Study details

Doctors at St. Paul's hospital in Vancouver, British Columbia, recruited three groups of people for their study:

• 24 healthy HIV negative subjects
• 47 symptom-free HIV positive subjects who had never used anti-HIV therapy
• 8 HIV positive subjects who had symptoms of higher-than-normal levels of lactic acid (hyperlactatemia — moderate-to-severe fatigue and rapid, unintentional weight loss)

The eight subjects were all taking combination anti-HIV therapy that included the nuke d4T (Zerit, stavudine). Technicians analysed blood samples from all subjects to measure levels of DNA in Mt as well as in cells. Lactic acid levels (lactate) measurements were also performed.

Results

The researchers found that HIV negative subjects had the highest level of Mt DNA. The second highest level was found in HIV positive subjects who had never been exposed to anti-HIV therapy; they had about half the amount of Mt DNA that HIV negative people had. The lowest level of Mt DNA was found in HIV positive subjects with symptoms of hyperlactatemia who were taking anti-HIV therapy. Indeed, their level of Mt DNA was about 22% of normal. These differences were statistically significant.

The good news is that the researchers had enough data on seven of the eight subjects with symptoms to make some important observations. They found that when seven subjects stopped taking their therapy because of severe side effects, Mt DNA levels gradually rose, reaching levels detected in HIV positive subjects who had never used combination therapy. This point is important as it shows that PHAs can recover from Mt damage. On average, it took between one and four months for Mt DNA to recover sufficiently so that PHAs could resume taking combination therapy.

There was no link between having symptoms of high levels of lactic acid and the following:

• CD4+ cell counts
• white blood cell counts
• liver enzyme levels

Key points

1. Levels of Mt DNA were very low in PHAs who were taking anti-HIV therapy and who had symptoms of Mt toxicity.
2. The decrease in Mt DNA occurred before lactic acid levels rose — confirming a link between Mt toxicity and lactic acid.
3. Levels of Mt DNA rose when PHAs stopped taking therapy to a level near those seen in PHAs who had never used HAART. However, this level was, on average, about 40% below that of healthy HIV negative subjects. This point is important because it is likely that Mt DNA levels may not be able to rise to normal. This is possibly because HIV produces proteins that damage mitochondria. These findings may, in part, explain the fatigue that is one of the hallmarks of HIV/AIDS.
4. All eight subjects who developed hyperlactatemia were using d4T as part of their combination regimen. It is possible that d4T may be more toxic to Mt than other nukes, but this needs to be confirmed in other studies.

More on nukes

In another study at the U.S. National Institutes of Health, researchers conducted laboratory experiments with cells and nukes. They found that all currently licensed nukes affected an important cellular enzyme. These researchers noted that most studies have focused on the ability of nukes to affect the activity of a cellular enzyme to some degree. However, more research needs to be done on what happens when nukes are taken up by, or incorporated into, Mt DNA. Once incorporation happens, then Mt toxicity may persist because the Mt is not quickly able to cleanse itself of the nuke, particularly if exposure to nukes continues. In light of these findings, perhaps it is not surprising that supervised drug holidays were necessary in order for subjects to recover from hyperlactatemia.

REFERENCES

1. Côté HCF, Brumme ZL, Craib KJP et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. New England Journal of Medicine 2002;346:811-820.

2. Walker UA, Bickel M, Volksbeck SIL, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. Journal of Acquired Immune Deficiency Syndromes 2002;29(2):117-121.

3. Lim SE and Copeland WC. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase . Journal of Biological Chemistry 2001;26:23616-23623.

4. Cazzalini O, Lazze MC, Iamele L, et al. Early effects of AZT on mitochondrial functions in the absence of mitochondrial DNA depletion in rat myotubes. Biochemical Pharmacology 2001; 62(7):893-902.

5. Jacotot E, Ferri KF, El Hamel C, et al. Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein R and Bcl-2. Journal of Experimental Medicine 2001;193(4):509-519.

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