Lactic Acidemia in Infection with Human Immunodeficiency Virus

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/ mitochondrial DNA-g, to the target tissue’s stores of L) is common to several toxicities associated with nu- natural nucleotides, and to the different dependency of cleoside analog reverse transcriptase inhibitors (NRTIs) specific tissues for mitochondrial function. In moderate and nucleotide analog reverse transcriptase inhibitors and severe lactic acidemia, the target organ is thought that may have a mitochondrial pathogenesis [1]. Vi- to be the liver because of the associated biochemical, rologically active triphosphate forms of NRTIs and nu- clinical, and pathological evidence of hepatic dysfunc- cleotide analog reverse transcriptase inhibitors can in- tion in many patients [4–13]. It is unclear, however, hibit mitochondrial DNA polymerase-g, which could whether milder lactic acidemia represents an increase in turn lead to impaired synthesis of mitochondrial in lactate production from one or more organs and/or enzymes that generate adenosine triphosphate by oxi- decreased degradation. dative phosphorylation of glucose and fatty acids [2, 3]. In vitro, this may manifest as increases in intracel- lular lactate, pyruvate, triglyceride, and fatty acids be- PREVALENCE AND RISK FACTORS cause neither glucose nor fatty acids can be oxidized normally. Lactic acidemia with no or mild symptoms was detected Most NRTI-associated toxicities are relatively tissue- in 8%–21% of patients receiving at least one NRTI and drug-specific (table 1). The polymerase-g hypoth- versus 0%–1% of patients receiving no antiretroviral esis suggests that this specificity may be due to intra- therapy [12, 14–17]. Symptomatic lactic acidemia is less ∼ cellular drug penetration and metabolism to the common ( 1.5%–2.5%). The incidence in 2 prospec- triphosphate form, to tissue-specific polymorphisms in tive studies was estimated to be 0.4–0.8 per 100 patient- years in adults. Mild acidemia does not appear to predict the development of subsequent more severe

Reprints or correspondence: Dr. Andrew Carr, HIV, Immunology, and Infectious acidemia. Diseases Clinical Services Unit, St. Vincent’s Hospital, Sydney 2010, Australia Most early cases of severe lactic acidemia were re- ([email protected]). ported in women, but there are no ﬁrm data regarding Clinical Infectious Diseases 2003;36(Suppl 2):S96–100 2003 by the Infectious Diseases Society of America. All rights reserved. differences by sex, race, or age. A report of 3 fatal cases 1058-4838/2003/3607S2-0008$15.00 of lactic acidemia in pregnant women receiving dual

S96 • CID 2003:36 (Suppl 2) • Carr Table 1. Known and possible mitochondrial toxicities of nucleoside analogue HIV reverse transcriptase inhibitors and their associations with lactic acidemia.

Laboratory Organ Clinical feature(s) ﬁndings Lactic acidemia Rate, % Drugs administereda Therapyb Aggravated byc

Liver Hepatomegaly, nausea, ascites, edema, dyspnea, Liver enzymes F Yes 1–2.5d All Riboﬂavin (?) Azoles, rifamycin, NNRTIs, PIs encephalopathy Muscle Fatigue, myalgia, proximal weakness, wasting Creatine kinase F No data 17 AZT — Corticosteroids Heart Dilated cardiomyopathy — No data Rare AZT — — Nerve Distal pain, numbness, paresthesia, legs and — Yes 10–30 ddC p d4T 1 ddI 1 3TC Tricyclic antidepressant Vinca alkaloid isoniazid arms with reduced reﬂexes or power valproate CNS Perinatal neurologic illness — Yes (including CSF) — — — — Fat Peripheral lipoatrophy, lipomata (?) — Sometimes — 50 d5T 1 others — Osteopenia Asymptomatic rare fractures — Sometimes 20–40 Unknown As in HIV-uninfected Hypogonadism, inactivity patients Pancrease Pancreatitis Amylase F Sometimes Rare ddI Nil 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 Mitochondrial toxicity of abacavir (ABC) monotherapy has not been reported. b Cessation of the causative drug is required for reversal; improvements are often slow and/or partial. c A complete list of drugs that might aggravate mitochondrial toxicity is provided at http://www.hivatis.org/trtgdlns.html#Adult (accessed 31 August 2002). d Asymptomatic elevations of liver transaminases (with normal bilirubin) are more common (5%–15%). Table 2. Indications for the measurement of plasma lactate NRTI-induced peripheral neuropathy, another mitochondrial in HIV-infected patients. NRTI toxicity, may also be present and can include ascending neuromuscular weakness in some cases. Recommended Overall mortality was 80% in patients with HIV-related lactic 1. Nucleoside analog recipients with new onset of features 1 consistent with lactic acidemia acidemia 10 mmol/L, whereas no deaths have been reported ! a. Clinical fatigue in those with lactate 10 mmol/L. Prognosis of lactic acidemia Dyspnea depends on the level at the time of diagnosis. In one study, Weight loss lactate levels (mean, 4.2 mmol/L) returned to normal at a mean Nausea of 3 months after NRTI cessation [12]. Clinical features may Liver failure take longer to resolve. Fatal chronic liver disease was described b. Metabolic low bicarbonate in one patient 2 years after complete clinical recovery from Hypoalbuminemia lactic acidemia with acute hepatitis [19], but the frequency of Raised anion gap chronic disease is unknown. Unexpected increases in liver enzymes Lactic acidemia has also been observed with other mito- Pregnant women receiving NRTIs chondrial toxicities, namely myopathy and postpartum neu- Patients recommencing NRTIs who have had lactic rologic toxicity [20–22]. Several studies have found associations acidemia previously between lactic acidemia and several other toxicities of unknown Unknown pathogenesis, peripheral lipoatrophy, peripheral sensory neu- 1. Infants with perinatal nucleoside analog exposure ropathy, and osteopenia [12, 16, 23–25]. Further, mild asymp- 2. Nucleoside analog recipients with osteopenia, peripheral tomatic lactic acidemia has been associated with more rapid neuropathy, and lipoatrophy onset of lipoatrophy [23], and 2 studies have demonstrated NOTE. NRTI, nucleoside reverse transcriptase inhibitor. mitochondrial depletions within peripheral adipocytes from some patients with lipoatrophy, although a cause-and-effect relationship has not been proven [26, 27]. 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 ASSESSMENT AND MONITORING all NRTIs, particularly if treatment duration is 16 months [4–17]. Potential factors that remain to be evaluated include Diagnosis of NRTI-related lactic acidemia requires demonstra- simultaneous exposure to 3 NRTIs, the contribution of pre- tion of increased lactate levels in the absence of other known existing liver disease, and concomitant use of other hepatotoxic causes, such as dehydration, vigorous exercise, sepsis, hypox- drugs. There are no data implicating non-NRTIs or protease emia, alcohol intoxication, renal failure, hyperthyroidism, and inhibitors in the pathogenesis of lactic acidemia. other drugs [28]. There is no universally accepted definition of severe NRTI-related lactic acidemia. On the basis of the high CLINICAL FEATURES risk of serious morbidity or death, a threshold for severe acidemia might be a confirmed level 110 mmol/L regardless of The primary clinical features of moderate to severe lactic aci- the clinical presentation, or 15 mmol/L in the presence of re- demia are fatigue, weight loss, myalgias, nausea and vomiting, lated new symptoms and signs. abdominal distension, and pain, dyspnea, and preterminal car- Care is required with sample collection and processing to diac dysrhythmias. The onset is acute or subacute (with symp- avoid falsely elevated readings. Patients should be advised not tom duration a median of 4 months in one series). Features to undertake vigorous exercise for 24 h beforehand and should of hepatic dysfunction are common and can include soft, tender be well hydrated at the time of blood collection. Blood should hepatomegaly, peripheral edema, ascites, and encephalopathy, be collected without fist clenching—and, if possible, without but jaundice is rare. Modest elevations in liver enzymes are stasis—into a prechilled, gray-top (fluoride-oxalate) tube, common, although even in fulminant hepatic failure, these are transported immediately on ice to the laboratory, and processed often not to levels 110-fold above normal, as with other forms within 4 h of collection. An elevated lactate level should always of acute hepatic failure. Hepatic steatosis is a common finding be confirmed by repeat measurement with the patient rested on imaging studies and biopsy, with necrosis evident in more and well hydrated, and other potential causes should be ex- fulminant cases. Hypovolemia and sepsis, common causes of cluded before one or more NRTIs are considered to be the lactic acidemia, are not seen. Patients with low-level lactic ac- cause. Measurement of arterial pH confirms the presence of idemia (2–5 mmol/L) may present with a milder constitutional acidosis, but this may not be necessary in many instances. and hepatic illness but are often asymptomatic. Features of Because no assay can predict who will develop lactic aci-

S98 • CID 2003:36 (Suppl 2) • Carr Table 3. Recommendations for the management of lactic acidemia in HIV-infected patients.

Symptoms Lactate, of lactic mmol/L 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 2–5 Yes Watch carefully; cease NRTI therapy if symptoms are pronounced No Nil !2 Yes Seek alternative care for symptoms

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 aci- of congenital mitochondrial diseases [29]. These include es- demia are nonspecific and can occur at any time. In view of sential vitamin coenzymes (thiamine and riboflavin), electron the absence of data correlating them with outcome, other mea- acceptors (coenzyme Q10 [ubiquinone]), antioxidants (vitamins sures of mitochondrial function, such as lactate-pyruvate ratio, C, E, and K), and L-carnitine. There are no adequate data cannot be recommended at this time. suggesting a role for any of these agents in the treatment or It is unknown whether or how often plasma lactate should prevention of NRTI-related lactic acidemia [30]. 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 CONCLUSIONS AND FUTURE DIRECTIONS nausea, low bicarbonate, chloride, or albumin, raised anion gap, Insufficient data exist as to the prevalence, type, diagnosis, and unexpected increases in liver enzymes, or new onset of clinical management of illnesses associated with lactic acidosis that may liver failure, as well as in pregnant women receiving NRTIs, complicate NRTI therapy. Assays that predict or more readily and in those recommencing NRTIs who have had lactic aci- diagnose such toxicities are needed. Therapies that will reduce demia previously (table 2). 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 References 1 well as those with confirmed lactate levels 5 mmol/L who are 1. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet symptomatic, all NRTIs should be discontinued if no other 2000; 356:1423–30. cause is evident (table 3). All concomitant antiretroviral drugs 2. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat should be ceased at the same time to avoid development of Med 1995; 1:417–21. 3. Brinkman K, ter Hofstede HJM, Burger DM, Smeitink JAM, Koopmans HIV drug resistance. Non-NRTI or protease inhibitor therapy PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial can be restarted after the lactate level normalizes and the as- toxicity as common pathway. AIDS 1998; 12:1735–44. sociated illness resolves. Reinstitution of alternative NRTIs in 4. Lai KK, Gang DL, Zawacki JK, Cooley TP. Fulminant hepatic failure associated with 23-dideoxyinosine (ddI). Ann Intern Med 1991; 115: patients with previous lactic acidemia may be possible in some 283–4. individuals [14] but should be closely monitored, with lactate 5. Le Bras P, D’Oiron R, Quertainmont Y, Halfon P, Caquet R. Metabolic, measured every 4 weeks for at least 3 months. hepatic and muscular changes during zidovudine therapy: a drug-in- ! duced mitochondrial disease? AIDS 1994; 8:716–7. For symptomatic patients whose levels are 5 mmol/L, lactate 6. McKenzie R, Fried MW, Sallie R, et al. Hepatic failure and lactic acidosis levels should be measured regularly. For asymptomatic patients due to fialuridine, an investigational nucleoside analogue for chronic in whom lactate levels are 2–5 mmol/L, there is no evidence hepatitis B. N Engl J Med 1995; 333:1099–105. to suggest that any change in antiretroviral therapy is necessary, 7. Bissuel F, Bruneel F, Habersetzer F, et al. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern but there are also no long-term safety data indicating whether Med 1994; 235:367–71. or not adverse consequences may occur at levels in this range. 8. Fortgang IS, Belitsos PC, Chaisson RE, Moore RD. Hepatomegaly and There is no proven intervention for lactic acidemia apart steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol 1995; 90:1433–6. from NRTI cessation. Several agents have been used with lim- 9. Freiman JP, Helfert KE, Hamrell MR, Stein DS. Hepatomegaly with ited success in the treatment of lactic acidemia in the setting 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 dovudine-induced mitochondrial myopathy is associated with muscle associated with stavudine treatment in an HIV patient: a case report. caritine deficiency and lipid storage. Ann Neurol 1994; 35:482–7. AIDS 1997; 11:1294–6. 21. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dys- 11. Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic acidosis function and perinatal exposure to antiretroviral nucleoside analogues. associated with stavudine administration: a report of five cases. Clin Lancet 1999; 354:1084–9. Infect Dis 2000; 30:198–200. 22. Delfraissy JF, Blanche S, Tardieu M, Barret B, Rustin P, Mayaux MJ. 12. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic Mitochondrial and mitochondrial-like symptoms in children born to acidemia and liver dysfunction associated with HIV nucleoside ana- HIV-infected mothers: exhaustive evaluation in a large prospective co- logue therapy: contribution to protease inhibitor-related lipodystrophy hort [abstract 625B]. In: Program and abstracts of the 8th Conference syndrome. AIDS 2000; 14:F25–32. on Retroviruses and Opportunistic Infections (Chicago). Alexandria, 13. Brivet FG, Nion I, Megarbane B, et al. Fatal lactic acidosis and liver VA: Foundation for Retrovirology and Human Health; 2001. steatosis associated with didanosine and stavudine treatment: a res- 23. White A, John M, Moore C, James IR, Nolan D, Mallal SA. Raised piratory chain dysfunction? J Hepatol 2000; 32:364–5. lactate levels are common and may be predictive of subcutaneous fat 14. Vrouenraets SME, Treskes M, Regez RM, et al. Hyperlactatemia in HIV- wasting. In: Program and abstracts of the 2nd International Workshop infected patients: the role of NRTI treatment [abstract 625]. In: Pro- on Adverse Drug Reactions and Lipodystrophy in HIV (Toronto). 2000. gram and abstracts of the 8th Conference on Retroviruses and Op- 24. Brew B, Tisch S, Law M. Lactate concentrations distinguish between portunistic Infections (Chicago). 2001. nucleoside neuropathy and HIV distal symmetrical sensory polyneu- 15. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral ropathy [abstract 9]. In: Program and abstracts of the 8th Conference therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001; 33:1931–7. on Retroviruses and Opportunistic Infections (Chicago). Alexandria, 16. Lonergan JT, Havlir D, Barber E, Mathews WC. Incidence and outcome VA: Foundation for Retrovirology and Human Health; 2001. of hyperlactatemia associated with clinical manifestations in HIV-in- 25. Carr A, Miller J, Eisman J, Cooper DA. Osteopenia in HIV-infected fected adults receiving NRTI-containing regimens [abstract 624]. In: men: association with lactic acidemia and weight pre-antiretroviral Program and abstracts of the 8th Conference on Retroviruses and therapy. AIDS 2001; 15:703–9. Opportunistic Infections (Chicago). Alexandria, VA: Foundation for 26. Walker UA, Bickel M, Lutke-Volksbeck SI, et al. Decrease of mito- Retrovirology and Human Health; 2001. chondrial DNA content in adipose tissue of HIV-1–infected patients 17. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIV- infected patients taking antiretroviral therapy. AIDS 2001; 15:17–23. treated with NRTIs. Antivir Ther 2000; 5(Suppl 5):5. 18. US FDA. FDA/Bristol Myers Squibb issues caution for HIV combi- 27. Shikuma C, Hu N, Milne C, Shiramizu B. Subcutaneous adipose tissue nation therapy with Zerit and Videx in pregnant women (FDA Talk mitochondrial DNA analysis from individuals with HAART-associated Paper). Available at: http://www.fda.gov/bbs/topics/answers/ans01063 lipodystrophy. Antivir Ther 2000; 5(Suppl 5):6. .html. Accessed 25 February 2003. 28. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med 19. Carr A, Morey A, Mallon PWG, WilliamsD, Thorburn DR. Fatal portal 1992; 20:80–93. hypertension, chronic liver failure and persistent mitochondrial dys- 29. Peterson PL. The treatment of mitochondrial myopathies and ence- function after HIV nucleoside analogue-induced acute hepatitis and phalomyopathies. Biochim Biophys Acta 1995; 1271:275–80. lactic acidemia. Lancet 2001; 357:1412–4. 30. Luzzati R, Del Bravo P, Di Perri G, Luzzani A, Concia E. Riboflavin 20. Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA. Zi- and severe lactic acidosis. Lancet 1999; 353:901–2.

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