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Conference
"Safeguarding the Future: Pharmacogenomics and the short and long term tolerability of abacavir/lamivudine" Dr. Simon Mallal (biography) English - 2005-11-19 - 39 minutes
(27 slides)
Summary : The combination of abacavir and lamivudine as a nucleoside backbone combines a favorable long-term safety and tolerability profile with limited short-term side effects, apart from abacavir hypersensitivity reactions (HSR). HSR is a well-characterized phenomenon typically occurring in some 4% to 8% of individuals in clinical studies, though lower and higher incidences have been observed, with a mean incidence across studies of around 5%. HSR occurs early, with a median time to onset of less than 2 weeks and with more than 90% of cases occurring within the first 6 weeks of abacavir exposure.
Accurate symptomatic diagnosis of HSR can be confounded by the variability of its clinical presentation, and by the overlap between common symptoms of HSR and clinical manifestations of immune restoration disease, other incurrent illnesses or drug side effects. Diagnostic precision of suspected HSR is materially assisted by the immunologically mediated nature of most if not all cases. Immunophenotyping by skin patch testing is a promising research approach to help differentiate true HSR from a confounded diagnosis, and has been shown to provide a positive signal for many months after an initial HSR event. Of particular interest, however, are data showing a strong genetic link with predisposition to immunologically-mediated abacavir hypersensitivity. The MHC class 1 allele HLA-B*5701 is strongly linked to patch test-positive cases of HSR, particularly in Caucasian populations, and may represent a potential means of prospective screening for propensity towards abacavir hypersensitivity. However, before routine HLA screening can be recommended, its utility will require careful and robust evaluation in diverse populations. Furthermore, it is well to consider that even a validated screening procedure will not necessarily eliminate abacavir HSR from the clinic, nor prevent the need for clinical vigilance. Clinical diagnosis must remain the basis of clinical decision making with respect to HSR.
For the majority of individuals who do not experience an abacavir HSR, data indicate very few short or long-term complications on abacavir/lamivudine. Neither drug displays obvious signature toxicities (other than HSR) and neither appears significantly linked to long-term issues such as cumulative mitochondrial toxicity or lipoatrophy. The extensive long-term safety and tolerability data on abacavir/lamivudine, and the fact that hypersensitivity to abacavir in a minority of individuals is the only significant short-term issue of note, make this combination a promising one for long-term administration.
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