inhibitors can inhibit mitochondrial DNA polymerase-g, which could in turn lead to impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate by oxidative phosphorylation of glucose and fatty acids [2, 3]. In vitro, this may manifest as increases in intracellular lactate, pyruvate, triglyceride, and fatty acids because neither glucose nor fatty acids can be oxidized normally. Most NRTI-associated toxicities are relatively tissueand drug-specific (table 1). The polymerase-g hypothesis suggests that this specificity may be due to intracellular drug penetration and metabolism to the triphosphate form, to tissue-specific polymorphisms in Reprints or correspondence: Dr. Andrew Carr, HIV, Immunology, and Infectious Diseases Clinical Services Unit, St. Vincent’s Hospital, Sydney 2010, Australia ([email protected]). Clinical Infectious Diseases 2003; 36(Suppl 2):S96–100 2003 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2003/3607S2-0008$15.00 S96 • CID 2003:36 (Suppl 2) • Carr mitochondrial DNA-g, to the target tissue’s stores of natural nucleotides, and to the different dependency of specific tissues for mitochondrial function. In moderate and severe lactic acidemia, the target organ is thought to be the liver because of the associated biochemical, clinical, and pathological evidence of hepatic dysfunction in many patients [4–13]. It is unclear, however, whether milder lactic acidemia represents an increase in lactate production from one or more organs and/or decreased degradation. PREVALENCE AND RISK FACTORS Lactic acidemia with no or mild symptoms was detected in 8%–21% of patients receiving at least one NRTI versus 0%–1% of patients receiving no antiretroviral therapy [12, 14–17]. Symptomatic lactic acidemia is less common (∼1.5%–2.5%). The incidence in 2 prospective studies was estimated to be 0.4–0.8 per 100 patientyears in adults. Mild acidemia does not appear to predict the development of subsequent more severe acidemia. Most early cases of severe lactic acidemia were reported in women, but there are no firm data regarding differences by sex, race, or age. A report of 3 fatal cases of lactic acidemia in pregnant women receiving dual Table 1. Known and possible mitochondrial toxicities of nucleoside analogue HIV reverse transcriptase inhibitors and their associations with lactic acidemia. Laboratory findings Lactic acidemia Rate, % Hepatomegaly, nausea, ascites, edema, dyspnea, encephalopathy Liver enzymes F Yes 1–2.5 All Muscle Fatigue, myalgia, proximal weakness, wasting Creatine kinase F No data 17 AZT Heart Dilated cardiomyopathy — No data Rare AZT — Nerve Distal pain, numbness, paresthesia, legs and arms with reduced reflexes or power — Yes 10–30 ddC p d4T 1 ddI 1 3TC Tricyclic antidepressant valproate Organ Clinical feature(s) Liver d a Drugs administered b Therapy Riboflavin (?) — CNS Perinatal neurologic illness — Yes (including CSF) — — — Fat Peripheral lipoatrophy, lipomata (?) — Sometimes — 50 d5T 1 others Osteopenia Asymptomatic rare fractures — Sometimes 20–40 Unknown Pancrease Pancreatitis Sometimes Rare ddI Amylase F As in HIV-uninfected patients Nil c Aggravated by Azoles, rifamycin, NNRTIs, PIs Corticosteroids — Vinca alkaloid isoniazid — — Hypogonadism, inactivity Alcohol abuse NOTE. Modified from Carr et al. [1] with permission of the publisher. 3TC, lamivudine; d4T, stavudine; ddC, zalcitabine; ddI, didanosine; NNRTI, nonnucleoside reverse transcriptase inhibitor; AZT, zidovudine; PI, protease inhibitor; F, increase. a b c d Mitochondrial toxicity of abacavir (ABC) monotherapy has not been reported. Cessation of the causative drug is required for reversal; improvements are often slow and/or partial. A complete list of drugs that might aggravate mitochondrial toxicity is provided at http://www.hivatis.org/trtgdlns.html#Adult (accessed 31 August 2002). Asymptomatic elevations of liver transaminases (with normal bilirubin) are more common (5%–15%). Table 2. Indications for the measurement of plasma lactate in HIV-infected patients. Recommended 1. Nucleoside analog recipients with new onset of features consistent with lactic acidemia a. Clinical fatigue Dyspnea Weight loss Nausea Liver failure b. Metabolic low bicarbonate Hypoalbuminemia Raised anion gap Unexpected increases in liver enzymes Pregnant women receiving NRTIs Patients recommencing NRTIs who have had lactic acidemia previously Unknown 1. Infants with perinatal nucleoside analog exposure 2. Nucleoside analog recipients with osteopenia, peripheral neuropathy, and lipoatrophy NOTE. NRTI, nucleoside reverse transcriptase inhibitor. nucleoside analog therapy suggests that pregnant women and their infants may be at higher risk [18]. Severe lactic acidemia has been described in association with all NRTIs, particularly if treatment duration is 16 months [4–17]. Potential factors that remain to be evaluated include simultaneous exposure to 3 NRTIs, the contribution of preexisting liver disease, and concomitant use of other hepatotoxic drugs. There are no data implicating non-NRTIs or protease inhibitors in the pathogenesis of lactic acidemia. CLINICAL FEATURES The primary clinical features of moderate to severe lactic acidemia are fatigue, weight loss, myalgias, nausea and vomiting, abdominal distension, and pain, dyspnea, and preterminal cardiac dysrhythmias. The onset is acute or subacute (with symptom duration a median of 4 months in one series). Features of hepatic dysfunction are common and can include soft, tender hepatomegaly, peripheral edema, ascites, and encephalopathy, but jaundice is rare. Modest elevations in liver enzymes are common, although even in fulminant hepatic failure, these are often not to levels 110-fold above normal, as with other forms of acute hepatic failure. Hepatic steatosis is a common finding on imaging studies and biopsy, with necrosis evident in more fulminant cases. Hypovolemia and sepsis, common causes of lactic acidemia, are not seen. Patients with low-level lactic acidemia (2–5 mmol/L) may present with a milder constitutional and hepatic illness but are often asymptomatic. Features of S98 • CID 2003:36 (Suppl 2) • Carr NRTI-induced peripheral neuropathy, another mitochondrial NRTI toxicity, may also be present and can include ascending neuromuscular weakness in some cases. Overall mortality was 80% in patients with HIV-related lactic acidemia 110 mmol/L, whereas no deaths have been reported in those with lactate !10 mmol/L. Prognosis of lactic acidemia depends on the level at the time of diagnosis. In one study, lactate levels (mean, 4.2 mmol/L) returned to normal at a mean of 3 months after NRTI cessation [12]. Clinical features may take longer to resolve. Fatal chronic liver disease was described in one patient 2 years after complete clinical recovery from lactic acidemia with acute hepatitis [19], but the frequency of chronic disease is unknown. Lactic acidemia has also been observed with other mitochondrial toxicities, namely myopathy and postpartum neurologic toxicity [20–22]. Several studies have found associations between lactic acidemia and several other toxicities of unknown pathogenesis, peripheral lipoatrophy, peripheral sensory neuropathy, and osteopenia [12, 16, 23–25]. Further, mild asymptomatic lactic acidemia has been associated with more rapid onset of lipoatrophy [23], and 2 studies have demonstrated mitochondrial depletions within peripheral adipocytes from some patients with lipoatrophy, although a cause-and-effect relationship has not been proven [26, 27]. ASSESSMENT AND MONITORING Diagnosis of NRTI-related lactic acidemia requires demonstration of increased lactate levels in the absence of other known causes, such as dehydration, vigorous exercise, sepsis, hypoxemia, alcohol intoxication, renal failure, hyperthyroidism, and other drugs [28]. There is no universally accepted definition of severe NRTI-related lactic acidemia. On the basis of the high risk of serious morbidity or death, a threshold for severe acidemia might be a confirmed level 110 mmol/L regardless of the clinical presentation, or 15 mmol/L in the presence of related new symptoms and signs. Care is required with sample collection and processing to avoid falsely elevated readings. Patients should be advised not to undertake vigorous exercise for 24 h beforehand and should be well hydrated at the time of blood collection. Blood should be collected without fist clenching—and, if possible, without stasis—into a prechilled, gray-top (fluoride-oxalate) tube, transported immediately on ice to the laboratory, and processed within 4 h of collection. An elevated lactate level should always be confirmed by repeat measurement with the patient rested and well hydrated, and other potential causes should be excluded before one or more NRTIs are considered to be the cause. Measurement of arterial pH confirms the presence of acidosis, but this may not be necessary in many instances. Because no assay can predict who will develop lactic aci- Table 3. Recommendations for the management of lactic acidemia in HIV-infected patients. Lactate, mmol/L Symptoms of lactic acidemia Therapy 110 Any Cease NRTIs if other causes not present 5–10 Yes Repeat; cease NRTI therapy if still elevated and other causes are not present No Repeat; dehydration or laboratory artefact likely Yes Watch carefully; cease NRTI therapy if symptoms are pronounced No Nil Yes Seek alternative care for symptoms 2–5 !2 NOTE. NRTI, nucleoside reverse transcriptase inhibitor. Recommence alternative NRTI therapy once lactate normalizes and illness resolves; and monitor lactate closely. Other known causes of lactic acidemia include dehydration, inappropriate sample collection, vigorous exercise, sepsis, hypoxemia, alcohol intoxication, renal failure, pancreatitis, hyperthyroidism, and other drugs (e.g., biguanides). demia, patients should be aware that symptoms of lactic acidemia are nonspecific and can occur at any time. In view of the absence of data correlating them with outcome, other measures of mitochondrial function, such as lactate-pyruvate ratio, cannot be recommended at this time. It is unknown whether or how often plasma lactate should be measured. Routine measurement is justified at this time only in NRTI recipients with clinical features consistent with lactic acidemia, such as new-onset fatigue, dyspnea, weight loss or nausea, low bicarbonate, chloride, or albumin, raised anion gap, unexpected increases in liver enzymes, or new onset of clinical liver failure, as well as in pregnant women receiving NRTIs, and in those recommencing NRTIs who have had lactic acidemia previously (table 2). of congenital mitochondrial diseases [29]. These include essential vitamin coenzymes (thiamine and riboflavin), electron acceptors (coenzyme Q10 [ubiquinone]), antioxidants (vitamins C, E, and K), and L-carnitine. There are no adequate data suggesting a role for any of these agents in the treatment or prevention of NRTI-related lactic acidemia [30]. CONCLUSIONS AND FUTURE DIRECTIONS Insufficient data exist as to the prevalence, type, diagnosis, and management of illnesses associated with lactic acidosis that may complicate NRTI therapy. Assays that predict or more readily diagnose such toxicities are needed. Therapies that will reduce the incidence and impact of lactic acidemia are required, as are newer, less toxic NRTI agents. TREATMENT In all patients with confirmed lactate levels 110 mmol/L, as well as those with confirmed lactate levels 15 mmol/L who are symptomatic, all NRTIs should be discontinued if no other cause is evident (table 3). All concomitant antiretroviral drugs should be ceased at the same time to avoid development of HIV drug resistance. Non-NRTI or protease inhibitor therapy can be restarted after the lactate level normalizes and the associated illness resolves. Reinstitution of alternative NRTIs in patients with previous lactic acidemia may be possible in some individuals [14] but should be closely monitored, with lactate measured every 4 weeks for at least 3 months. For symptomatic patients whose levels are !5 mmol/L, lactate levels should be measured regularly. For asymptomatic patients in whom lactate levels are 2–5 mmol/L, there is no evidence to suggest that any change in antiretroviral therapy is necessary, but there are also no long-term safety data indicating whether or not adverse consequences may occur at levels in this range. There is no proven intervention for lactic acidemia apart from NRTI cessation. Several agents have been used with limited success in the treatment of lactic acidemia in the setting References 1. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000; 356:1423–30. 2. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1:417–21. 3. Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12:1735–44. 4. Lai KK, Gang DL, Zawacki JK, Cooley TP. Fulminant hepatic failure associated with 23-dideoxyinosine (ddI). Ann Intern Med 1991; 115: 283–4. 5. Le Bras P, D’Oiron R, Quertainmont Y, Halfon P, Caquet R. Metabolic, hepatic and muscular changes during zidovudine therapy: a drug-induced mitochondrial disease? AIDS 1994; 8:716–7. 6. McKenzie R, Fried MW, Sallie R, et al. Hepatic failure and lactic acidosis due to fialuridine, an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 1995; 333:1099–105. 7. 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; 235:367–71. 8. Fortgang IS, Belitsos PC, Chaisson RE, Moore RD. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol 1995; 90:1433–6. 9. Freiman JP, Helfert KE, Hamrell MR, Stein DS. Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS 1993; 7:379–85. Lactic Acidemia in HIV Infection • CID 2003:36 (Suppl 2) • S99 10. Lenzo NP, Garas BA, French MA. Hepatic steatosis and lactic acidosis associated with stavudine treatment in an HIV patient: a case report. AIDS 1997; 11:1294–6. 11. Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic acidosis associated with stavudine administration: a report of five cases. Clin Infect Dis 2000; 30:198–200. 12. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000; 14:F25–32. 13. Brivet FG, Nion I, Megarbane B, et al. Fatal lactic acidosis and liver steatosis associated with didanosine and stavudine treatment: a respiratory chain dysfunction? J Hepatol 2000; 32:364–5. 14. Vrouenraets SME, Treskes M, Regez RM, et al. Hyperlactatemia in HIVinfected patients: the role of NRTI treatment [abstract 625]. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections (Chicago). 2001. 15. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001; 33:1931–7. 16. Lonergan JT, Havlir D, Barber E, Mathews WC. Incidence and outcome of hyperlactatemia associated with clinical manifestations in HIV-infected adults receiving NRTI-containing regimens [abstract 624]. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections (Chicago). Alexandria, VA: Foundation for Retrovirology and Human Health; 2001. 17. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIVinfected patients taking antiretroviral therapy. AIDS 2001; 15:17–23. 18. US FDA. FDA/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women (FDA Talk Paper). Available at: http://www.fda.gov/bbs/topics/answers/ans01063 .html. Accessed 25 February 2003. 19. Carr A, Morey A, Mallon PWG, WilliamsD, Thorburn DR. Fatal portal hypertension, chronic liver failure and persistent mitochondrial dysfunction after HIV nucleoside analogue-induced acute hepatitis and lactic acidemia. Lancet 2001; 357:1412–4. 20. Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA. Zi- S100 • CID 2003:36 (Suppl 2) • Carr 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. dovudine-induced mitochondrial myopathy is associated with muscle caritine deficiency and lipid storage. Ann Neurol 1994; 35:482–7. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354:1084–9. Delfraissy JF, Blanche S, Tardieu M, Barret B, Rustin P, Mayaux MJ. Mitochondrial and mitochondrial-like symptoms in children born to HIV-infected mothers: exhaustive evaluation in a large prospective cohort [abstract 625B]. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections (Chicago). Alexandria, VA: Foundation for Retrovirology and Human Health; 2001. White A, John M, Moore C, James IR, Nolan D, Mallal SA. Raised lactate levels are common and may be predictive of subcutaneous fat wasting. In: Program and abstracts of the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV (Toronto). 2000. Brew B, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV distal symmetrical sensory polyneuropathy [abstract 9]. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections (Chicago). Alexandria, VA: Foundation for Retrovirology and Human Health; 2001. Carr A, Miller J, Eisman J, Cooper DA. Osteopenia in HIV-infected men: association with lactic acidemia and weight pre-antiretroviral therapy. AIDS 2001; 15:703–9. Walker UA, Bickel M, Lutke-Volksbeck SI, et al. Decrease of mitochondrial DNA content in adipose tissue of HIV-1–infected patients treated with NRTIs. Antivir Ther 2000; 5(Suppl 5):5. Shikuma C, Hu N, Milne C, Shiramizu B. Subcutaneous adipose tissue mitochondrial DNA analysis from individuals with HAART-associated lipodystrophy. Antivir Ther 2000; 5(Suppl 5):6. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 1992; 20:80–93. Peterson PL. The treatment of mitochondrial myopathies and encephalomyopathies. Biochim Biophys Acta 1995; 1271:275–80. Luzzati R, Del Bravo P, Di Perri G, Luzzani A, Concia E. Riboflavin and severe lactic acidosis. Lancet 1999; 353:901–2.