Lactic acidosis during nucleoside antiretroviral HIV therapy.To the Editor: Morbidity and mortality associated with human immunodeficiency virus human immunodeficiency virus
Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans. (HIV) have decreased with the administration of nucleoside reverse transcriptase inhibitors (NRTIs) in the setting of highly active antiretroviral therapy Noun 1. highly active antiretroviral therapy - a combination of protease inhibitors taken with reverse transcriptase inhibitors; used in treating AIDS and HIV
drug cocktail, HAART (HAART HAART highly active antiretroviral therapy.
HAART Highly active antiretroviral therapy, triple combination therapy AIDS The concurrent administration of 2 nucleoside reverse transcriptase inhibitors–eg, AZT and 3TC, and a protease ). However, the use of NRTIs has been increasingly recognized as a cause of lactic acidosis. We report a case of fatal NRTI-induced lactic acidosis that occurred 4 months after stavudine, didanosine didanosine /di·dan·o·sine/ (-dan´o-sen) 2, an analogue of dideoxyadenosine; an antiretroviral agent used for the treatment of advanced HIV-1 infection and acquired immunodeficiency syndrome, administered orally. , and tenofovir were initiated.
A 58-year-old woman with HIV infection was being treated with HAART. She had a CD4 cell count of 250 cells/[micro]l and an HIV-1 RNA viral load of 82 copies/ml. She presented to the Emergency Department with severe abdominal pain and nausea in the absence of any vomiting, diarrhea, fever, or chills. Her symptoms worsened during the week before her admission. She had been treated with stavudine, didanosine, and tenofovir for the previous 4 months.
The physical examination revealed that her blood pressure was 191/91 mm Hg, her pulse rate was 102 beats/min, her respiratory rate was 18 breaths/min, and her body temperature was 96.4[degrees]F. Abdominal examination revealed mild tenderness over the epigastric region without rebound, guarding, or organomegaly. The laboratory studies showed a white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. of 12,000/[micro]l, hemoglobin level of 16 g/dl, carbon dioxide of 23 mmol/L, anion gap of 20, and creatinine level of 0.6 mg/dl. Her serum lactate was 10.6 mmol/L, amylase was 702 U/L, and lipase was 800 U/L.
Abdominal computed tomography revealed acute pancreatitis. The patient was treated for pancreatitis and lactic acidosis but rapidly became disoriented, dyspneic, and hypotensive hypotensive /hy·po·ten·sive/ (-ten´siv) marked by low blood pressure or serving to reduce blood pressure.
1. Of or characterized by low blood pressure.
2. . She was transferred to the Intensive Care Unit and treated with intravenous fluids, bicarbonate infusion, riboflavin riboflavin: see coenzyme; vitamin.
or vitamin B2
Yellow, water-soluble organic compound, abundant in whey and egg white. It has a complex structure incorporating three rings. , and thiamine. Her lactate levels continued to increase, and she underwent emergent dialysis. Her course was complicated by respiratory failure asystole asystole /asys·to·le/ (a-sis´to-le) cardiac standstill or arrest; absence of heartbeat.asystol´ic
The absence of contractions of the heart. , and she died after 6 days.
Chronic use of NRTIs has been described as a cause of severe and fatal lactic acidosis. (1) Mitochondrial toxicity seems to be the mechanism by which this occurs. Although NRTIs preferentially inhibit HIV reverse transcriptase, they can also inhibit mammalian nuclear DNA polymerases, in particular DNA polymerase [gamma]. This enzyme is key to mitochondrial DNA replication, and its inhibition leads to mitochondrial DNA depletion and an inability of the cell to generate adequate ATP for cellular energy requirements. This dysfunction may result in lactic acidosis, hepatic steatosis steatosis /ste·a·to·sis/ (ste?ah-to´sis) fatty change.
See fatty degeneration.
fatty degeneration. See also muscular steatosis. , pancreatitis, myopathies, and peripheral neuropathy.
Toxicity occurs with the use of agents exhibiting more potent antimitochondrial activity, in the following general order: zalcitabine zalcitabine /zal·ci·ta·bine/ (zal-si´tah-ben) 2'3'-dideoxycytidine, an antiretroviral agent that inhibits the action of reverse transcriptase; used in the treatment of HIV infection.
n. [greater than or equal to] didanosine [greater than or equal to] stavudine > lamivudine > zidovudine > and abacavir. (2) Hyperlactatemia has been seen most frequently in association with the combination of stavudine and didanosine. (3)
Multiple risk factors may predispose a patient to lactic acidosis, including pregnancy, inherited mitochondrial mitochondrial
pertaining to mitochondria.
a unique set of tRNAs, mRNAs, rRNAs, transcribed from mitochondrial DNA by a mitochondrial-specific RNA polymerase, that account for about 4% of the total cell RNA that dysfunction, increased age, female sex, obesity, liver failure, steatosis, and malnutrition. Pregnancy seems to be the most clearly predisposing condition. (4)
The most important treatment of lactic acidosis secondary to NRTI administration includes prompt discontinuation of the drug. Other treatment modalities include bicarbonate, mechanical ventilation, L-carnitine, riboflavin, hemodialysis, thiamine, coenzyme Q, and vitamin C. (5) No controlled studies designed to demonstrate the efficacy of these treatments have been conducted. In our patient, acidosis was not reversed by bicarbonate, riboflavin, thiamine, and hemodialysis, and her death was likely due to her late presentation.
(1.) Freiman JP, Helfert KE, Hamrell MR, et al. Hepatomegaly hepatomegaly /hep·a·to·meg·a·ly/ (hep?ah-to-meg´ah-le) enlargement of the liver.
The abnormal enlargement of the liver. Also called megalohepatia. with severe steatosis in HIV-seropositive patients. AIDS 1993;7:379-385.
(2.) 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 2002;34:838-846.
(3.) Moyle GJ, Datta D, Mandalia S, et al. Hyperlactataemia and lactic acidosis during antiretroviral therapy: Relevance, reproducibility and possible risk factors. AIDS 2002;16:1341-1349.
(4.) Carr A. Lactic acidemia acidemia /ac·i·de·mia/ (as?i-de´me-ah) increased acidity of the blood. For those characterized by increased concentration of a specific acid, see at the acid. in infection with human immunodeficiency virus. Clin Infect Dis 2003;36(Suppl 2):S96-S100.
(5.) 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 2001;33:1914-1921.
Fares J. Khater, MD
Souad Youssef, MD
Said B. Iskandar, MD
James W. Myers, MD
Jonathan P. Moorman, MD
Department of Internal Medicine
James H. Quillen College of Medicine
East Tennessee State University East Tennessee State University (ETSU) is an accredited American university, founded October 21911 and located in Johnson City, Tennessee. It is part of the Tennessee Board of Regents system of colleges and universities. Medical Service
James H. Quillen VA Medical Center
Johnson City, TN
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