A Look at Lactic Acidosis
by James Learned
Some of the long-term side
effects that people with HIV experience are certainly due
to mitochondrial damage caused by nucleoside analogs (the
drug class that includes AZT and Zerit). Mitochondria, found
inside all human cells, use oxygen, fat and sugar to produce
energy for the cells. A single human cell can have thousands
of mitochondria, depending on how much energy is required
for the cell to function properly.
Mitochondrial damage caused
by nucleoside analogs has been recognized since the introduction
of AZT in 1987. Some of the resulting symptoms may have been
under-diagnosed in the past, but as people have been on these
drugs for longer periods of time, increasing attention is
being paid to their role in metabolic and morphologic changes.
The degree to which each of the nucleosides contributes to
mitochondrial damage is unclear. Mitochondrial damage may
be responsible for many of the common side effects of the
nucleoside analogs: myopathy (inflammation of muscle tissue),
peripheral neuropathy (nerve damage in the feet and hands),
pancreatitis, and low levels of red blood cells (anemia),
neutrophils (neutropenia), or platelets (thrombocytopenia).
Two particularly serious conditions
can also result from mitochondrial damage—lactic acidosis
and hepatic steatosis, or fatty liver. All of us are familiar
with the aching muscles that often follow a physical workout.
That soreness is caused by a buildup of lactate. Our bodies
usually clear excess lactate, but mitochondrial damage can
create very high levels of lactate in the blood, sometimes
leading to lactic acidosis, a rare but potentially fatal condition.
Symptoms of lactic acidosis are difficult to discern. They
can include shortness of breath, abdominal pain, nausea, vomiting,
fatigue and weight loss, subtle symptoms that can easily be
ignored or mistaken for something else. If you experience
these symptoms while on nucleoside analogs, see your doctor
right away.
There are no simple blood
tests to check lactate levels. However, serum bicarbonate
levels are measured as part of routine blood work, and low
levels are a sign that some kind of excess acid production
is occurring. If you’re taking a nucleoside and your
serum bicarbonate levels are low, lactic acidosis should be
suspected. Although riboflavin and coenzyme Q10 are sometimes
used to treat lactic acidosis, there is no evidence yet to
support the value of either. Usually, the only recourse is
to stop nucleoside analog therapy or, if appropriate, reduce
the dose.
At the recent 7th Conference
on Retroviruses and Opportunistic Infections (CROI), a poster
(printed report) from the Netherlands described four cases
of fatal lactic acidosis. The four people had been on nucleoside-containing
combinations (all with d4T, brand name Zerit) for six to 20
months, and all had previously experienced at least one nucleoside-related
side effect. They entered the hospital with gastrointestinal
and respiratory problems and died within three weeks.
A team from Johns Hopkins
University looked at lactate levels in 509 individuals who
had been on combinations that included two nucleosides and
a protease inhibitor for varying lengths of time. Although
these data are only suggestive, people on combinations that
included d4T/3TC had significantly higher lactate levels than
those on AZT/3TC (Retrovir/Epivir), d4T/ddI (Zerit/Videx)
or AZT/ddI (Retrovir/Videx). The potential for these people
to develop lactic acidosis is unclear.
Another poster discussed abnormally
high lactate levels in 20 patients on nucleoside analog-containing
regimens (again, all included d4T) at the University of California
Medical Center in San Diego from July 1998 to September 1999.
The problems were identified early enough that no deaths resulted,
and all 20 had normal lactate levels within seven to 176 days
of stopping antiviral therapy. Three of the 20 resumed antiviral
therapy (without d4T), and still had normal lactate levels
three months later.
A disturbing poster described
the history of a child who developed extreme mitochondrial
damage. At three months of age, he started AZT/ddI/nelfinavir
(Viracept), which resulted in a good clinical response—undetectable
viral load and rising CD4s. A year and a half later, however,
he had unusual patches on his brain, elevated lactate levels,
liver damage, severe atrophy of muscle and nerve fibers, and
an astounding 79% depletion of mitochondrial DNA compared
to HIV negative children his age. He was taken off antiviral
therapy for three weeks, during which time his viral load
rebounded. Then he was started on a combination of ritonavir/nelfinavir/
efavirenz (Norvir/Viracept/Sustiva) and his condition has
improved. This is the first reported case of a child experiencing
such severe mitochondrial damage, seemingly as a direct result
of nucleoside analogs.
Early last year, investigators
in France reported on two HIV negative one-year-olds who died
of neurologic disease associated with mitochondrial damage
and whose mothers had taken AZT/3TC during pregnancy. As more
attention is directed at the potential for nucleoside analogs
to cause damage to the mitochondria, an effort is underway
in the United States to look at HIV negative children born
to positive women who took nucleosides (primarily AZT) during
pregnancy. Using databases from the National Institutes of
Health and the Centers for Disease Control, this effort has
so far focused on 227 HIV negative children who have died
for any reason. Mitochondrial damage has not been found in
any of these cases. The next step is to look for possible
mitochondrial damage in the thousands of children who are
alive.
Taken with permission from
a longer article in the Spring 2000 CRIA Update. James
Learned is the National Technical Assistance Program Director
at the Community Research Initiative on AIDS (CRIA) and a
founding member of the Hepatitis C Action & Advocacy Coalition
(HAAC).
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