The so far only therapy of mitochondrial toxicity under unchanged NRTI-treatment consists of the supplementation of uridine or its precursors. As outlined above, any respiratory chain impairment also results in the inhibition of DHODH, an essential enzyme for the synthesis of uridine and its derived pyrimidines (Fig 2). This decrease in intracellular pyrimidine pools leads to a relative excess of the exogenous pyrimidine nucleoside analogs, with which they compete at polymerase-gamma. A vicious circle is closed and contributes to mtDNA-depletion. By supplementing uridine this vicious circle can be interrupted, resulting in increased mtDNA-levels.

Indeed, uridine abolished in hepatocytes all the effects of mtDNA-depletion and normalized lactate production, cell proliferation, the rate of cell death and intracellular steatosis. (Walker 2003). In contrast, vitamin cocktails were not beneficial in this model. Uridine also normalizes the lipoatrophic phenotype in adipocytes exposed to d4T (Walker 2006b).

Uridine is well tolerated by humans, even at high oral and intravenous doses (van Groeningen 1986, Kelsen 1997). A food supplement called Mitocnol was shown to have a more than 8-fold uridine bioavailability over conventional uridine (Venhoff 2005). Mitocnol was studied in a randomized placebo-controlled double-blind trial in lipoatrophic subjects under continued therapy with d4T or AZT where it has objectively improved subcutaneous fat (Sutinen 2007). In comparison with switch strategies (e.g. the replacement of stavudine and zidovudine by antivirals with a reduced potential of mitochondrial toxicity), the effect of Mitocnol on subcutaneous fat gain was more rapid and quantitatively more pronounced (Fig 3).

Figure 3: Subcutaneous fat gain with Mitocnol under d4T and AZT treatment (in comparison with strategies sparing thymidine-analogue NRTI).

Figure 3: Subcutaneous fat gain with Mitocnol under d4T and AZT treatment (in comparison with strategies sparing thymidine-analogue NRTI).

A second trial has also suggested Mitocnol to be efficacious with regard to patient and physician assessed lipoatrophy scores (McComsey 2007). In vitro, animal and clinical data indicate, that Mitocnol also antagonizes mitochon-drial steatohepatitis. (Walker 2004b, Banasch 2006, Lebrecht 2007). Animal data indicate that uridine supplementation also counteracts AZT-induced hematotoxicity and myopathy (Sommadossi 1988).

Mitocnol is well tolerated and adverse events have not been observed so far. In one study, a clinically insignificant HDL-decline was suggested, while another trial showed no change in HDL cholesterol (McComsey 2007). There are no known negative interactions of uridine with the efficacy of the antiretroviral treatment (Sommadossi 1988, Koch 2003, McComsey 2007, Sutinen 2007). In Europe and North America, Mitocnol is available as a dietary supplement called NucleomaxX® and can be acquired in pharmacies and the internet (www.nucleomaxX.com). In symptomatic hyperlactatemia and in lactic acidosis, all NRTIs should be immediately discontinued (Brinkman 2000). The supplementation of vitamin cocktails has been recommended, but there are no data that demonstrate the efficacy of this intervention with respect to mtDNA-depletion (Walker 1995, Venhoff 2002). After discontinuation of NRTIs, normalization of lactate may require several weeks. More mitochondrial friendly NRTIs may then be reintroduced, but patients should be monitored closely. The proposed supportive treatment of hyperlactatemia and lactic acidosis is summarized in Table 2.

Table 2. Supportive treatment of lactate elevation in HIV-infected patients (non-pregnant adults)

Lactate 2-5 mmol/L + symptoms

Lactate > 5 mmol/L or lactic acidosis

Discontinue mitochondrial toxins

Discontinue NRTIs and all mitochondrial toxins

Consider vitamins and

Intensive care

NucleomaxX (36g TID on 3 con

Maintain hemoglobin > 100 g/L

secutive days/ month)

Avoid vasoconstrictive agents

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