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Conference
"Learning to live with ART : Managing long-term tolerability" Dr. Mina John (biography) English - 2003-04-11 - 53 minutes
Summary : Since the beginning of HAART use, there have been some well-documented benefits in terms of morbidity and mortality. In the early days of HAART there was considerable anxiety over what the long-term consequences of metabolic toxicities might be, and whether these would abrogate the benefits of HAART. Recently, however, we have been gaining a clearer understanding about these questions, notably in pathogenesis findings, and how we can circumvent these toxicities. Also there have been a number of newer drugs coming out, which incorporate drug toxicity considerations early on in drug development. Here we will focus on class-specific metabolic abnormalities, and drug-specific effects within each class. NRTIs are associated with a higher risk of lipodystrophy/SC fat wasting, and within this class there is a hierarchy of conferred risk with d4T carrying the highest risk, followed by ZDV and lastly 3TC or ABC. PI-associated abnormalities include insulin resistance, increased triglycerides, increased LDL, VLDL, sHDL, and truncal obesity, and even within this class, different drugs are being found to have varying effects. Some recent pathogenesis findings will also be presented to further validate some of these claims.
Learning objectives : The participant will learn about class- and drug-specific risks for metabolic abnormalities in HAART, and will be exposed to new data reflecting the pathogenesis of some of these abnormalities:
- Lipodystrophy/ sub-cutaneous fat wasting is predominantly associated with NRTI use, with d4T conferring the highest risk, followed by ZDV, and then 3TC and ABC.
- PI-associated abnormalities include insulin resistance, increased triglycerides, increased LDL, VLDL, sHDL, and truncal obesity
- Research now reflects the validity hypothesis that NRTI (stavudine) therapy does cause mitochondrial depletion (Nolan D et al, 4th Lipo Workshopo, San Diego, CA), and subsequent cellular and tissue toxicity (fat wasting or fat loss) over time.
- The MITOX Study showed that a switch from d4T to ABC significantly improved fat wasting. These results are supported by the Tarheel (d4T switched to ABC or ZDV) and Perth Switching (d4T and/or PI switched to Combivir/ABC) studies.
- Switch studies show that this stavudine-induced mitochondrial depletion can be improved with ZDV or ABC (Nolan D et al, 4th Lipo Workshop, San Diego, CA).
- The risk of hyperlactatemia was found to be higher with d4T or ddI use compared to ABC use (John M. Curr Opin Inf Dis. 2002; 15:23-29).
- Certain host susceptibility factors exist predisposing to lipoatrophy, e.g. gender, race, and a TNF alpha polymorphism, TNF alpha G238A.
- NFV is associated with higher rates of hypercholesterolemia and hypertriglyceridemia compared to ABC, and NFV seems to have a synergistic effect with d4T in raising triglycerides (Kumar P et al. 9th CROI. 2002:abstract 33).
- The D:A:D Study showed that there was a 27% increased rate of MI per year over the first 7 years of HAART therapy.
- Switch studies from PI to NVP or ABC show favourable metabolic/insulin sensitivity and/or virologic effects, whereas an improvement in fat wasting was only seen in the switch from an NNRTI or PI-based regimen to Trizivir (TRIZAL Study).
Bibliographic references : John M, Mallal S. 2002. Hyperlactatemia Syndromes in People with HIV Infection. Curr Opin Infect Dis.15(1):23-9
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