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-naÔve 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.
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.
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-naÔve. 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.
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.
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.
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.