Download 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/
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
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