Andrew Carr and David Cooper from Australia (St Vincent’s Hospital; 2 National Centre in HIV Epidemiology and Clinical Research, Sydney) reported on a case study of one patient who presented with a high lactate level of 7 mmol/L and acute liver failure, but there were no other causes of liver failure identified. Antiretroviral therapy was stopped, and the patient appeared to recover, but symptoms 20 months later severe symptoms emerged. I think a normal lactate is 2 mmol/L or lower. I think such high levels of lactate as experienced by this patient are unusual but raise the question of how closely to monitor lactate levels.

ABSTRACT:

Introduction:
Acute hepatitis with lactic acidosis is a life-threatening but reversible mitochondrial toxicity of HIV NRTI therapy that requires NRTI cessation. The long-term outcome of patients who do not die is unknown. We report delayed-onset chronic liver failure with persistent mitochondrial dysfunction in a patient who had recovered from NRTI-related acute hepatitis and lactic acidemia over 18 months prior.

Results:
A 65 year old man with asymptomatic HIV infection for 9 years on d4T/ddI for 14 months (but never an NNRTI or PI) presented with lactic acidemia and acute liver failure. No other cause of liver failure was identified. Antiretroviral therapy was ceased. The illness, lactate, albumin and liver enzymes normalised after 5 months, but weight gain was partial. 20 months later, the patient complained of 3 months increasing pitting edema. There was also mild ascites, encephalopathy, and 4 cm non-tender splenomegaly. Lactate and liver enzymes remained normal, but serum albumin as 30 g/l and pro-thrombin time increased. Imaging revealed a shrunken, fibrotic liver, and portal hypertension but no portal vein occlusion. The encephalopathy responded to lactulose, and the edema and ascites to reinstituted diuretics, but the patient had bleeding from oesophageal varices that were sclerosed and banded. Biopsy showed severe peri-portal steatosis, fibrosis or obliteration of intrahepatic portal veins, mild periportal inflammation, minimal hepatocyte necrosis, preserved bile ducts but no bridging fibrosis or cirrhosis. EM in areas of steatosis showed abnormally large mitochondria with crystalline inclu-sions, fatty accumulation, and smooth ER proliferation. Hepatic mitochondrial complexes were grossly depleted (complex I 13%; complex II 44%; complex III 37%; complex IV 96%).

Conclusion:
Chronic hepatic failure with portal hypertension, synthetic fail-ure and persistent mitochondrial dysfunction can develop after resolution of acute liver failure secondary to NRTI-lactic acidemia.

What about the person who has hepatitis c? Can lactic acidosis (elevated lactate) and mitochondrial toxicity due to NRTIs contribute to HCV progression? Do HIV medications do harm to the liver of an HCV infected person, and if so how much harm? I don't think we know the answer to either of these questions. Expert opinion is mixed on whether HIV medications accelerate HCV progression. This Carr study is only one case and may be an unlikely scenario but research needs to address these questions. One study presented at Dallas AASLD (October 2000) liver conference and reviewed on the NATAP web site in AASLD Conference Reports reported liver abnormalities upon biopsy for persons taking HAART.

In The Lancet October 21 2000 issue, Carr and Cooper authored an article called Adverse Effects of Antiretroviral Therapy.

The following are excerpts from that article:

Nucleoside and monophosphorylated nucleotide-analogue reverse-transcriptase inhibitors (NRTIs and NtRTIs, respectively) are both phosphorylated intracellularly to active triphosphate forms, and are then incorporated into new DNA strands synthesised by HIV reverse transcriptase.3,4 The lack of a 39 hydroxyl in NRTIs and NtRTIs results in HIV DNA chain termination.

The major toxicities of NRTI and NtRTI therapy, particularly over the medium-term to long-term, are thought to be secondary to inhibition of mitochondrial DNA polymerase , resulting in impaired synthesis of mitochondrial enzymes that generate ATP by oxidative phosphorylation. These include myopathy (zidovudine); neuropathy (stavudine, didanosine, zalcitabine); hepatic steatosis and lactic acidaemia (didanosine, stavudine, zidovudine); and possibly also peripheral lipoatrophy (possibly all NRTIs, although predominantly with stavudine); and pancreatitis (didanosine). The principal features and known prevalence rates of these toxicities are shown in table 1. The most serious mitochondrial toxicities are lactic acidosis and pancreatitis; mortality was 80% in patients with plasma lactate concentrations greater than 10 mmol/L. Although lactic acidosis is rare, lactic acidaemia (mild elevations) is far more common (about 15%), and is often associated with mild constitutional symptoms, mild increases in concentrations of liver enzymes, and peripheral lipoatrophy. NRTIs and NtRTIs active against other viruses can also exert mitochondrial toxicity (fialuridine, ganciclovir, aciclovir, and cidofovir), at least in vitro.

Mitochondrial toxicities at the clinical level are generally gradual in onset and offset, but may occur within days of the start of therapy. Overall, their prevalence and severity increase with more prolonged therapy. Some, such as peripheral neuropathy and renal tubular acidosis, may worsen for several weeks after drug cessation (the so-called "coasting" phenomenon). Similarly, the capacity of tissue to recover after cessation of reverse-transcriptase inhibitors varies. This capacity may be dependent upon tissue regenerative capacity, the duration and severity of the toxicity, and the duration of therapy. For example, didanosine-induced pancreatitis usually resolves rapidly and completely although we do not know what occurs at the tissue level. In contrast, peripheral neuropathy improves slowly and there may be a permanent deficit, especially if it is severe, or if cessation of therapy is delayed.

Another striking feature of these toxicities is their relative tissue-specific and drug-specific nature. The "pol- hypothesis"3,9 suggests that this specificity may be due to tissue-specific drug penetration and metabolism to the triphosphate form, to tissue-specific polymorphisms in mitochondrial DNA polymerase-, to the target tissue's stores of natural nucleotides, and to the dependency of a given tissue upon mitochondria for function. For example, the proximal renal tubular toxicity of adefovir might be due to its selective accumulation within proximal renal epithelia by the protein organic anion transporter. Although the weight loss seen with adefovir therapy is unexplained, that this transport molecule is also highly expressed in skeletal muscle is of note.

Diagnosis of mitochondrial toxicity is difficult only if patients are receiving other drugs with overlapping toxicities. Furthermore, no diagnostic (metabolic or serological) assay predicts who will develop toxicity. In particular, plasma NRTI concentrations do not reflect intracellular NRTI-triphosphate concentrations. Measurement of the latter is difficult and time-consuming, and may only be relevant if the target organ is sampled.

Of course, most patients treated with NRTIs or NtRTIs do not develop mitochondrial toxicity. Factors that may contribute to toxicity include underlying organ dysfunction (eg, chronic liver disease and NRTI-associated hepatic steatosis, prior pancreatitis and didanosine, prior NRTI-associated neuropathy and stavudine), concomitant HIV-1 opportunistic disease, and particularly the administration of other drugs with similar toxicity profiles (eg, peripheral neuropathy, vinca alkaloids and zalcitabine or didanosine). The management of mitochondrial toxicities is generally limited to cessation of the causative drug and sometimes of other drugs that might exacerbate the condition. Co-administration of other drugs, including other antiretroviral agents, with potentially additive or synergistic toxicities should of course be avoided. Given that toxicity can be of late onset, clinical screening for drug toxicity should be done throughout therapy.

Several agents have been used in the treatment of congenital mitochondrial diseases with limited success. These agents include essential vitamin coenzymes (thiamine and riboflavin), electron acceptors (vitamin C), antioxidants (compound Q), and L-carnitine. Patients with zidovudine-induced myopathy and NRTI-induced peripheral neuropathy have been shown to have reduced concentrations of L-carnitine. Nevertheless, adefovir is routinely given with L-carnitine (to avoid toxicity from its dipovoxil moiety), and clearly does not prevent all renal toxicity. The usefulness of these agents in the treatment or prevention of NRTI and NtRTI-induced mitochondrial disease is unknown.