Durban World AIDS Conference
July 9-14, Durban, South Africa

REPORT 29

Long-term complications in Durban: Mitochondrial toxicity: Reported by Kees Brinkman, MD, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

Although the special focus of this conference was not especially directed on treatment issues, such as long term toxicities, several reports were presented on mitochiondrial toxicity. Shortly, mitochondrial toxicity is an acquired decrease in mitochondrial function (mitochonria are an important element in cells) induced by NRTIs. This can result in several clinical syndromes like myopathy, neuropathy and lactic acidosis. Of special concern is the issue whether such a toxicity can lead to (irreversible?) damage to the developing child, if exposed to NRTIs during pregnancy

Lactate Levels

Harris et al. (Vancouver ñ Canada)  and Vrouenraets et al. (Amsterdam ñ The Netherlands), presented data on the relatively frequent (19 ñ 36%) occurrence of mildly elevated levels of lactic acid in NRTI treated patients. An increased risk was found for patients on d4T treatment. The significance of such a finding is not known so far and during the oral poster presentation it was emphasised that lactates below 5 mmol/L should not be used as an argument to change treatment in asymptomatic patients. Routine lactate measurements should therefore implemented with caution, to avoid unnecessary treatment alterations.

Lactate Levels During Exercise

Roge et al. (Copenhagen ñ Denmark) could not find an altered lactate production, nor an altered lactate normalisation in 6 patients with signs of lipoatrophy during exercise, compared to matched controls. On the other hand, Th–ni et al. (Montpellier ñ France), showed an impaired aerobic capacity in lipoatrophic patients during a similar experimental setting. This latter finding was a confirmation of an earlier report at the Salvage meeting in Chicago (2000) by Harris et al. (Vancouver ñ Canada), which showed a similar impaired aerobic metabolism in NRTI treated patients. Exercise testing seems to be an attractive opportunity to study metabolic abnormalities. It is unclear so far, whether patients (and controls) need to have a similar basic sporting-condition, to allow a fair comparison.

Mitochondrial Toxicity & Lipodystrophy

Regarding the possible role of mitochondrial toxicity in the induction of lipodystrophy syndrome, especially lipoatrophy, Mallal and Nolan (Perth ñ Australia) showed in the late breaker poster session on Thursday impressive electron microscopy pictures of adipose tissue, taken from patientís with clear symptoms of lipodystrophy. Both in patients treated with or without protease inhibitors (but always NRTIs), there were clear abnormalities in mitochondrial structure, together with an accumulation of lipid droplets (steatosis), compared with control specimens. Furthermore, there was an unexplained deposition of granular material on the inner aspect of the adipocyte membrane.

(comments from Jules Levin: in PI-experienced, Mallal concluded there appeared to be more severe abnormalities; see the additional report on this study containing more details).

Risk Factors for Lipodystrophy

In the oral session about risk factors for lipodystrophy, Bernasconi et al (Lugano ñ Switzerland) confirmed on behalf of the SWISS cohort (n=1379) earlier observations from other cohorts of an association between the development of lipoatrophy and the exposure to either d4T (OR 2.1) or d4T/ddI (OR 1.5). They furthermore showed a significant association between lipoatrophy and increased lactate levels, which was lacking in situation of fat accumulation.

(comments from Jules Levin: a number of studies have shown association of d4T with lipodystrophy but some researchers think these studies are difficult to interpret for several reasons including pre-treatment with AZT and/or other NRTIs. So, you're not certain what's causing lipodystrophy or of the contribution by d4T. Long-term prior NRTI use may contribute. Adding a PI to long-term prior NRTI use could also contribute, as well as more potent viral load suppression from HAART).

Mitochondrial toxicity & newborns

The issue of perinatally induced mitochondrial toxicity was addressed by several authors. Launay et al. (Creteil ñ France) reported 2 cases of transitory lactic acidosis in children with antiretroviral exposure around birth. Gabioni et al. (Turin ñ Italy) described a neonate with clear symptoms of mitochondrial disease with depletion of mitochondrial DNA, related to AZT exposure during pregancy. Chotpitayasunondh et al (Bangkok ñ Thailand) could not find any clinical case of mitochondrial dysfunction in a prospective study of 395 children (196 AZT exposed), and also other cohorts were unable to find serious toxicities during prevention studies of Mother to Child Transmission.