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Summary

  1. Top of page
  2. Summary
  3. Case report
  4. Laboratory studies
  5. Discussion
  6. References

A 57-year-old man with mild neuropathy who was positive for hepatitis B and C viruses was treated with lamivudine 300 mg.day−1. After 3 months he presented with dysphonia and progressive muscle weakness. Subsequently, he developed tetraparesis followed by acute respiratory failure requiring mechanical ventilation, which was complicated by sudden cardiac arrest. After lamivudine was stopped, the neuropathy improved and respiratory capacity improved. Unfortunately, the patient died suddenly in spite of haemodynamic, ventilatory and metabolic support. Electrophysiological studies showed evidence of a sensory-motor axonal neuropathy. Nerve biopsy, muscle biopsy, biochemistry and mitochondrial DNA molecular genetics suggested possible widespread iatrogenic mitochondrial damage. Mitochondrial DNA dysfunction could be a potential cause of the sudden cardiac arrest. Stopping lamivudine treatment sooner after the onset of peripheral neuropathy or its exacerbation is important as continued therapy could lead to acute respiratory failure requiring mechanical ventilation and intensive care unit admission.

Lamivudine is a nucleoside reverse transcriptase inhibitor given for hepatitis virus infection and acquired human immunodeficiency syndrome [1, 2]. Therapy with several nucleoside reverse transcriptase inhibitors has been associated with mitochondrial DNA polymerase-gamma inhibition with mitochondrial DNA depletion [3, 4]. Moreover, the data indicate additive or synergistic long-term mitochondrial toxicity in some nucleoside reverse transcriptase inhibitors combinations [5]. The nucleoside reverse transcriptase inhibitor-induced mitochondrial dysfunction may restrict the clinical application of these agents, especially at high doses and when used in combination. These agents have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling genetic mitochondrial disorders [3, 6]. Peripheral neuropathy is one of the most common clinical features of this iatrogenic damage.

Lamivudine leads to significant mitochondrial impairment when it is administered simultaneously with other nucleoside reverse transcriptase inhibitors in long-term therapy [7]. Lamivudine alone is commonly believed to exhibit no mitochondrial toxic effects and cause only mild or moderate peripheral neuropathy. However, the level of mitochondrial mutations has not been assessed in patients treated with lamivudine.

We present a case of fatal exacerbation of pre-existing mild peripheral neuropathy leading to tetraparesis, acute respiratory failure and cardiac arrest in a patient after therapy with lamivudine.

Case report

  1. Top of page
  2. Summary
  3. Case report
  4. Laboratory studies
  5. Discussion
  6. References

A 57-year-old man had a 25-year history of diabetes requiring insulin treatment for 10 years. He had been serologically positive for antihepatitis B and C viruses antibodies for 10 years and had a 2-year history of painful but stable paraesthesia and cramps distally in the legs. Because of his infection, lamivudine therapy at 300 mg daily was prescribed. Three months later, he was admitted to our neurological department because of a 2-month history of progressive proximal and distal lower limb weakness with difficulty in walking, dysphonia and mild upper limb involvement. Neurological examination showed an unsteady gait with bilateral foot drop, marked distal upper and lower limb weakness, absent tendon reflexes, reduction of all sensory modalities in a ‘glove and stocking’ distribution including distal loss of joint position and vibration sense. Biochemical and haematological screening was normal apart from an erythrocyte sedimentation rate of 49 mm.h−1, aspartate aminotransferase 88 u.l−1 (normal range 10–42 u.l−1), alanine aminotransferase 165 u.l−1 (normal range 10–50 u.l−1), and gamma glutamyltranspeptidase 173 u.l−1 (normal range 10–50 u.l−1). Cerebrospinal fluid examination, thyroid function serum, vitamin B12, folate, antinuclear antibodies, rheumatoid factor, antiganglioside-GM1, antisulphatides, antimyelin-associated glycoprotein, antineuronal nuclear antibody 1, anti-Purkinje cell, and antineuronal nuclear antibody 2, and amphiphysin onconeural antibodies were normal. Electrophysiological studies showed evidence of a sensory-motor axonal neuropathy. A sural nerve biopsy and a peroneus brevis muscle biopsy were performed. The patient was also treated with prednisone (75 mg.day−1) and received a 5-day course of intravenous immunoglobulins (0.4 g.kg−1.day−1) without benefit.

One month later, 4 months after starting lamivudine therapy, his gait deteriorated because of severe lower limb weakness; he was unable to walk unassisted and required re-admission to hospital. The patient underwent plasmapheresis treatment, but his clinical condition worsened and on day 23 after admission he developed tetraparesis. Computed tomography, magnetic resonance imaging of the head and cervical spine, electroencephalography, cerebrospinal fluid examination and a large battery of laboratory investigations were normal.

On day 25, the patient was awake but had occasional respiratory pauses. Spo2 was 98%. One hour later, the patient suddenly had a respiratory arrest. Tracheal intubation was performed and the patient was supported with intermittent positive-pressure ventilation. Despite an arterial blood pressure of 128/78 mmHg, heart rate 103 beat.min−1, Spo2 99% (Fio2 0.4) and blood gas analysis values in the normal range, the patient suffered a cardiac arrest.

Following 5 min of cardiopulmonary resuscitation, electrocardiographic activity was restored. His Glasgow Coma Score was 3 and the patient had an areflexic flaccid tetraparesis without any respiratory activity. Biochemical and haematological screenings shortly afterwards were normal apart from blood glucose 9.1 mmol.l−1. His blood gases were pH 7.36, Paco2 7.3 kPa, Pao2 15.3 kPa (Fio2 0.4)., base excess 5.1 mmol.l−1. He was then transferred to the intensive care unit. His blood glucose level was corrected with continuous infusion of insulin to obtain values between 4 and 5.5 mmol.l−1. Lamivudine administration was stopped.

On day 28, 3 days after ICU admission, the patient was still awake but presented flaccid tetraparesis with absence of deep-tendon reflexes and no respiratory activity. On day 31, 6 days after ICU admission, the patient was awake and able to move his fingertips. Respiratory drive resumed and mechanical support was switched to synchronised intermittent mandatory ventilation. Nevertheless, on day 34, 9 days after ICU admission, the patient died suddenly in spite of haemodynamic, ventilatory and metabolic support.

Laboratory studies

  1. Top of page
  2. Summary
  3. Case report
  4. Laboratory studies
  5. Discussion
  6. References

Nerve biopsy

Sural nerve biopsy showed severe loss of myelinated fibres, some regenerative clusters and thickening of the perineural cells (Fig. 1A). An immunohistochemical study for the macrophage differentiating antigen CD68, CD22, CD4 and CD8 cell subsets, and for the terminal complement complex C5b-9 (membrane attack complex) revealed some endoneural and epineural perivascular CD68 and CD8 positive cells (Fig. 1B) and a membrane attack complex C5b-9 positive stain in most of the epi- and endoneural vessel walls (Fig. 1C).

image

Figure 1. Sural nerve biopsy findings. A) Severe loss of myelinated fibres (bsl00079), regenerative clusters ([RIGHTWARDS ARROW]), endoneural capillary basal laminal reduplication with thickening of the perineural cells (▸). B) Endoneural ([RIGHTWARDS ARROW]) and epineural (▸) perivascular CD8 positive cells and (C) strong C5b-9 positive stain in most of the epi- (▸) and endoneural ([RIGHTWARDS ARROW]) vessel walls as observed by immunocytochemistry.

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Muscle biopsy

Muscle biopsy displayed several atrophic angular fibres and some hypertrophic fibres. Grouping of type I and type II fibres was detected on ATPase reaction. The findings were consistent with recent denervation and previous denervation followed by re-innervation.

Muscle biochemistry and mitochondrial DNA molecular genetics

The activities of the mitochondrial enzymes NADH dehydrogenase, succinate dehydrogenase, NADH-cytochrome C-reductase, succinate-cytochrome C-reductase, cytochrome C-oxidase and citrate synthase were measured in skeletal muscle homogenate [8]. Mitochondrial enzyme activities of Complex 1 (NADH dehydrogenase) and Complex IV were decreased (74% and 39%, respectively), indicating a severe reduction of mitochondrial functioning (Table 1). Southern blot analysis of muscle mitochondrial DNA revealed the presence of a faint band at 16.6 Kb level, suggesting a severe mitochondrial DNA reduction (Fig. 2). Using different concentrations of mitochondrial DNA taken from patient and control samples, on dot blot analysis, the ratio mitochondrial DNA patient/mitochondrial DNA controls was between 37.8 and 39.6%(Fig. 3). These data confirmed about 60% mitochondrial DNA depletion.

Table 1.  Mitochondrial enzyme activities (expressed in nmol. min−1.mg−1 proteins) in the muscle tissue of the patient treated with lamivudine compared to controls.
EnzymesPatient (%)Controls (SD)
  1. SD: Standard deviation.

NADH dehydrogenase298 (74.8)398 (68)
Succinate dehydrogenase7.5 (66.3)11.3 (3.01)
NADH-cytochrome C – Reductase17.4 (45.8)38 (6.1)
Succinate-cytochrome C – Reductase7.1 (40.6)17.5 (4.0)
Cytochrome C – Oxidase19.1 (39.8)48 (10)
Citrate synthase122 (93.8)130 (45)
image

Figure 2. Southern Blot analysis. Mitochondrial DNA band 16.6 Kb faint in the patient (C) compared to controls (A, B).

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image

Figure 3. Dot Blot analysis. Decreased level of intensity progressively with total DNA concentrations hybridised with mitochondrial DNA probes. A) control (B) patient.

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Discussion

  1. Top of page
  2. Summary
  3. Case report
  4. Laboratory studies
  5. Discussion
  6. References

Our patient with diabetes, serologically positive for hepatitis B and C viruses infection and a mild polyneuropathy, suffered, after therapy with lamivudine, a fatal tetraparesis with respiratory failure requiring mechanical ventilation. Electrophysiological studies suggested a sensory-motor axonal neuropathy. An iatrogenic role of lamivudine is strongly suggested by the exacerbation of the neurological condition on treatment and the mild improvement after discontinuation of the nucleoside reverse transcriptase inhibitor.

Patients treated with nucleoside reverse transcriptase inhibitor therapy may develop a variable degree of myopathy or neuropathy. Zidovudine causes myopathy; zalcitabine, didanosine and lamivudine cause neuropathy and stavudine and fialuridine cause neuropathy, myopathy and lactic acidosis [3].

There are few reports of lamivudine and peripheral neuropathy, but opinions vary. It was previously suggested that lamivudine was different from other nucleoside reverse transcriptase inhibitors and did not exert any toxic effect on peripheral nerves [9]. Markus and Brew presented cases of an improvement of peripheral neuropathies in two patients with human immunodeficiency virus infection treated with lamivudine and other nucleoside reverse transcriptase inhibitors (zidovudine and indinavir in the first patient, zidovudine in the second) [10]. Based on this, lamivudine treatment was not discontinued in our patient after the initial exacerbation of the neuropathic symptoms.

Lamivudine has been considered neurotoxic and capable of causing or exacerbating peripheral neuropathies, even if less frequently than other nucleoside reverse transcriptase inhibitors [11]. Cupler and Dalakas reported a 33-year-old man with human immunodeficiency virus infection who experienced exacerbation of underlying peripheral neuropathy when treated with lamivudine [12]. In this case, as in our patient, there was a worsening of peripheral neuropathy within a few weeks with a similar lamivudine dosage (300–600 mg daily). Fortunately, that patient rapidly improved after the nucleoside reverse transcriptase inhibitor was stopped.

Nucleoside reverse transcriptase inhibitors cause mitochondrial toxicity, inhibiting cellular polymerases by most notably mitochondrial DNA polymerase gamma [5, 11]. Studies of lamivudine in enzyme assays and cell cultures demonstrate that it acts as an inhibitor in the same way as other nucleoside reverse transcriptase inhibitors (hierarchy of mitochondrial DNA polymerase gamma inhibition: zalcitabine > didanosine > stavudine > lamivudine > tenofovir > zidovudine > abacavir) [11–13]. Inhibition of DNA polymerase gamma and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity with clinical manifestations resembling those of inherited mitochondrial diseases [11–13]. Mitochondrial DNA dysfunctions are associated with sudden cardiac death [14–16]. This could have been a possible cause of the sudden cardiac arrest in our patient despite the haemodynamic, ventilatory and metabolic support. Therefore, it has been suggested that mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors could be a problem in long-term antiretroviral therapy [17]. Nevertheless, it was reported that depletion of mitochondrial DNA seems to be reversible, since it has been demonstrated that a substantial and a concomitant pronounced increase in muscle mitochondrial DNA content occurs when nucleoside reverse transcriptase inhibitor therapy is discontinued [18].

In our patient, molecular and biochemical mitochondrial studies, performed in skeletal muscle specimens, demonstrated the presence of a severe depletion of mitochondrial DNA compatible with an iatrogenic role of lamivudine. Therefore, it is likely that a similar mitochondrial toxicity has also occurred in peripheral nerves, inducing a fatal neuropathy exacerbation. Despite previous reports demonstrating that lamivudine causes only a neuropathy, our study suggests mitochondrial toxicity in skeletal muscle. We suggest that lamivudine should be promptly stopped when a peripheral neuropathy or an exacerbation occurs, since it could lead to acute respiratory failure requiring mechanical ventilation and ICU admission.

References

  1. Top of page
  2. Summary
  3. Case report
  4. Laboratory studies
  5. Discussion
  6. References
  • 1
    Lagget M, Rizzetto M. Current pharmacotherapy for the treatment of chronic hepatitis B. Expert Opinion on Pharmacotherapy 2003; 4: 18217.
  • 2
    Martin AM, Hammond E, Nolan D, et al. Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. American Journal of Human Genetics 2003; 72: 54960.
  • 3
    Dalakas MC. Peripheral neuropathy and antiretroviral drugs. Journal of the Peripheral Nervous System 2001; 6: 1420.
  • 4
    Yerroum M, Pham-Dang C, Authier FJ, Monnet I, Gherardi R, Chariot P. Cytochrome c oxidase deficiency in the muscle of patients with zidovudine myopathy is segmental and affects both mitochondrial DNA- and nuclear DNA-encoded subunits. Acta Neuropathologica 2000; 100: 826.
  • 5
    Walker UA, Setzer B, Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS 2002; 16: 216573.
  • 6
    Parra D, Gonzalez A, Mugueta C, Martinez A, Monreal I. Laboratory approach to mitochondrial diseases. Journal of Physiology and Biochemistry 2001; 57: 26784.
  • 7
    Gerschenson M, Nguyen V, Ewings EL, et al. Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine. AIDS Research and Human Retroviruses 2004; 20: 91100.
  • 8
    DiMauro S, Moraes CT, Shanske S, et al. Mitochondrial encephalomyopathies: biochemical approach. Revue Neurologique 1991; 147: 4439.
  • 9
    Honkoop P, Scholte HR, De Man RA, Schalm SW. Mitochondrial injury. Lessons from the fialuridine trial. Drug Safety 1997; 17: 17.
  • 10
    Markus R, Brew BJ. HIV-1 peripheral neuropathy and combination antiretroviral therapy. Lancet 1998; 352: 19067.
  • 11
    Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical Therapeutics 2000; 22: 685708.
  • 12
    Cupler EJ, Dalakas MC. Exacerbation of peripheral neuropathy by lamivudine. Lancet 1995; 345: 4601.
  • 13
    Lee H, Hanes J, Johnson KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 2003; 42: 147119.
  • 14
    Opdal SH, Rognum TO. The sudden infant death syndrome gene: does it exist? Pediatrics 2004; 114: 50612.
  • 15
    Gilbert-Barness E. Review. Metabolic cardiomyopathy and conduction system defects in children. Annals of Clinical and Laboratory Science 2004; 34: 1534.
  • 16
    Yoon KL, Ernst SG, Rasmussen C, Dooling EC, Aprille JR. Mitochondrial disorder associated with newborn cardiopulmonary arrest. Pediatric Research 1993; 33: 43340.
  • 17
    Brinkman K, Kakuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy? Current Opinion in Infectious Diseases 2000; 13: 511.
  • 18
    Arnaudo E, Dalakas M, Shanske S, Moraes CT, DiMauro S, Schon EA. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991; 337: 50810.