Near-Fatal Metabolic Acidosis, Liver Failure in Mitochondrial (mt) DNA Depletion in an HIV-Infected Child Treated with Combination Antiretroviral Therapy (ART)

J. CHURCH*, W. MITCHELL, I. GONZALEZ-GOMEZ, R. BOLES, R. WETZEL, and T. VU. Childrens Hosp., Los Angeles, CA; Columbia Univ. Coll. of Physicians & Surgeons, New York, NY

Metabolic complications of the nucleoside components of ART may result from mtDNA depletion caused by inhibition of DNA polymerase g. A now 2 yo boy was diagnosed with PCP disseminated CMV and HIV (RNA= 106 cc/ml) at 3 mos and was treated with ZDV+ddI+NFV with good clinical response; by 15 mos, HIV RNA was <50 and CD4 count was 502/mm². At 19 mos, he developed an unsteady gait. MRI showed patchy hyperdense areas in white and gray matter; CSF was negative for HIV RNA and CMV. At 22 mos, he was referred for evaluation of progressive neurologic deterioration; HIV RNA was <50 and CD4 count was 804. Work-up revealed metabolic acidosis (total CO₂ 10 mEq/L), UPARROW serum lactate 3.66 mmol/L (n=0.45-2.2), DOWNARROW plasma free carnitine 12 µmol/L (31-82), UPARROW urine free carnitine 795 mmol/mol creatine (1.2-10.3), DOWNARROW CPK (20 u/L), and UPARROWUPARROW generalized organic aciduria. Despite discontinuation of ART, the patient deteriorated and was treated with prolonged mechanical ventilation and vasopressor support, frequent electrolyte adjustment, parenteral nutrition, L-carnitine, Co-enzyme Q and continuous drip insulin and glucose. Blood pH reached 7.05, lactate 7.11, total bilirubin 30.6, albumin 2.3, PT 19.4 and PTT 56. Muscle biopsy revealed atrophy of all fiber types, no ragged red fibers, reduced mt number, atrophic fascicles and demyelemated nerve twigs; quantitative Southern blot of DNA showed 79% depletion of mtDNA compared to the average content in 7 age-matched controls. Eventually, his clinical condition improved and repeat MRI revealed reduction in size of the hyperdense areas in his gray and white matter. RNA rose to 728,000 3 wks after discontinuation of ART and RTV+NFV+ EFV were started.
In conclusion, this is the first child reported with these ART-associated complications, and one of the few patients to have survived.

Key Words: antiretroviral complications, lactic acidosis, mitochondrial DNA

© 7th Conference on Retroviruses and Opportunistic Infections,
Foundation for Retrovirology and Human Health