NATAP: Hyperlactatemia in HIV

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Hyperlactatemia in HIV: Frequency, risk factors and features of

hyperlactatemia in a large number of patients undergoing antiretroviral therapy

AIDS 2003; 17(14):2131-2133

RESEARCH LETTERS

o Manfredia; o Mottab; a Patronob; Leonardo Calzaa;

Francesco Chiodoa; Paola Bonib

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.

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. Although a

severe outcome has been reported 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 univariateand 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. 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. 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. Controlled data regarding the frequency, risk

factors, and features of hyperlactatemia are still

limited. 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, 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 disorders, often

associated with NA administration, as suggested by in-vitro studies. Symptomatic

disease was reported more frequently from inpatients. 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.

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, together with the

suspension of NA. The management of patients who have recovered from symptomatic

hyperlactatemia is controversial, as is the need for the withdrawal of NA. An

isolated laboratory finding is more frequent among asymptomatic outpatients.

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. 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. 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, but lamivudine

and other NA were also mentioned. Antiretroviral-mediated damage is expected

to contribute to the pathogenesis of hyperlactatemia, 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), is suggested, whereas age, sex, and

disease stage did not predict hyperlactatemia.

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.

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