(Update in Process 8/1/06)
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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.

One option for people is a clinical trial. Clinical trials offer close monitoring of participants. Some trials use experimental tests of immune system function that aren't available elsewhere. Sean Hosein of CATIE wrote a comprehensive review of the use of uridine to treat or prevent mitochondrial toxicity. The A5157 study of a supplement called Nucleomaxx, which contains uridine, is now taking place at the Adult AIDS Clinical Trial Group (AACTG)

Dealing With Mitochondrial Toxicity:

It's currently thought that toxicity to mitochondria may be involved in many of the well-known side effects of NRTI anti-HIV drugs. 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.

One of these is switching drugs. Different NRTI drugs are associated with certain types of mitochondrial toxicity. For example, the "d" drugs didanosine (ddI, Videx), zalcitabine (ddC, HIVID), stavudine (d4T, Zerit) seem more likely to cause neuropathy, whereas zidovudine (AZT, Retrovir) is more likely to cause bone marrow problems. The drug lamivudine (3TC, Epivir) seems to cause mitochondrial toxicity more rarely than other NRTI drugs, although the risk may increase with long-term use. The drug emtricitabine (Emtriva) may cause less damage than Epivir, at least in test tube studies.

Because of the 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 zidovudine or abacavir (Ziagen). The reverse (e.g. switching to zidovudine for stavudine) might be possible if you're taking zidovudine and develop bone marrow problems. In a recent report of five cases of lactic acidosis linked to stavudine, 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 study has suggested that L-acetyl carnitine may help treat neuropathy by repairing nerve damage caused by NRTIs. To enroll in an ongoing neurological study go here for more information.

L-acetyl carnitine is harder to find than L-carnitine, but it can be obtained from a buyer's club. For a very extensive review of supplements and other alternative treatments download the latest guide from The New York Buyers' Club.

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. A recent, very large study called SMART was recently stopped because a significant number of people who stopped their regimens developed opportunistic infections and AIDS. Some people died as well. 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. Sometimes the side effects that started when you first began taking the drug or combination either come back, or new ones develop. This could be very dangerous with drugs such as NNRTIs such as Sustiva or Viramune, and Ziagen. You cannot restart Ziagen ever again if you have had a hypersensistivity reaction, which could be life threatening.

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.

At this point it is unknown when if it safe for someone to take a break - unless your doctor determines the side effects of your treatment combination are doing a lot of harm. Additional research is ongoing in this area, but at this point in time most scientists are highly suspicious that they will cause more harm than good.