Frequency, risk factors and features of hyperlactatemia in a large number of patients undergoing antiretroviral therapy
Manfredi, Robertoa; Motta, Robertob; Patrono, Danielab; Calza, Leonardoa; Chiodo, Francescoa; Boni, Paolab
aDipartimento di Medicina Clinica Specialistica e Sperimentale, Sezione di Malattie Infettive, Università di Bologna, Bologna, Italy; and bLaboratorio Centralizzato Clinico, Azienda Ospedaliera di Bologna, Policlinico S. Orsola-Malpighi 2, Bologna, Italy.
Received: 11 October 2002; revised: 1 April 2003; accepted: 7 May 2003.
Among 743 HIV-infected patients, a 6-month case–control study disclosed a 35.9% rate of hyperlactatemia in those with a longer duration of anti-HIV therapy, lipodystrophy, and elevated triglyceride, creatine phosphokinase, and aldolase levels. The 52 patients with sustained lactacidemia and the five with grade 4 hyperlactatemia showed no different supporting factors and courses compared with those with isolated or low-level abnormalities. No relationship emerged with nucleoside analogue use. Hyperlactatemia, although frequently transient and asymptomatic, warrants careful attention.
Altered lactacidemia is an emerging complication of HIV disease [1–14]. Although a severe outcome has been reported [1,12,15], the aetiology and consequences on the disease course and continuation of highly active antiretroviral therapy (HAART) are still unknown. The aim of this study was to assess the frequency, risk factors, and features of hyperlactatemia among approximately 1000 HIV-infected patients.
A prospective case–control study started in January 2002. Patients with fewer than two determinations of lactacidemia in 6 months, and those with a less than 90% compliance to antiretroviral treatment when prescribed, were excluded. All patients with conditions leading to lactacidemia (chronic liver-muscle disease) were excluded. Abnormal lactic acid levels (> 18 mg/dl) were evaluated according to epidemiological, clinical, and therapeutic variables. The 267 patients who had one or more elevated lactacidemia incidences were compared with the 476 controls with normal lactatemia in a univariate and multivariate logistic regression analysis. Fasting patients had their blood drawn after at least a 30 min rest, with tourniquet use limited to immediately before venipuncture. Automated assays determined serum lactic acid (range 9–18 mg/dl), triglycerides (74–172 mg/dl), cholesterol (< 200 mg/dl), creatine phosphokinase (0–195 U/l), and aldolase (0.5–3.1 U/l) levels. Lipodistrophy syndrome was evaluated by physical examination, patients’ self-assessment, dual-energy X-ray absorptiometry (DEXA), and bioelectric impedance assay, whereas osteopenia or osteonecrosis were confirmed by X-ray, mineral metabolism, and DEXA.
A total of 267 patients out of 743 had at least one episode of hyperlactatemia (mean value 24.7 ± 8.2, range 19–50 mg/dl), leading to a crude 35.9% frequency. Of the 267 individuals with hyperlactatemia, only 52 (19.5%) had two or more consecutive altered examinations, with a tendency to increase in 71.2% of cases. A grade 4 toxicity (levels > 39.6 mg/dl) was noticed once in five patients (1.9%). Comparing patients with one or more episode of altered lactatemia with controls, no major differences with regard to sex, age, risk of HIV infection, duration of seropositivity, disease stage, virological-immunological markers, and previous and present anti-HIV regimens, were shown. Neither was a relationship found between the above-mentioned parameters and repeated abnormal lactacidemia, or its grade 4 levels. On the contrary, a longer duration of antiretroviral therapy and HAART was found in patients who developed hyperlactatemia versus controls (P < 0.004 and P < 0.003, respectively), whereas single-drug selection and duration of use, with particular attention to nucleoside analogues (NA), did not differ between groups (Table 1). Among metabolic and bone/mineral abnormalities, a concurrent lipodystrophy syndrome (P < 0.006), elevated triglyceride (P < 0.02), creatine phosphokinase (P < 0.03), or aldolase (P < 0.0001) levels proved more frequent in patients with hyperlactatemia versus controls. Mild- to-moderate fatigue-weakness, and other non-specific symptoms possibly related to hyperlactatemia did not show differences in frequency and severity: 21% among patients with one or more episode of hyperlactatemia versus 25% among controls. Most of these signs and symptoms were undistinguishable from HIV-associated conditions, and involved only one patient with an occasional 40 mg/dl lactatemia.
After the introduction of HAART, abnormalities involving glucose and lipid metabolism, muscle, nerves, and bone became apparent and were probably related to NA-associated mitochondrial damage, potentially responsible for lactic acidosis, phosphocreatine depletion, and intracellular fat accumulation [15–17]. These pathogenetic pathways seemed to be responsible for muscle wasting, lipoatrophy, weight loss, myalgia, fatigue, hyperlipidemia, altered glucose-insulin metabolism, elevated muscle enzyme levels, neuropathy, pancreatitis, hepatosteatosis, anaemia, and osteoporosis [1–4,13,15,16,18,19]. Controlled data regarding the frequency, risk factors, and features of hyperlactatemia are still limited [1,4–13]. Fourteen adults with symptomatic hyperlactatemia were identified during a 2-year survey (incidence 0.8% per year) . A one-month study disclosed an 8.3% rate of hyperlactatemia among 880 patients with a moderate-to-severe (> 2.2 times) alteration corresponding to 1% of patients . In a 516 patient-year survey, John et al.  described two cases of fulminant lactic acidosis, five patients with symptomatic hyperlactatemia, and a more frequent and chronic asymptomatic lactic acid increase in HAART-treated patients. A recent cross-sectional survey of 750 patients with two or more on-therapy lactic acid samples  showed a 13.6% frequency of abnormalities, with women involved more frequently, and with didanosine doubling the hazard of hyperlactatemia. Abacavir and thymidine analogues seemed to be protective . Hyperlactatemia and mitochondrial dysfunction were found either as asymptomatic  or symptomatic [1,11,14] disorders, often associated with NA administration , as suggested by in-vitro studies [15–18]. Symptomatic disease was reported more frequently from inpatients [1,11,14]. Approximately 100 cases of an unexplained lactacidemia associated with acid-base disturbance and a 33–57% fatality rate was reported . Fatigue, tachycardia, weight loss, abdominal pain, paraesthesia, and dyspnoea may be the presentation, and the diagnosis of hyperlactatemia was confirmed by ultrastructural studies of end-organ mitochondria [1,17]. Among symptomatic patients, hepatic alterations usually exist, and mortality is high: five out of 11 hospitalized patients reported by Coghlan et al.  experienced fatal multi-organ failure.
When a severe metabolic acidosis is present, an aggressive supportive therapy and riboflavin–thiamine administration might be useful [6,11,20], together with the suspension of NA [8,9]. The management of patients who have recovered from symptomatic hyperlactatemia is controversial, as is the need for the withdrawal of NA [9,17,20]. An isolated laboratory finding is more frequent among asymptomatic outpatients [10,14]. As NA are part of almost all HAART regimens, NA-mediated cumulative toxicity may be expected in many patients, although other factors probably contribute to make this toxicity evident [3,15,19]. Carr et al.  detected an association between asymptomatic hyperlactatemia, NA use, and osteoporosis. In our experience lactacidemia, although often asymptomatic, is more commonly observed than previously reported, and involved over one-third of patients [1,4,8,13]. In our study, this abnormality was usually transient, and only 7% of 743 patients experienced two or more alterations during 6 months. No significant difference emerged between patients and controls as to numerous epidemiological, clinical, and therapeutic features, including selected NA. In previous studies, didanosine–stavudine played a major role [1,4–6,8,9,13,14], but lamivudine and other NA were also mentioned . Antiretroviral-mediated damage is expected to contribute to the pathogenesis of hyperlactatemia [2,3,15,16,18,19], although we did not demonstrate a correlation with any NA and its length of administration. A relationship with overall anti-HIV therapy duration (including HAART), and other emerging toxicity with related pathogenetic pathways (lipodystrophy, dyslipidemia, skeletal muscle damage) [2,4, 15,18,19,21], is suggested, whereas age, sex, and disease stage did not predict hyperlactatemia [4,13]. Hyperlactatemia associated with lipoatrophy, hyperlipidemia and hyperglycemia had already been noted  and deserves investigation, because links between NA, prolonged HAART effects, and HIV itself may variably contribute. Hyperlactatemia was also considered to be a broad spectrum of abnormalities, from fulminant metabolic acidosis, to partly compensated lactate excess, and chronic-intermittent low-grade asymptomatic lactacidemia [22,23].
1. Gérard Y, Maulin L, Yazdanpanah Y, De La Tribonniere X, Amiel C, Maurage CA, et al
. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS
2. Hernan JS, Easterbrook PJ. The metabolic toxicities of antiretroviral therapy. Int J STD AIDS
3. Pao D, Watson C, Peters B, Lucas SB, Miller RF. Hyperlactataemia and hepatic steatosis: mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. Sex Transm Infect
4. Boubaker K, Flepp M, Sudre P, Furrer H, Haensel A, Hirschel B, et al
. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis
5. Miller KD, Cameron M, Wood LV, Dalakas MC, Kovacs JA. Lactic acidosis and hepatic steatosis assoociated with use of stavudine: report of four cases. Ann Intern Med
6. Shaer AJ, Rastegar A. Lactic acidosis in the setting of antiretroviral therapy for the acquired immunodeficiency syndrome. A case report a review of the literature. Am J Nephrol
7. Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: association with asymptomatic lactic acid acidemia and lower weight pre-antiretroviral therapy. AIDS
8. John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, et al
. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS
9. 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
10. Boffito M, Marietti G, Audagnotto S, Raiter R, Di Perri G. Lactacidemia in asymptomatic HIV-infected subjects receiving nucleoside reverse-transcriptase inhibitors. Clin Infect Dis
11. Falco V, Rodriguez D, Ribera E, Martinez E, Miró JM, Domingo P, 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
12. Shahmanesh M, Cartledge J, Miller R. Lactic acidosis and abnormal liver function in advanced HIV disease. Sex Transm Infect
13. Moyle GJ, Datta D, Mandalia S, Morleslese J, Asboe D, Gazzard BG. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS
14. Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS, Johnson VA. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Clin Infect Dis
15. White AJ. Mitochondrial toxicity and HIV therapy. Sex Transm Infect
16. Foli A, Benvenuto F, Piccinini G, Bareggi A, Cossarizza A, Lisziewicz J, et al
. Direct analysis of mitochondrial toxicity of antiretroviral drugs. AIDS
17. Cote HC, Brumme ZL, Craib KJ, Alexander CS, Wynhoven B, Ting L, et al
. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med
18. Benbrik E, Chariot P, Bonavaud S, Ammi-Said M, Frisdal E, Rey C, et al
. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci
19. Jain RG, Furfine ES, Pedneault L, White AJ, Lenhard JM. Metabolic complications associated with antiretroviral therapy. Antiviral Res
20. McComsey GA, Lederman MM. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. AIDS Reader
21. Manfredi R, Motta R, Patrono D, Calza L, Chiodo F, Boni P. A prospective case–control survey of laboratory markers of skeletal muscle damage during HIV disease and antiretroviral therapy. AIDS
22. John M, Mallal S. Hyperlactatemia syndromes in people with HIV infection. AIDS
23. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS
© 2003 Lippincott Williams & Wilkins, Inc.