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The Body Covers: The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
Improvements in Mitochondrial DNA Levels After Substituting ABC or ZDV for d4T in HIV-Infected Patients With Lipoatrophy

September 30, 2002

  • Improvements in Mitochondrial (mt) DNA Levels After Substituting ABC or ZDV for d4T in HIV-Infected Patients With Lipoatrophy (LA) (Abstract H-1930)
    Authored by G. McComsey, D. Paulsen, T. Lonergan, S. Hessenthaler, C. Hoppel, V. Williams, R. Fisher, C. White-Owen, J. Hernandez, L. Ross
    Poster Presentation: View the original abstract


During the past few years, several studies have accumulated data implicating some nucleoside thymidine analogues, specifically d4T (stavudine, Zerit), as playing a very important role in the development of some metabolic complications and lipodystrophy. Prospective data is now being collected by several investigators on the possible role of d4T and maybe others nucleosides, on the onset or worsening of these metabolic manifestations.

Earlier this year, Dr. Andrew Carr, from St. Vincent's Hospital in Sydney, Australia, presented data on the possible reversion of lipoatrophy after switching d4T or AZT (ZDV, zidovudine, Retrovir) to abacavir (ABC, Ziagen) in patients with lipoatrophy (see The Body's coverage of CROI 2002, abstract 32). In that study, the reversion of lipoatrophy was "modest" at best, but the prospective follow-up of that study was only 24 weeks.

Other studies have continued to add more compelling evidence implicating d4T as at least partially responsible for some of the lipoatrophy observed in these patients (see The Body's coverage of CROI 2002, The Perth Study, abstract 700-T). In the same conference, Dr. McComsey presented 24-week data on a study evaluating improvement of lipoatrophy after d4T was replaced with abacavir or AZT (see The Body's coverage of CROI 2002, abstract 701-T). The 48-week results of that study are now presented in this poster.

This study was a sub-study from a larger trial of 118 patients, in which patients were enrolled to assess the regression of lipoatrophy and hyperlactatemia potentially resulting from a d4T-containing regimen. The results of that trial were also presented at this conference (see The Body's coverage of abstract H-1929). The 118 patients were AZT- or abacavir-naive, virologically suppressed, on a d4T-containing regimen for at least six months and had physical findings of lipoatrophy or hyperlactatemia. All study patients switched d4T with either abacavir or AZT. They underwent extensive evaluation with DEXA and an abdominal CT scan to quantify the amount of subcutaneous fat present at baseline, 24 and 48 weeks. Those radiography studies suggested a progressive gain in body fat through week 48 when d4T was replaced with either abacavir or AZT.

In this poster, Dr. McComsey describes a subgroup of patients (N=16) from the original 118 study patients who agreed to undergo further evaluation with PMBC (blood cells), muscle and adipose (fat tissue) biopsies at baseline and at week 48. The results of those tissue biopsies were compared to matched study controls. Sophisticated tissue analysis was performed to extract and measure mitochondrial DNA in all groups. Comparisons were made between study patients at baseline versus week 48, and with study controls.

Both mitochondrial DNA depletion and functional abnormalities were noted in the d4T-treated patients with lipoatrophy. The mitochondrial DNA in PMBCs, muscle and adipose cells increased from baseline through week 48 in all patients after they were switched from d4T to abacavir or AZT. Although the mitochondrial DNA in muscle returned to normal after 48 weeks, only modest improvements were seen in the adipose mitochondrial DNA.

In this study, a positive correlation was observed when comparisons were made between the muscle and adipose mitochondrial DNA levels and the DEXA scan results in those patients at week 48. The improvement seen in muscle mitochondrial DNA suggests that the adipose tissue may further improve later, but at a much slower rate. On the other hand, other factors not still elucidated within the adipose tissue metabolism may interfere with further improvement. Long term follow up may answer that question.

The increasing mitochondrial DNA in these tissues is an indirect marker of DNA gamma polymerase activity (which is the main enzyme involved in mitochondrial DNA replication). All nucleosides to some extent have been found to inhibit mitochondrial DNA replication by inhibiting this enzyme. In some in vitro studies, d4T has been found to inhibit this enzyme more profoundly. It is also possible that other nucleosides, such as AZT and even abacavir, may start to cause significant mitochondrial DNA alterations with a longer exposure time than what was needed for d4T. This is another issue that hopefully long-term prospective data will also clarify.

So, what can we do with this information at this time?

We should all be aware of the progression and follow-up of these studies. As new information becomes available, we need to know if the evidence continues to point at d4T as the main cause of these mitochondrial alterations. We also need to know if there is a significant clinical correlation between these intracellular findings and clinical manifestations, such as lipoatrophy.

I personally think that d4T is a great antiretroviral agent with proven efficacy and tolerability in diverse patient populations. For this reason, I am not ready to dismiss this drug. On the other hand, as more information becomes available, it appears reasonable to purposely avoid using d4T in patients with other treatment options, such as naive patients.




  
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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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