Survival of a human immunodeficiency patient with nucleoside-induced lactic acidosis—role of haemodialysis treatment

Rochelle Chodock1, Eleftherios Mylonakis1,2, Douglas Shemin1,3, Valgerdur Runarsdottir2, Paul Yodice1,2, Richard Renzi1,2, Karen Tashima1,2, Christopher Towe2 and Josiah D. Rich1,2

1 Brown University School of Medicine, 2 The Miriam Hospital, Brown University School of Medicine and 3 Rhode Island Hospital, Division of Renal Diseases, Providence, Rhode Island

Correspondence and offprint requests to: Josiah D. Rich, MD, MPH, Department of Medicine, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906, USA.

Keywords: AIDS; haemodialysis; HIV; lactic acidosis; nucleoside analogue



   Introduction
 Top
 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 
Combination antiretroviral therapy has become standard of care for treatment of human immunodeficiency virus (HIV) infection [1].The most commonly utilized regimens involve dual nucleoside analogues in combination with a protease inhibitor. A syndrome of lactic acidosis with fatty infiltration of the liver has been reported with the use of nucleoside analogues, and especially zidovudine [2]. The outcome for patients with this syndrome, as reported in the literature, is usually fatal, despite discontinuation of the offending drug [3].We report the case of a woman who developed metabolic acidosis related to nucleoside analogue therapy and survived with the transient use of haemodialysis.



   Case
 Top
 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 
A 35-year-old woman was admitted to the hospital with complaints of diarrhoea for 3 weeks and 1 week of nausea and vomiting. She had been on various nucleoside reverse transcriptase inhibitors, which included zidovudine, lamivudine and stavudine, for 6 years prior to admission. Three months prior to admission, her antiretroviral treatment had been changed to a regimen of didanosine (ddI), stavudine and nelfinavir which she initially tolerated well. Because of the above-noted symptoms, all of her medications, except phenytoin, were discontinued 1 week prior to admission. Her past medical history was significant for HIV infection, diagnosed 9 years earlier, with the last CD4 count of 305x106 cells/l and viral load of 3000 copies/ml of plasma. Other medical problems included a history of seizure disorder, previous injection drug use (with the last episode of injection 9 years prior to admission), alcoholism (with last alcohol intake 2 years prior to admission), herpes zoster and herpes simplex.

On admission, she was an afebrile, obese (112 kg, 1.55 m) woman in no acute distress. Her blood pressure was 126/76 mmHg with a pulse of 116 beats per min supine; blood pressure 100/59 mmHg and a pulse of 128 beats per min standing. Mucous membranes were dry, and the rest of the physical examination was unremarkable.

Laboratory tests on admission revealed white blood cell count of 3500 cells/mm3; haemoglobin 15 g/dl, sodium 141 mmol/l, potassium 3.5 mmol/l, chloride 100 mmol/l, bicarbonate 16 mmol/l, blood urea nitrogen 4 mg/dl, creatinine 0.6 mg/dl and glucose 89 mg/dl. The patient initially was thought to be volume depleted and was treated with intravenous saline, H2 blockers and antacids. Her condition improved, and her orthostasis resolved during the first two hospital days. On the morning of the third hospital day, she was noted to be acutely ill with tachypnoea, persistent nausea and vomiting, and diffuse abdominal pain. She was also found to have profound acidaemia, with a pH of 7.1, PCO2 of 7.5 mmHg, HCO3 of 2.3 mmol/l and PO2 of 154 mmHg. Her lactate level was 70.7 mg/dl but peaked at 168 mg/dl by the following day. Other laboratory values included aspartate aminotransferase of 85 U/l and a prothrombin time of 15.7 s. Albumin, amylase and toxin screens were unremarkable. Computerized tomography scan of the abdomen without the use of contrast revealed fatty liver and a possible umbilical hernia. Given the lack of another obvious cause for lactic acidosis and the difficult clinical examination due to her obesity, it was felt that her disease might be due to an incarcerated umbilical hernia. The patient underwent emergency laparotomy which revealed a small umbilical hernia with no evidence of incarceration and a completely normal bowel.

The history and clinical presentation in combination with the absence of significant findings on exploratory laparotomy and no other identifiable aetiology suggested that the lactic acidosis was secondary to the use of nucleoside analogue agents. Given the high mortality of this condition, she was admitted to the intensive care unit (ICU) on the third hospital day and treated vigorously with mechanical ventilation to produce hyperventilation, and with bicarbonate boluses and a drip to compensate for the metabolic acidosis. She underwent haemodialysis on days four and five. The femoral vein was used for access with a dual lumen catheter, and she was dialysed for 4 h/session with a polysulforne F8 membrane. The blood flow was 250–350 ml/min, and the dialysate flow was 800 ml/min. The dialysate sodium was 140 mmol/l, the dialysate potassium 4.0 mmol/l, the dialysate bicarbonate 35 mmol/l and the dialysate calcium 3.0 mmol/l. The ultrafiltration rate was set at zero, and she received liberal amounts of sodium chloride when her systolic blood pressure dropped below 90 mmHg. She tolerated this well, with an improvement in her lactate level (Figure 1Go). The bicarbonate drip was stopped at day five, and the patient was extubated on day six, 3 days post-intubation. She steadily improved over the following week and was discharged on hospital day thirteen.



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Fig. 1. Course of lactate and pH vs time in an HIV-infected patient with nucleoside analogue-associated lactic acidosis.

 
Subsequent to the episode of lactic acidosis, the patient has continued taking protease inhibitors, and her lactate levels have remained normal. Her most recent CD4 and viral load 9 months after the episode are 262x106 cells/l and 40 000 copies/ml of plasma, respectively.



   Discussion
 Top
 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 
We report an HIV-infected woman who presented with severe lactic acidosis associated with nucleoside therapy. The patient had a history of zidovudine treatment followed by dual nucleoside analogue therapy. She eventually presented with non-specific symptoms and was found to have severe type-B lactic acidosis which, despite extensive evaluation, had no other explanation. With aggressive supportive treatment, ICU monitoring and haemodialysis, the patient survived.

The pathophysiology of nucleoside-associated lactic acidosis is unclear. It has been postulated that there is nucleoside-induced mitochondrial dysfunction altering oxygen metabolism which leads to accumulation of lactate. The damage may result from depletion of mitochondrial enzymes secondary to inhibition of mitochondrial DNA replication [4,5].Disruption of the enzymes that encode the respiratory chain may inhibit the transport of lactate into the mitochondria and therefore cause the accumulation of lactate in the cytoplasm, resulting in severe metabolic acidosis [6].

Lactic acid can be produced in large quantities and can pose a threat to acid–base homeostasis. Although renal acid excretion increases in normal renal function, it does not do so at a sufficiently rapid rate to dispose of extra acid, and lactic acidosis can develop [7].Fialuridine, a nucleoside analogue with activity against hepatitis B virus replication, has been associated with mitochondrial injury and pyruvate oxidation inhibition [8]. In addition, fialuridine has been associated with severe multiorgan toxicity characterized by delayed onset and refractory lactic acidosis, pancreatitis, hepatic failure and death [810]. The nucleoside analogues zidovudine, didanosine and zalcitabine have also been shown to induce mitochondrial injury [4,8].

In a retrospective study of 1590 HIV-infected patients taking nucleoside analogue therapy and 2220 person-year of follow-up, Fortgang et al. concluded that the incidence of lactic acidosis is 1.3 cases per 1000 person-year of antiretroviral drug use [11].Using the key words `HIV, AIDS, lactic acidosis and nucleoside' in a MEDLINE and AIDSLINE search, we were able to identify 21 previously reported cases in the literature. The majority of the patients were female and obese, as with our patient [6,12,13].Zidovudine was the nucleoside analogue in 18 of the cases, while ganciclovir, clofazimine and stavudine were associated with one case each. The involvement of zidovudine in the majority of the cases is probably due to the fact that it was the most common nucleoside inhibitor used. The most common symptoms in the reported group included nausea, vomiting, weakness and fever. The vague and variable symptoms began anywhere from 11 weeks to 1 year following the implementation of the nucleoside analogue. Sodium bicarbonate and respiratory support were used most frequently for treatment. Fourteen of the 21 patients died due to complications from lactic acidosis.

Despite normal renal function, our patient underwent bicarbonate haemodialysis in an attempt to improve lactic acidosis by equalizing lactate levels. It is possible that the use of haemodialysis had an effect on the patient's outcome. Bicarbonate is freely dialysable. The effects of bicarbonate dialysis on the serum bicarbonate level are to some extent mitigated by several factors, including an increase in organic acid production and extracellular volume contraction during dialysis [14]. However, the use of bicarbonate in the dialysate bath clearly increases the serum bicarbonate level, and is superior to baths containing other anions, such as acetate, in transfer of bicarbonate to the patient and increasing the pH [15].

It is unclear what antiretroviral therapy should be given to patients who have survived this syndrome. It would be wise to monitor lactate levels and hepatic and renal function closely, although our patient had minimal disturbances in measures of liver function or hepatic injury. As there are no reports of rechallenge after survival, it is probably prudent to avoid nucleoside therapy in such patients, with combination protease inhibitors and non-nucleoside reverse transcriptase inhibitors as reasonable alternatives.



   Conclusion
 Top
 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 
Life-threatening lactic acidosis is an unusual but significant complication of antiretroviral treatment with nucleoside analogues. This complication should not deter physicians from the use of combination antiretroviral therapy, the mainstay of present HIV treatment. Physicians should be aware of this complication which may present with non-specific complaints. Discontinuation of the nucleoside analogue, intensive supportive care and high dose intravenous bicarbonate may not be sufficient therapy. Haemodialysis may confer added benefits and improve survival.



   Note added in proof
 Top
 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 
Since submission of this report, others have reported on the potential efficacy of Riboflavin to treat nucleoside associated lactic acidosis [16] and an additional case of fatal nucleoside associated lactic acidosis has been reported as well [17].



   Acknowledgments
 
J.D.R. is supported by the National Institutes of Health, National Institute on Drug Abuse K20 grant, DA00268.



   References
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 Introduction
 Case
 Discussion
 Conclusion
 Note added in proof
 References
 

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Received for publication: 29. 3.99
Accepted in revised form: 28. 5.99