The NRTI’s inhibit gamma DNA polymerase, which is found in mitochondria, and the resulting cellular damage in turn leads to organ damage. It appears that different NNRTIs preferentially affect different organ systems. Hence peripheral neuropathy, pancreatitis, anaemia and myopathy are examples of organ specific mitochondrial toxicity caused by some NRTIs but not others.
The most important clinical manifestations of mitochondrial toxicity are those which lead to serious morbidity and possible fatality. The 2 main organ specific toxicities that can prove fatal are pancreatitis and lactic acidosis, the latter of which is a result of hepatic toxicity. The former condition is dealt with under the general sections relating to the NRTIs. We will discuss lactic acidosis separately, as it is a relatively newly recognised and under recognised condition and it is difficult to screen for.
Lactic acidosis and lactic acidaemia
The above terms are not interchangeable. Blood pH is not often measured in conjunction with serum lactate, and without this measurement the term lactic acidosis is incorrect.
Lactic acidosis: arterial pH £
7.35, venous lactate > 2mmol.
Mild lactic acidaemia, which may be considered as a level between 2-5mmol is often asymptomatic, and providing the drugs are stopped then does not proceed to cause major problems, and the biochemical and clinical features resolve.
Moderate levels, between 5-10mmol are usually accompanied by clinical features, and although rarely leads to severe disease or death if treated, if untreated then it might progress to a severe irreversible fatal outcome. A level above 10mmol is usually accompanied by marked symptoms and is usually (circa 80%) of cases, fatal.
Management of lactic acidaemia/lactic acidosis
There is no rationale for performing routine serum lactate measurements, as they are not predictive of the development of lactic acidosis. Similarly, there is no evidence to support the use of anion gap or lactate:pyruvate ratios.
Instead it is important to maintain a high index of suspicion for lactic acidosis on the basis of associated symptoms and signs, where the measurement of serum lactate could be justified:
These are:
1. Non-specific features nausea, malaise, weight loss, symptoms of liver disease including abdominal pain, and the onset or worsening of hepatic enzyme abnormalities.
2. Chronic features that have been associated with an increased risk of the development of mitochondrial induced lactic acidosis are peripheral neuropathy, lipoatrophy and osteopenia, and the measurement of serum lactate can be considered in these circumstances.
3. Introducing NRTIs in patients who have had previous acidosis would justify monitoring the serum lactate.
If the serum lactate is above 10 mmol/L with any illness then the drugs should be stopped and non-HAART causes excluded. Similarly, if the level is 5-10 mmol, with clinical disease, then the drugs should be stopped until and unless other causes are found, and the features resolve. If there are no symptoms at this level, then it is likely that the measurement reflects marked dehydration or even artefact. At levels of 2-5 mmol, if there are symptoms then either stopping the ART or else frequent observation and monitoring is indicated. If there are no symptoms, then monitoring the patient in the clinic for the onset of clinical features and monitoring the serum lactate levels are indicated.
A summary of the minimal recommended requirements for the management of lactic acidaemia is:
- Pre-therapy counselling: all patients should be counselled as to the known incidence, symptoms and outcomes of NRTI induced lactic acidaemia.
- All clinicians should be fully conversant with the clinical presentations of lactic acidaemia and have immediate access to means to measure lactic acid levels in specified patients.
- All clinicians should be aware of the management of high lactic acid levels, particularly how to identify those symptomatic patients in whom it is necessary to immediately stop their current antiretroviral medication.