Treatment break of at least six months needed before improvement in mitochondrial function

Anti-HIV therapy needs to be interrupted for at least six months before the mitochondrial content of immune system cells increases from baseline levels, Italian researchers have found. In a study published in the October 14^th edition of AIDS the investigators found that mitochondrial DNA in CD8 cells increased significantly in the first year of a break from antiretroviral treatment, but that the increase only started six months after treatment was interrupted.

“This study is the first to show that mitochondrial DNA content increases in CD8 lymphocytes in individuals who discontinue HAART, but this process is not immediate”, write the investigators.

Mitochrondria carry energy in cells.Treatment with anti-HIV drugs, particularly some from the nucleoside analogue (NRTI) class have been associated with damage to mitochondria in nerve and fat cells, leading to a variety of side-effects including lactic acidosis, peripheral neuropathy and body fat changes. It is also known that HIV itself can affect mitochondria, and it is thought that the damage which HIV infection can cause to mitochondria can predispose HIV-positive patients to the mitochondrial toxicities which NRTIs can cause.

Altering HIV treatment regimens and structured treatment interruptions have been explored as ways of controlling the side-effects associated with mitochondrial toxicity.

Between late 2001 and the end of 2003 a total of 30 HIV-positive individuals who had a CD4 cell count of at least 500 cells/mm³, and who had been taking potent antiretroviral therapy for at least a year, were recruited by investigators in Italy to determine the impact of a CD4 cell-guided treatment interruption on mitochondrial DNA in CD4 and CD8 cells.

At the time of treatment discontinuation, the patients had a median CD4 cell count of 702 cells/mm³ and 21 (70%) had a viral load below 50 copies/ml. The median age of the patients was 41 years, and the median duration of anti-HIV therapy before the treatment break was started was 107 months. Treatment was stopped for a median of eleven months.

At baseline, and during the break from treatment, mitochondrial DNA content was analysed in highly purified, platelet free CD4 and CD8 cells. Taking a break from treatment did not have any impact on the level of mitochondrial DNA in CD4 cells. However, levels of mitochondria in the DNA of CD8 cells did increase significantly during the first year of the treatment break (p = 0.0018).

The investigators emphasise that this increase only occurred after treatment had been interrupted for at least six months (increase in first six months of treatment break, 5.12 copies/cell [p = 0.3] versus 27 copies/cell from months six to twelve [p

Increases in mitochondrial DNA levels were most marked in patients who had the largest increases in their CD4 cell count during treatment (0.34 copies/cell for each CD4 cell increase, p = 0.03).

No association was found between CD4 and CD8 cell counts, viral load and the lowest ever CD4 cell count before anti-HIV therapy was started and changes in mitochondrial DNA during the treatment break. The investigators therefore suggest, “our results...reflect a recovery from drug-related toxicity.”