How to Evaluate a Rise in Serum Lactate Levels in HIV-Infected Patients Undergoing
Antiretroviral Therapy:

Data From a Prospective,
Case-Control Survey

 

Roberto Manfredi, MD

Leonardo Calza, MD

Francesco Chiodo, MD

 

Department of Clinical and Experimental Medicine, Division of Infectious Diseases,
University of Bologna "Alma Mater Studiorum", S. Orsola Hospital, Bologna, Italy

 

KEY WORDS: serum lactic acid, HIV infection, antiretroviral therapy, frequency, causes, effects, outcome

ABSTRACT

Objective: The goal of our study is to assess the frequency, risk factors, and features of hyperlactatemia in a cohort of about 1,000 patients with HIV disease.

Methods and Results: In a prospective 6-month case-control study involving about 1,000 HIV-infected patients, a 35.9% crude frequency of serum lactic acid abnormalities was found among the 743 evaluable individuals. However, no difference emerged between patients with hyperlactatemia and control subjects as to multiple investigated factors, except a longer duration of antiretroviral therapy and highly active antiretroviral therapy, a lipodystrophy syndrome, and elevated serum triglyceride, creatinphosphokinase, and aldolase levels, which involved more significantly patients with altered lactatemia compared with those who had not serum lactic acid anomalies. The 52 patients who developed repeated hyperlactatemia and the 5 individuals who suffered from a very high (grade 4 toxicity) rise of serum lactic acid levels, did not show different supporting factors and course, compared with all the remaining subjects with isolated or low-level hyperlactatemia. No significant relationship was found with the administration and length of use of each single anti-HIV nucleoside analogue.

Conclusion: Hyperlactatemia, although frequently transient and asymptomatic, is still an underestimated problem of HIV infection and antiretroviral therapy, which deserves careful attention on the epidemiologic, etiopathogenetic, and clinical point of view, to plan therapeutic and preventive strategies of this possibly life-threatening complication of treated HIV disease.

INTRODUCTION

Alterations of serum lactic acid levels are emerging complications of HIV disease and its pharmacologic management with highly active antiretroviral therapy (HAART).1-13 However, the causes, correlations, and consequences on disease course and HAART continuation are still under intensive investigation. When other confounding conditions are excluded, epidemiologic, clinical, and therapeutic features, and the concurrent evaluation of other laboratory parameters, may contribute to allowing a better assessment of  the frequency, role, supporting factors, and outcome of hyperlactatemia in this field, because a severe and life-threatening outcome has been reported in patients with HIV disease.1,12,15

The goal of our study was to assess the frequency, risk factors, and features of hyperlactatemia in a cohort of approximately 1,000 HIV-infected patients.

PATIENTS AND METHODS

A prospective case-control epidemiologic and clinical study was begun in January 2002 at our tertiary care center. Patients with less than two determinations of lactacidemia in 6 months were excluded, as were those with a less than 90% compliance to antiretroviral therapy when prescribed (as assessed on the ground of patient declarations and monthly drug accountability). All patients with concurrent conditions potentially leading to abnormal lactate levels (those with chronic liver or muscle disease), had been carefully ruled out. Abnormal serum lactic acid levels (>18 mg/dL), were evaluated according to several epidemiologic, clinical, laboratory, and therapeutic variables. The 267 patients who had at least one altered lactic acid testing were compared with the 476 evaluable subjects with persistently normal lactatemia, who served as controls, in an univariate and a multivariate logistic regression analysis. Automatized assays determined serum lactic acid (normal range, 9-18 mg/dL), triglycerides (74-172 mg/dL), cholesterol (<200 mg/dL), creatinphosphokinase (0-195 U/L), and aldolase (0.5-3.1 U/L) levels. The definition of fat redistribution ("lipodystrophy") syndrome was measured by physical examination, patient self-assessment with specific questionnaires, dual energy X-ray absorptiometry (DEXA), and bioelectric impedance assay, and a diagnosis of osteopenia, osteoporosis, or osteonecrosis was confirmed by combined radiographic examination and mineral metabolism and DEXA studies. Statistical assessment was performed with Mantel-Haenszel chi-square test, Fisher exact test, Student t test, and multivariate Cox's proportional hazards model where appropriate.

RESULTS

Of 743 patients, 267 consecutive patients had at least one episode of hyperlactatemia (mean value, 24.7±8.2 mg/dL; range, 19-50 mg/dL), leading to a crude overall frequency of 35.9%. Of the 267 subjects with hyperlactatemia, only 52 (19.5%) had 2 or more consecutive altered determinations of venous lactic acid levels, with a tendency to increase observed in 71.2% of cases and to decrease in 15 cases only. Moreover, a grade 4 toxicity value (> 39.6 mg/dL) was noticed once in 5 patients only. When comparing patients with at least one episode of altered lactatemia and all the remaining HIV-infected control subjects, the analysis of several variables failed to show significant differences as to gender, age, type of risk for HIV infection, duration of known seropositivity, stage of HIV infection (including eventual diagnosis of AIDS), virologic and immunologic markers of HIV disease progression, type of previous and present antiretroviral therapy, and its temporal sequency (Table 1). No relationship was also found between the above-mentioned parameters and repeated abnormal lactacidemia or its grade 4 levels.

On the other hand, when considering overall duration of antiretroviral therapy and HAART, both tested longer in patients who developed hyperlactatemia (P < .004 and P < .003 vs controls, respectively), whereas single drug selection and duration of use (with particular attention deserved to nucleoside analogues, taken by all study patients), did not differ between the two groups (Table 1). Among all examined metabolic and bone/mineral abnormalities, a concurrent lipodystrophy syndrome (P < .006), elevated serum triglyceride (P < .02), creatinphosphokinase (P < .03), and aldolase levels (P < .0001), proved significantly more frequent in patients with elevated lactic acid levels as compared with control subjects. Again, no relationship was found when focusing on patients with repeated or greater lactic acid abnormalities (data not shown). Mild to moderate fatigue, weakness, and other aspecific symptoms referred by patients and possibly related to hyperlactatemia, did not show differences in frequency and severity between the two patient groups (21% in patients with at least one episode of elevated serum lactic acid levels vs 25% among controls). Most of these signs and symptoms were indistinguishable from HIV-associated conditions, and involved only one patient with an occasional evidence of lactatemia of 40 mg/dL.

DISCUSSION

After extensive HAART introduction, abnormalities involving glucose and lipid metabolism, muscle, nerves, and other organs and tissues became increasingly apparent, and most of these disorders were related to mitochondrial damage probably associated with nucleoside analogue use. This was also potentially responsible for lactic acidosis as well as phosphocreatine depletion and intracellular fat accumulation.15-17 These pathogenetic pathways seem responsible for muscle wasting, lipoatrophy, weight loss, myalgia, weakness, fatigue, hyperlipidemia, altered glucose metabolism and insulin resistance, elevated muscle enzyme levels, peripheral neuropathy, pancreatitis, hepatic steatosis, anemia, osteoporosis, and a broad spectrum of metabolic disturbances, with predominant involvement of lipidemia.1-4,13,15,16,18,19

Because the majority of literature observations are represented by small series or anecdotal reports, limited controlled studies evaluating the frequency, risk factors, and features of hyperlactatemia have been performed until now.1,4-13 Fourteen adults with symptomatic hyperlactatemia were identified during a 2-year observational study, leading to an overall incidence of 0.8% per year.1 A 1-month cross-sectional survey disclosed a 8.3% crude frequency of hyperlactatemia in 880 examined patients; this elevation was moderate to severe (> 2.2 times upper normal limits) in 9 patients only (1%).4 In 516 patient-years of observation, John et al. noted two cases of fulminant lactic acidosis, five patients with symptomatic hyperlactatemia, and a proportionally frequent and chronic asymptomatic rise of serum lactic acid levels in patients taking HAART.8

A very recent cross-sectional and longitudinal survey considered 750 patients with at least two on-therapy samples evaluating lactic acid (as in our study). A 13.6% crude frequency of abnormalities was shown, with lactic acidosis recognized more frequently among women and didanosine use doubling the relative hazard of hyperlactatemia, while abacavir and thymidine analogues seemed to express a protective effect.13 Anyway, hyperlactatemia associated with mitochondrial dysfunction was reported either as a asymptomatic10 or symptomatic disorder.1,11,14 This was often associated with nucleoside analogue administration, compared with protease inhibitors or non-nucleoside reverse transcriptase inhibitors,3 In vitro studies confirmed the role of nucleoside analogue in causing mitochondrial damage of human cells.15-18 Symptomatic disease was more frequently reported from hospitalized patients, in whom one or more cofactors could act and lead to a more complicated or severe lactatemia.1,11,14

Approximately 100 cases of an apparently unexplained lactic acidosis associated with acid-base disturbances and with a fatality rate ranging from 33% to 57% was reported by the international literature.11 Severe fatigue, tachycardia, weight loss, abdominal pain, paresthesia, and dyspnea are variably included in the clinical presentation, and the diagnosis of lactic acidosis may be confirmed by an ultrastructural study of mitochondria alteration in end organs.1,17 Among patients with symptomatic disease alteration of hepatic enzymes usually concurs, and a high mortality rate proved evident: 5 of 11 hospitalized patients reported on by Coghlan et al. experienced a fatal multiorgan failure.14 When a severe metabolic acidosis is present, an aggressive supportive therapy and the administration of specific cofactors (such as riboflavin and thiamine), may considerably improve the outcome6,11,20 in association with temporary suspension or change of nucleoside analogues.8,9

The optimal management of patients who recovered from severe or symptomatic hyperlactatemia is controversial, as is definitive withdrawal of nucleoside analogues from combined antiretroviral therapy in these patient.9,17,20 Conversely, when evaluating entire patient cohorts (as in our experience), an isolated laboratory recognition is more frequent among asymptomatic outpatients.10,14 Because nucleoside analogues are the basis of almost all recommended antiretroviral regimens, cumulative toxicity mediated via the combined nucleoside analogues may be expected in a great number of subjects treated for HIV disease, although other supporting factors are probably necessary to make this toxicity clinically evident.3,15,19 Carr et al. detected an association between asymptomatic hyperlactatemia, nucleoside analogue administration, and osteoporosis.7 However, in a subsequent editorial they noted severe lactate alterations in pregnant women only, and recommended withdrawal of nucleoside analogues only for symptomatic lactacidemia and serum levels exceeding 5 mmol/L [21].

According to our experience, alteration of serum lactic acid levels, although asymptomatic in the majority of cases, is a novel and emerging complication of HIV disease and its treatment. It may be more common than expected, because it involves over one third of HIV-infected patients (a crude frequency greater than those observed until now).1,4,8,13 However, this abnormality was usually transient, because only 7% of the 743 evaluable patients (but 19.5% of those with repeatedly elevated lactatemia), experienced 2 or more alterations in the considered 6-month period. No significant difference emerged between patients and controls as to numerous investigated epidemiologic, clinical, therapeutic, and laboratory features, including duration of use of nucleoside analogues, the drugs more suspected for this toxicity.1,3,10,15,16,18 In fact, in previous studies, didanosine and stavudine seemed to have a major role,1,4-6,8,9,13,14 but lamivudine and other nucleoside analogues were also reported as risk factors.6

From a pathogenetic point of view, mythocondrial damage possibly caused by antiretroviral drugs is expected to primarily contribute to hyperlactatemia,2,3,15,16,18,19,21 although our series failed to show a correlation with each single nucleoside analogue and its length of administration. Conversely, a relationship with the overall duration of anti-HIV therapy, including HAART (which is always based on nucleoside analogues), to other emerging toxicities with common or related pathogenetic pathways (lipodystrophy, dyslipidemia, and skeletal muscle damage)2,4,15,18,19,21,22 is highly suspected according to our data. We also confirmed that age, gender, and HIV disease stage are not predictive for hyperlactatemia.4,13 An association of hyperlactatemia and lipoatrophy and hyperlipidemia and hyperglycemia was already noticed.4 This feature deserves major investigation, because links between nucleoside analogue activity, toxicity of other antiretroviral drugs, the effects of prolonged HAART, and HIV disease itself may variably contribute to this phenomenon.

John and Mallal23 pointed out hyperlactatemia as a broad spectrum of abnormalities, varying from fulminant metabolic acidosis, partially compensated states of lactate excess, and chronic or intermittet low-grade asymptomatic lactic acid increase, but factors affecting the occurrence of one of these conditions are still completely unknown. Very recently, Bonnet et al.24 reported seven cases of lactic acidosis, and in their control study pointed out a possible link with altered creatinine clearance, and a low CD4+ lymphocyte count, while no relationship with exposure to nucleoside analogues was found.

In conclusion, hyperlactatemia, although frequently asymptomatic and transient, is still an underestimated problem associated with HIV infection itself and antiretroviral therapy. Some authors claim that the significance of serum lactate permanent monitoring is limited in asymptomatic individuals, due to its chronic alteration and a proportionally low risk of developing severe hyperlactatemia.9,13,21,25 The causative role of HIV infection and related disorders, selected antiretroviral drugs and their duration of use, and all postulated pathogenetic pathways leading to multiple associated metabolic disorders, deserve further investigation. This investigation would assist in planning therapeutic and preventive measures and determining whether screening of lactatemia may prove useful for the assessment of incoming severe mitochondrial toxicity, of probably cumulative origin.

REFERENCES

1. Gérard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic hyperlactataemia: An emerging complication of antiretroviral therapy. AIDS 14:2723-2730, 2000.

2. Hernan JS, Easterbrook PJ. The metabolic toxicities of antiretroviral therapy. Int J STD AIDS 12:555-562, 2001.

3. Pao D, Watson C, Peters B, et al. Hyperlactataemia and hepatic steatosis: Mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. Sex Transm Infect 77:381-384, 2001.

4. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: The Swiss HIV Cohort Study. Clin Infect Dis 33:1931-1937, 2001.

5. Miller KD, Cameron M, Wood LV, et al. Lactic acidosis and hepatic steatosis assoociated with use of stavudine: Report of four cases. Ann Intern Med 133:192-196, 2000.

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 20:332-338, 2000.

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 15:703-709, 2001. 

8. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS 15:717-723, 2001.

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 33:2072-2074, 2001.

10. Boffito M, Marietti G, Audagnotto S, et al. Lactacidemia in asymptomatic HIV-infected subjects receiving nucleoside reverse-transcriptase inhibitors. Clin Infect Dis 34:558-559, 2002.

11. 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 34:838-846, 2002.

12. Shahmanesh M, Cartledge J, Miller R. Lactic acidosis and abnormal liver function in advanced HIV disease. Sex Transm Infect 78:139-142, 2002. 

13. Moyle GJ, Datta D, Mandalia S, et al. Hyperlactataemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS 16:1341-1349, 2002.

14. 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 33:1914-1921, 2001.  

15. White AJ. Mitochondrial toxicity and HIV therapy. Sex Transm Infect 77:158-173, 2001.

16. Foli A, Benvenuto F, Piccinini G, et al. Direct analysis of mitochondrial toxicity of antiretroviral drugs. AIDS 15:1687-1694, 2001.

17. Cote HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 346:811-820, 2002.

18. Benbrik E, Chariot P, Bonavaud S, et al. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci 149:19-25, 1997.

19. Jain RG, Furfine ES, Pedneault L, et al. Metabolic complications associated with antiretroviral therapy. Antiviral Res 51:151-177, 2001.

20. McComsey GA, Lederman MM. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. AIDS Read 12:222-224, 2002.

21. Carr A. Lactic acidemia in infection with human immunodeficiency virus. Clin Infect Dis 36(Suppl 2):S96-S100, 2003.

22. Manfredi R, Motta R, Patrono D, et al. A prospective case-control survey of laboratory markers of skeletal muscle damage during HIV disease and antiretroviral therapy. AIDS 16:1969-1971, 2002.

23. John M, Mallal S. Hyperlactatemia syndromes in people with HIV infection. AIDS 15:23-29, 2002.

24. Bonnet F, Bonarek M, Morlat P, et al. Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-trascriptase inhibitors: A case-control study. Clin Infect Dis 36:1324-1328, 2003. 

25. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 15:795-797, 2001.

 

Table 1. Epidemiological, clinical, laboratory, and treatment features of 267 consecutive patients who showed at least one altered serum lactic acid assay, compared with those of the 476 consecutive subjects who did not show hyperlactatemia in the same 6-month evaluation time

 

                                                                                  Patients with elevated         Control patients with
Patients' features                                                         lactatemia (n=267)       normal lactatemia (n=476)

 

Mean patients' age (y ± SD)                                              37.9 ± 8.0                           37.6 ± 7.7

Gender (male/female)                                                           186/81                               329/147

IV drug addicts/Heterosexual/                                           157/64/46                          278/124/74
   Homosexual or bisexual men

Patients with a prior diagnosis of AIDS                                   36                                       59

Mean duration of known HIV infection                             40.9 ± 16.7                         41.5 ± 17.2
   (mo ± SD)

Mean CD4+ lymphocyte count (cells/µL ± SD)                401.2± 121.4                     392.9 ± 118.7

Mean plasma HIV-RNA levels (copies/mL ± SD)            5,930 ± 2,846                     6,112 ± 2,672

Patients undergoing antiretroviral therapy                              221                                     403
   (>6 mo)

Mean overall duration of anti-HIV treatment                     27.5 ± 12.3                         25.0 ± 10.1
   (mo ± SD)

-mean duration of HAART* (mo ± SD)                             20.1 ± 8.2                           18.3 ± 7.4

-mean duration of stavudine administration                    18.1 ± 6.3                           17.8 ± 6.9
(mo ± SD)

-mean duration of lamivudine administration                   16.0 ± 6.8                           16.3 ± 7.0
(months ± SD)                                                                           

-mean duration of didanosine administration                    9.4 ± 3.5                             9.5 ± 3.7
(mo ± SD)

-mean duration of  zidovudine administration                   9.5 ± 3.8                             9.7 ± 4.2
(mo ± SD)

-mean duration of zalcitabine administration                    3.9 ± 2.0                             3.8 ± 1.9
(mo ± SD)

-mean duration of abacavir administration                       3.4 ± 1.9                             3.3 ± 1.6
(mo ± SD)

Patients with elevated serum glucose/triglyceride/             7/86/29                             14/114/42
   cholesterol levels

Patients with a fat redistribution                                              85                                      107
   ("lipodystrophy") syndrome

Patients with osteopenia, osteoporosis,                                 15                                       41
   or ostenecrosis

Patients with high serum creatinphosphokinase/                  53/15                                   64/4
   aldolase levels

Patients suffering from (referring) fatigue or                          56                                      119
   muscle weakness

 

*HAART=highly active antiretroviral therapy, including two nucleoside analogues plus one or two protease inhibitors, and/or one non-nucleoside reverse transcriptase inhibitor.