Lactic acidosis is a life-threatening condition observed in less than 1% of patients taking nucleoside analogues in any given year. It has been widely suggested that lactic acidosis is a consequence of cumulative mitochondrial toxicity caused by nucleoside analogues, and that elevations in plasma lactate levels will provide advance warning that the risk of developing lactic acidosis is increased.
However, two studies presented at the Third International Workshop on Adverse Events and Lipodystrophy in HIV in Athens last week suggest that this assumption is wrong.
Lactate is the end product of glucose metabolism in the body, and Dr Ove Anderson of Hvidovre University Hospital in Denmark set out to investigate whether disrupted glucose metabolism was paralleled by changes in lactate production, and whether potential damage to mitochondrial DNA by nucleoside analogues played a role in this disturbance.
He compared two groups: 18 individuals with lipodystophy and a mean of 32 months of PI-containing therapy and 18 individuals on HAART without lipodystrophy. Patients received an infusion of insulin and then received enough glucose to ensure normal blood levels of glucose (this amount will vary from one individual to another according to the degree of insulin resistance present in muscle tissue and other cells). No difference in the rate of glucose loss was found between the two groups, suggesting that mitochondria are able to process glucose normally even when hypothetically stressed. A weakness of this study is that no HIV-negative or untreated control group was studied; reduction in mitochondrial DNA content in cells has been documented even when lipodystrophy is not present, and appears to be a lengthy and insidious process. Furthermore, Cecilia Shikuma from the University of Hawaii reported no difference in the quantity of mitochondrial DNA recovered from cells in people on HAART with and without lipodystrophy, while Dr Graeme Moyle pointed out that in familial mitochondrial syndromes (in which mitochondrial defects are inherited), mitochondrial DNA content must usually be reduced to approximately 5-10% of normal levels before any physical symptoms develop.
Hyped up fat and sugar metabolism – or sluggish liver?
Lactate is released from fat cells in the presence of high levels of glucose, although it is not clear whether lactate elevations in HIV are a consequence of elevated plasma glucose (and increased turnover of glucose within cells corresponding to elevated resting energy expenditure observed in patients with lipodystrophy), or simply a consequence of reduced clearance of lactate in the liver (due either to liver damage, co-infection with hepatitis B or C, or preferential toxicity of NRTIs on mitochondrial DNA within the liver).
Dr Graeme Moyle reported on the incidence of lactic acidosis and hyperlactatemia in 1239 patients receiving treatment at the Chelsea and Westminster Hospital, London, together with a control group of 253 untreated patients. Lactate samples were available for all patients, and 8.7% had a measurement above 2.5mmol/L (considered to be elevated). The median level was 1.4mmol/L for treated patients and 1.1mmol/L for untreated patients. Four cases of lactic acidosis were seen in this cohort..
Elevated levels of lactate were poorly predictive of a subsequent elevated plasma lactate; only 38% of elevated lactates were followed by a second elevated lactate.
Didanosine most strongly associated with lactate increases
The rate of hyperlactatemia was greatest in those receiving d4T and ddI together (17%), but only current ddI treatment was associated with an increased risk of hyperlactatemia compared to the control group, but when ddI-based therapy was compared with 3TC-based therapy, there was no significant difference. Combined use of abacavir and 3TC, and d4T and 3TC, were associated with a reduced risk of hyperlactatemia compared to d4T and ddI.
Hyperlactatemia was also associated with elevation of the liver enzyme ALT and of plasma glucose.
Dr Moyle concluded that screening of lactate is of limited relevance in individuals without symptoms of hyperlactatemia.
Anderson O et al. Different lactate metabolism in patients with and without HIV-associated lipodystrophy syndrome. Antiviral Therapy 6 (supp 4): 7, 2001.
Moyle GJ et al. Hyperlactatemia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. Antiviral Therapy 6 (supp 4): 66, 2001.
Shiramizu B, Shikuma C et al. Competitive PCR-analysis of subcutaneous adipose tissue mitochondrial DNA from individuals with highly active antiretroviral therapy-associated lipodsytrophy. Antiviral Therapy 6 (supp 4): 15, 2001.