Mitochondrial Toxicity (Part 2)

Mitochondria live inside each cell and reproduce themselves inside the cell. Overall damage can occur when a certain amount of damage has been done to mitochondria. Then, they are unable to function at peak efficiency.  Mitochondrial dysfunction or damage may result in impaired energy production which is needed for cells, tissues and organs to function properly. Mitochondrial dysfunction may lead to impaired neutralization of free radicals and oxidation of free fatty acids. Mitochondrial damage can occur from HIV environmental affects,  inherited genetically, and with age.  Clinical symptoms that may be linked to mitochondrial toxicity or inadequate mitochondrial functioning include a number of already identified NRTI side effects:  neuropathy (numbess and pain in the periphery--legs, feet, arms); myopathy (muscle wasting); cardiomyopathy (related to the heart and possible heart failure); hepatic steatosis (fatty liver); lactic acidosis (discussed below in first report); pancreatitis. There may also be affects of mitochondrial damage on the central nervous system and the brain. I don't think this area has been well explored yet, but it makes sense to me that mitochondrial dysfunction can affect cells in the CNS and brain just as in other organs. It is not known why different nucleosides may lead to different toxicities or damage to different  organs. But different  nukes may have different tissue specificities or may be drawn to different  types of cells. Different NRTIs may not penetrate all cells equally well. For example, adefovir (a nucleotide that was not approved by the FDA) showed an affinity for causing harm to the kidney. DDI and d4T can lead to neuropathy in feet, legs, and hands. DDI and d4T both appear to affect the liver, while ddI affects the pancreas. For AZT, it appears the main affects are to the blood (low blood cell counts, anemia), muscles (fatigue), and liver. A recent study reported at the Intl AIDS Conference in Durban and detailed in the current issue of NATAP Reports newsletter and on our web site in the Durban Conference summaries, was stopped due to unexpected high incidence of neuropathy in individuals receiving hydroxyurea + d4T + ddI in treatment-na‘ve individuals. Study participants started hydroxyurea with a dose of 600 mg twice daily while the generally used dose is 500 mg twice daily.

HIV itself may lead to some of the effects described above attributed to NRTIs, and this can cause difficulty in assessing the actual causation. HIV can affect the central nervous system and lead to neuropathy. Also counfounding the situation is neuropathy is associated with diabetes, alcoholism, possibly rarely with B-12 vitamin deficiency, and possibly with use of interferon. HIV may be associated with myopathy.

Hepatic steatosis (fatty liver) appears associated with NRTI use but also with hepatitis. Triglyceride elevations may be associated with fatty liver. I suspect that fatty liver may play a role in hepatitis. The liver is involved in eliminating lactate from the blood, and metabolizing protein & fats. I hypothesize that hepatitis may lead to fatty liver, which in turn may encourage lipodystrophy. Conversely, elevated lipids from HIV medications may lead to fatty liver, which in turn may worsen liver condition and hepatitis. These are speculations that need to be researched.

The actual connection of these effects  have been observed in animal experiments and in lab studies, but remain to be proven in humans, although accumulated research  suggests a causation. Still, a number of cases have been reported of persons who are using NRTIs (experimental or approved) who have had mild or severe symptoms described above such as pancreatitis, myopathy, etc. You may recall FIAU (fialuridine), a nuke studied for the treatment of hepatitis B. Several persons in clinical trials for this drug died or needed transplants, as it was associated with liver failure, lactic acidosis, neuropathy, and lactic acidosis. Development of the drug was stopped. Of course, no other NRTI has had such severe toxicities as FIAU. As NRTI use increased over the years, reports of lactic acidosis and hepatic steatosis increased. The FDA required drug manufacturers to label NRTIs with appropriate warnings that use of the NRTI could lead to these affects. Reports have been made to the FDA of individuals who have been using NRTIs for generally more than 6 months, experienced symptoms (elevated lactate, nausea, malaise, vomiting, abdominal pain, fatty liver, triglycerides elevations, pancreatitis) and died, or recovered after stopping therapy.

There are likely a number of steps in the process leading to NRTI caused mitochondrial toxicity: the NRTI must penetrate the susceptible cell; the NRTI must be triphosporylated within the cell; the triphosphorylated NRTI has to be transported to the cellular mitochondria, and incorporated into mitochondria DNA; the triphosphorylated NRTI must persist in the mitochondrial DNA. These steps all present ways for researchers to better understand the process and the differing affects of different NRTIs, and this may lead to ways to possibly intervene or prevent harm with treatments. This also reflects how complicated the process is.

Lipodystrophy and Body Changes

Elevated truglycerides and cholesterol, insulin resistance, and a low rate of diabetes have been seen in people taking protease inhibitors. Fat loss or depletion in the periphery (face, arms, legs) and/or fat accumulation usually in the stomach have been seen in individuals taking combination therapy of a PI or a NNRTI with NRTIS, but have also been seen in individuals who have never taken a PI or NNRTI and have only taken NRTIs. The most current prevalent thinking is that there may be several distinct syndromes at work simultaneously, leading to the several manifestations described above. There may be different causes leading to lipo-atrophy than those leading to fat accumulation. I think there may be overlap in the causations. The effects of  protease inhibitors, NRTIs, and NNRTIs may play independent or overlapping roles in contributing to these syndromes. For example, elevated tryglicerides may contribute to lipo-atrophy and fat accumulation. HDL, LDL (types of cholesterol), insulin resistance, and obesity may also play roles. As well, liver dysfunction and accumulation of fat in the liver (hepatic steatosis) may play roles. Exercise and diet may play important roles in helping to fend off some of these effects--elevated cholesterol, triglycerides, glucose, insulin resistance, and the potential for premature heart disease. I suggest you read the NATAP summaries of the recent 2nd Intl Workshop on Adverse Drug reactions and Lipodystrophy in HIV. Researchers are beginning to better understand the syndromes. I stress beginning, as much more work needs to be done and the understanding is still very preliminary. But the influx of recent government and industry grants to this area of research is beginning to yield initial and preliminary yet interesting information. The syndromes resulting in fat redistribution or body changes are very complicated and may have many causes. Reports at this conference suggested a connection with mitochondrial toxicity, as has been previously hypothesized.

Testing Lactate Levels

In the study reports at the Lipodystrophy Workshop, elevated lactate levels were associated with mitochondrial toxicity. Lactate levels >2.0 mmol/L have been seen in individuals with lipodystrophy. The current NATAP Reports newsletter (also detailed on NATAP web site in Durban Conference summaries) discusses data reported at Durban by Marianne Harris from Vancouver, British Columbia on the relative frequent (19-36%) occurrence of mildly elevated levels of lactic acid in NRTI treated patients. She and others have reported that individuals taking d4T have a propensity towards higher lactate levels, which may only be a little higher. Other studies have shown mild lactate elevations in 10% of NRTI treated and 8% in HIV+ treatment-na‘ve. The significance of such mild lactate elevations is not known and so far is not considered dangerous. It has been emphasized by several researchers that lactates below 5 mmol/L should not be used as an argument to change therapy if there are no signs or symptoms. It's suggested that routine lactate measurements should be implemented with caution to avoid unnecessary treatment alterations, and because if lactate is below 5 mmol/L without symptoms doctors will not do anything as it is not known what such mild elevations mean. The ACTG is currently starting to follow mild elevations to see if they are meaningful. It appears as if acute severe symptomatic NRTI high lactate levels is rare, but chronic asymptomatic mildly elevated lactate levels are common in persons taking NRTIs. Individuals with high lactate levels (>5 mmol/L) may also have hepatic steatosis (fatty liver). Elevated lactate levels appear to return to normal within 2 weeks to 3 months after the NRTIs are stopped. Previously, it was thought that lactate levels could not be measured with any accuracy. However, a recent study by Marianne Harris from Vancouver, Britsh Columbia suggests how they can be measured and now it appears as though leading researchers accept her approach. Her study and test approach is described on NATAP web site in Salvage Therapy Workshop Reports which can be found in Conference Reports.

Increased Hear Disease Risk

The potential for developing premature heart disease has been receiving increasing attention. Elevations in tryglicerides, cholesterol, glucose, smoking, bad diet, lack of exercise, and diabetes are risk factors for heart disease in people without HIV. However, most experts agree that HIV drugs leading to these abnormal lab tests is likely to create a risk for premature heart disease. This was discussed extensively at the Lipodystrophy Workshop and ICAAC and will be the subject of a NATAP report soon.

Experimental Intervention in Mitochondrial Toxicity

A number of therapetic interventions for mitochondrial toxicity have been suggested and used experimentally including L-acetyl carntine, riboflavin, thiamine, coenzyme Q-10, vitamin supplementation including C and E. But there has been little or no research  to explore their usefulness or potential harm. Iron free vitamins are recommended for persons with hepatitis C. At the Digestive Diseases Weekly liver conference held in May 2000, M Prasad from Wayne State University in Detroit reported  on one individual who was taking d4T+3TC+nelfinavir and developed severe lactic acidosis (serum lactate >11 mmol/L) with liver biopsy showing macrovesicular steatosis. He was started on 50 mg once daily of riboflavin, which reportedly led to dramatic improvement in serum lactate levels to normal accompanied by symptomatic improvement. Discontinuation of the NRTIs therapy alone failed to resolve the lactic acidosis. According to Prasad this is the third case of successful  treatment of lasctic acidosis with riboflavin in the world literature and the second of its kind in the US literature. Kees Brinkman has suggested that serum lactate below 2 mmol/L is considered normal. If a person has 2-5 mmol/L, monitor regularly, and if symptoms develop stop or switch NRTIs. If a person has >5 mmol/L he recommends to repeat the test and if still >5 stop or switch NRTIs. For lactic acidosis, he recommends interrupt NRTIs, intravenous fluid support, vitamin supplementation (vitamin B complex forte of 4 mL twice daily including 20 mg of riboflavin twice daily and 100 mg of thiamin twice daily), L-carnitine (1000 mg twice daily), and continue treatments until lactate levels are normal. Mike Youle reported at the Salvage Therapy Workshop that 1500 mg of L-acetyl carnitine resulted in nerve regeneration and improved neuropathy but other researchers do not believe these study results.

Switching HAART Regimens

To address concerns about lipodystrophy (body changes, abnormal lipids) a number of studies have been conducted switching persons from a PI regimen to a NNRT or triple NRTI regimen. Most of these studies have not been well designed controlled and randomized studies. And the follow-up so far is no more than about 1 year. The results have been mixed. Abnormal lipids tend to improve more consistently with a switch to nevirapine or an abacavir based triple NRTI regimen. Abnormal lipids may improve but less consistently with a switch to efavirenz. It appears as though maintenance of viral load suppression is best accomplished with a switch to efavirenz. Individuals who had prior exposure and several resistance mutations to AZT appear to be less able to maintain viral suppression after switching to an abacavir triple NRTI regimen. None of these studies have shown convincingly that body changes are reversed. It's possible that with further time such improvements may occur, but not so far. Several studies have suggested that d4T may be associated with lipo-atrophy and that stopping d4T may reverse the effect. One researcher reported that he found lipo-atrophy reversed after switching patients from d4T to another NRTI. However, these studies were generally not adequately designed to produce confident conclusions about improving body changes and additional studies are planned by the ACTG and others.