TREATMENT REVIEW 32 - 33 - Fall/Winter 2000

* peripheral neuropathy

* myopathy and cardiomyopathy

* myositis

* lactic acidosis and hepatic steatosis

* lactic acid and lypodistrophy

* pancreatitis

* bone marrow suppression

The approved anti-HIV drugs that belong to the nucleoside analog reverse transcriptase inhibitor (NRTI) class are:

* Retrovir (AZT, zidovudine)

* Videx (ddI, didanosine)

* HIVID (ddC, zalcitabine)

* Zerit ( d4T, stavudine)

* Epivir (3TC, lamivudine)

* Ziagen( abacavir)

* Combivir (Retrovir + Epivir in one pill)

*Trizivir (Retrovir + Epivir + Ziagen in one pill)

Mitochondria are energy-producing parts (the scientific term is organelles) of human cells. They perform their functions separately from the rest of the cell. Mitochondria also have their own genetic machinery or DNA that is separate from the DNA that controls the rest of the cell's function. For example, a T-cell's main DNA makes the special chemicals (called cytokines) that the T-cell uses to fight infections. The mitochondria uses its own DNA for the sole purpose of supplying the T-cell with the energy it needs to stay alive. If you think of a cell as being like a machine, the mitochondria act like a battery.

It has been known for a long time that nucleoside analog anti-HIV drugs (NRTIs) can sometimes be toxic to mitochondria. NRTIs act as fake pieces of DNA. They work against HIV by tricking the virus into using the fake DNA as it tries to make more copies of HIV. If this happens, the fake DNA stops the copying process.

When the main DNA in human cells uses the fake DNA from NRTIs when making new cells, there are special repair mechanisms that prevent damage to the cell. But mitochondrial DNA is simpler and doesn't have these repair mechanisms. If fake DNA from nucleoside analogs gets used when mitochondria are copying themselves, the mitochondria can get damaged. Damaged mitochondria can't supply energy to a cell properly. The cell may become dysfunctional or even die.

Peripheral neuropathy

This side effect is thought to be caused by damage to cells that form a protective sheath (called myelin) around your nerves. It's important to note that, more rarely, HIV itself can also be associated with neuropathy.

Symptoms: Symptoms are burning, tingling pains and numbness in the feet and/or hands. The pain can get so severe that walking becomes very difficult.

Drugs: The drugs most often associated with this side effect are HIVID, Videx, Zerit and (more rarely) Epivir.

Risk of experiencing this side effect: It's estimated that around 20% (1 in 5) to a quarter (1 in 4) of people taking "d" drugs (Zerit, Videx, HIVID) may experience neuropathy. Neuropathy has also been reported from Epivir, but much more rarely.

Diagnosis: Peripheral neuropathy is usually diagnosed by physical exam and/or using a kind of nerve testing called electrophysiology.

Treatment: There is no proven treatment for peripheral neuropathy. Currently, therapy usually involves vitamin supplementation and/or drugs that help mask the symptoms (see article in Treatment Review #31). NRTI drugs may also be switched to try and eliminate neuropathy.

Myopathy and cardiomyopathy

This side effect is thought to be caused by damage to the mitochondria in muscle cells.

Symptoms: Symptoms are weakness and loss of muscle tissue in the arms, legs and buttocks. This type of toxicity can also affect the heart muscle, a problem called cardiomyopathy.

Drugs: This side effect is most often associated with Retrovir, but has also been reported with Zerit.

Risk of experiencing this side effect: Myopathy has been reported in 6% (around 1 in 20) of people taking Retrovir for more than 6 months, although the problem may have been more frequent when higher doses were used. A study has also found that the length of time taking the drug is the biggest risk factor for developing myopathy. There is no information on the risk of developing Retrovir-related myopathy in people taking the drug for more than two years. A very recent report has shown that Zerit can cause myopathy, but the number of people likely to experience this problem is not yet known for certain.

The risk of developing cardiomyopathy is uncertain. A recent experimental study in mice found that HIV proteins were linked to cardiomyopathy, but that Retrovir made the problem significantly worse. What happens in people is more difficult to figure out. A 1995 study found that children taking Retrovir were over 8 times more likely to develop this problem than children taking ddI or no treatment. An Italian study from 1998 found that people taking Retrovir were at greater risk for developing cardiomyopathy, but that the problem was also linked to HIV infection regardless of treatment. In this study, 76 out of a group of 952 people (8%, or about 1 in 12) were diagnosed with cardiomyopathy. A study from Cook County hospital in Chicago found evidence of cardiomyopathy in 20 out of 84 people (1 in 4), but the differences between this and the Italian study may be due to the history of drug use in the people involved. A history of cocaine abuse has been linked to cardiomyopathy, and this can make it even harder to sort out how much Retrovir and/or HIV contribute to the problem. As yet, there is no information on Zerit and cardiomyopathy.

Diagnosis: A blood test for an enzyme called creatinine kinase (CK or CPK) is used to help diagnose myopathy. CK levels are often higher than normal in people with myopathy. Normal CK levels are generally 10-79 u./L for women and 17-148 u./L for men. Taking a small piece of muscle tissue (a muscle biopsy) and studying it under the microscope can show if the mitochondria in muscle cells are damaged. In the case of cardiomyopathy, a heart test called an echocardiogram can help look for problems with heart function. Studies are needed to work out if regular echocardiograms should be done in people taking anti-HIV drugs, particularly Retrovir or Zerit.

Treatment: Because there is no known treatment for NRTI-related myopathy, the best approach may be to identify the drug that is causing it. If possible, an alternative anti-HIV drug can then be substituted. A study published in 1998 looked at muscle biopsies from people with Retrovir-related myopathy. The researchers found that mitochondrial damage in the muscle tissue improved rapidly after Retrovir was stopped.

Myositis

A related problem is called myositis, which is when toxicity to mitochondria in the muscle tissue causes inflammation, pain and muscle damage. Like with myopathy, Retrovir is the most commonly reported cause of myositis. Myositis can be acute, which means it happens soon after starting the drug. The major symptom is muscle pain. Switching to another drug is necessary if myositis develops.

Lactic acidosis and hepatic steatosis

This rare but very serious side effect is caused by damage to the mitochondria in liver cells. Lactic acid is a waste product made by cells that aren't getting enough energy from their mitochondria. Build up of lactic acid in the body can be life-threatening. Secondary to lactic acidosis, droplets of fat can build up inside liver cells, a problem called hepatic steatosis. The liver can also become enlarged, a condition which doctors call hepatomegaly.

Symptoms: Symptoms are severe nausea, vomiting and abdominal pain that doesn't go away. Shortness of breath and/or rapid breathing may also occur. If you experience nausea, vomiting and abdominal pain it's very important to contact your healthcare provider immediately. If you have lactic acidosis the NRTIs must be stopped to avoid further complications, which can be fatal.

Drugs: This problem has been reported with Retrovir, Videx and Zerit but can potentially be caused by all available NRTIs.

Risk of experiencing this side effect: Reports so far indicate this side effect is very rare. A report based on 10,000 people that had taken Retrovir found six cases of lactic acidosis and hepatic steatosis. When doctors at the large Johns Hopkins Clinic in Baltimore searched their records for the period July 1989 to July 1994, they found two cases out of 1,836 people. The US Food and Drug Administration (FDA) recently looked all the reports they'd received of life-threatening lactic acidosis. Since NRTI drugs have been available, there have been 60 cases reported to the FDA. The majority of the cases were women, and the FDA reported that obesity seemed to increase the risk of developing lactic acidosis.

More recent studies have found that while life-threatening cases of lactic acidosis are rare, changes in the levels of lactic acid in the blood (see below) with mild or no symptoms are more common. A report by Swiss doctors found that lactic acid was above normal levels in 107 out of 1598 (about 10% or 1 in 10) people studied. Only 14 of these people (about 1% or 1 out of 100) had levels that were more than twice the normal levels.

Diagnosis: Blood tests can help diagnose lactic acidosis. Measurements of lactic acid in the blood (called serum lactate levels) are taken. Lactate levels above 5 mmol/L are considered dangerous, but it's important to note that lactic acidosis can sometimes develop even though lactate levels are below this level.

Doctors can also measure the acidity of the blood by testing what's called the blood pH. Normal blood pH is generally between 7.35 and 7.45. In cases of lactic acidosis, the pH may drop to less than 7.35. Levels of something called serum bicarbonate may also fall below normal levels. The normal range for serum bicarbonate is generally 21-28 mEq/L. A procedure called a liver biopsy may sometimes be done to help diagnose lactic acidosis. This usually involves taking a small piece of tissue from the liver to look for evidence of fat droplets in the cells (hepatic steatosis).

Treatment: There is no proven treatment for lactic acidosis other than stopping the NRTI drugs as quickly as possible. In serious cases, hospitalization and supportive care may also be needed. One or two reports have suggested that the vitamin supplements riboflavin (vitamin B2) or co-enzyme Q-10 may help speed recovery from lactic acidosis, but this is not yet proven.

Lactic Acid and Lipodystrophy

Some researchers think that mild increases in lactate levels may contribute in some way to the body shape changes known as lipodystrophy. In particular, the loss of fat tissue in the face (causing a shrunken or wasted look) may be linked to damage to mitochondria. A study presented at the recent International AIDS Conference in Durban, South Africa looked at fat tissue from people with lipodystrophy under a special microscope. The researchers saw evidence of damage to mitochondria along with a build up of fat droplets (steatosis). More research is needed to confirm these findings and work out how best to treat the problem.

Pancreatitis

The pancreas is a small organ located just behind the stomach. The pancreas produces insulin which helps the body process sugars in your body. Pancreatitis is when the pancreas becomes inflamed or damaged.

Symptoms: Symptoms of pancreatitis include nausea, vomiting and a persistent (sometimes severe) pain in the stomach area that may go right through to your back.

Drugs: The most common cause of pancreatitis is the NRTI drug Videx. Less commonly, pancreatitis can also be a side effect of Zerit. Epivir has been associated with the development of pancreatitis in children.

Risk of experiencing this side effect: In studies, up to 7% (around 1 in 14) of people taking Videx experienced pancreatitis. In studies of Zerit, less than 1% of people developed the problem. Recent reports suggest that people taking Videx in combination with Zerit and/or hydroxyurea may be at increased risk of getting pancreatitis. It is recommended that people with other risk factors for pancreatitis use Videx with extreme caution and only if there are no other alternatives. Some of the known risk factors for pancreatitis include: a past history of pancreatitis, ongoing alcohol use, severe obesity, high triglyceride levels, gallstones, a medical procedure called endoscopic retrograde cholangiopancreatography (ERCP), and many other medications that can have pancreatitis as a side effect (such as intravenous pentamidine). In studies in children with a history of treatment with other NRTIs, Epivir was associated with pancreatitis in 14-18% (about 1 out of 6) of the participants.

Diagnosis: Monitoring for pancreatitis involves blood tests to measure the levels of substances called amylase and lipase. Increased levels of amylase and lipase can warn of damage to the pancreas before symptoms appear. Your doctor can then confirm if there is damage by doing additional tests.

Treatment: NRTI drugs should be stopped if pancreatitis is suspected. There is no specific treatment for pancreatitis, but hospitalization and supportive care may be needed in serious cases. If damage to the pancreas is permanent (a condition called chronic pancreatitis), changes in diet may be needed to prevent pancreatitis from happening again. Doctors recommend that Videx be permanently stopped if a diagnosis of pancreatitis is confirmed. Restarting Zerit after a case of pancreatitis should be done with caution.

Bone marrow suppression

Toxicity to the bone marrow can cause the numbers of important blood cells to drop. A drop in the level of red blood cells can lead to a condition called anemia. Other blood cells that can be affected include bacteria-fighting white blood cells called neutrophils (a low level of these cells is called neutropenia). Less commonly, all blood cells can be affected and this condition is called pancytopenia.

Symptoms: Symptoms of anemia can be tiredness, shortness of breath and dizziness. Neutropenia can lead to an increased risk of bacterial infection.

Drugs: Retrovir is the most common cause of bone marrow toxicity. More rarely Epivir has also been associated with neutropenia.

Risk of experiencing this side effect: In Retrovir studies, the risk of developing anemia was related to the stage of HIV disease and the dose of Retrovir used. Out of the people with T-cell counts less than 200, around a third developed anemia. In people with higher T-cell counts, around 1-4% (1 in 100 to 1 in 25) developed anemia. The risk of developing neutropenia followed a similar pattern.

Diagnosis: Bone marrow suppression is diagnosed by testing blood cell levels on your regular blood work.

Treatment: The problem is usually treated by switching NRTI drugs. Most commonly, this involves changing from Retrovir to Zerit. In severe cases, bone marrow stimulating drugs may also be used. The drug erythropoietin (Epogen, Procrit) can help increase production of red blood cells. The drug filgrastim (Neupogen) can help increase production of neutrophils. In the past, blood transfusions were sometimes used as a treatment for anemia. Recent studies have found that blood transfusions should be avoided in people with HIV if at all possible. This is because blood transfusions are associated with increases in HIV viral load and more rapid disease progression.

Dealing With Mitochondrial Toxicity

At the current time, the best way of dealing with mitochondrial toxicity isn't clear. Until more information is available, there are three main strategies being used.

Switching Drugs

Different NRTI drugs are associated with certain types of mitochondrial toxicity. For example, the "d" drugs (Videx, HIVID, Zerit) seem more likely to cause neuropathy, whereas Retrovir is more likely to cause bone marrow problems. The drug Epivir seems to cause mitochondrial toxicity more rarely than other NRTI drugs, although the risk may increase with long-term use. Because of these differences between NRTIs, you can sometimes deal with mitochondrial problems by switching drugs. For example, if you're taking a "d" drug and develop neuropathy, it may be possible to switch to Retrovir or Ziagen. The reverse (e.g. switching Retrovir for Zerit) might be possible if you're taking Retrovir and develop bone marrow problems. In a recent report of five cases of lactic acidosis linked to Zerit, four of the people were eventually able to restart combinations that included alternative NRTIs.

The fifth individual in this report avoided NRTIs by restarting treatment with a combination of the protease inhibitors Viracept (nelfinavir), Fortovase (saquinavir) and the NNRTI drug Viramune (nevirapine). This suggests that in some cases of severe mitochondrial toxicity, it may be possible to switch to anti-HIV combinations that don't include NRTIs. Cassy Workman, MD, a well-known HIV specialist from Australia, is also trying this idea in people with severe loss of fat from their face (facial wasting). Like the combination described above, this approach would usually use two protease inhibitors and one non-nucleoside (NNRTI). Since information on these combinations is extremely limited, they are considered very experimental at the current time. There are also important interactions between NNRTIs and protease inhibitors that can require dosing adjustments when these drugs are used in combination.

Nutritional Support

One of the supplements that is commonly suggested for use with NRTIs is L-carnitine. This supplement is available in health food stores or by prescription under the brand name Carnitor (Medicaid and many other health insurers cover Carnitor prescriptions). Some researchers think L-carnitine may help prevent NRTI-related myopathy. Another slightly different version of this supplement is called L-acetyl carnitine. One small study has suggested that L-acetyl carnitine may help treat neuropathy by repairing nerve damage caused by NRTIs. L-acetyl carnitine is harder to find than L-carnitine, but it can be obtained from a buyer's club called DAAIR (Direct AIDS Alternatives Information Resources). DAAIR can be reached toll-free at 1-888-951-5433 or on the internet at http://www.daair.org.

Spanish researchers have studied high doses of antioxidant vitamins in people taking Retrovir. The study was very small, with eight people taking Retrovir along with 1 gram of vitamin C and 600mg of vitamin E daily. The researchers found that markers of mitochondrial muscle damage improved in the people taking these vitamins. Larger studies are needed to confirm these results and see how well high-dose vitamin supplementation might work over the long haul.

Taking a Break

One approach that has been shown to reduce symptoms of mitochondrial toxicity is stopping HIV drugs for a while. At one time, the idea of taking a break from HAART combinations (a "drug holiday") was very controversial. As the long-term side effects of the drugs have become clearer, researchers have realized that drug holidays may - in some specific situations - be a good idea. Everyone agrees that drug holidays must be planned very carefully and in close collaboration with your doctor.

Regular monitoring and bloodwork during any drug holiday is very important. Studies have shown that drug holidays usually result in an increase in viral load. The viral load may "spike," which means the viral load temporarily goes higher than it was before HAART was started. A month or two after stopping the drugs, studies have found that the viral load usually falls to roughly the same level it was before HAART was begun.

T-cell counts may also drop. In studies of people with fairly good T-cell counts (over 350 or so), the drop in T-cells after stopping HAART has not been severe. There can be a temporary dip in T-cell count if the viral load spikes, but it usually takes some time for the count to fall to where it was before HAART was begun.

In a study of people with T-cell counts less than 200, stopping HAART had a bigger effect on T-cell counts. On average, people's T-cells dropped 90 cells. This study shows that people with low T-cell counts need to be very cautious about stopping HAART.

One option for people interested in taking a break from HAART is a clinical trial. Clinical trials offer close monitoring of participants. Some trials may use experimental tests of immune system function that aren't available elsewhere. Unfortunately, there are very few open clinical trials investigating stopping HAART in the New York area. Several large trials are in the planning stage, call The Network for updates.
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