February 27, 2002
Simple combinations for the treatment of HIV have been a holy grail for years, and are being furiously researched by many investigators and pharmaceuticals. Recent advances have been manifold, resulting in regimens with lower pill count, lower dosing frequency and lower side effect profile. The makers of the triple nucleoside combination (AZT/3TC and abacavir), GlaxoSmithKline, have taken this to one extreme in the triple co-formulation, Trizivir.
Previous research studies from the Amsterdam-based research group led by Dr. Joep Lange have suggested that four- or even five-drug combinations may offer increased potency over their three-drug brethren. The CHARM study, presented in poster form today, addressed Trizivir-based, four- or five-drug regimens that added either nevirapine (NVP; Viramune) or hydroxyurea (HU).
This was a prospective, randomized international study (Europe, South Africa) that enrolled 229 patients. Patients were also randomized to receive prednisolone (dose not stated). The study concluded that the addition of hydroxyurea to AZT/3TC/ABC added no potency and resulted in a slower increase in CD4 cell counts. Adding nevirapine was stated to increase the rate of reaching undetectable viral loads, but only by three days (165 vs. 168 days; median). Both the hydroxyurea and nevirapine addition also resulted in a statistically significant increase in treatment-limiting complications. Interestingly, there were more reports of abacavir hypersensitivity among persons receiving NVP than people receiving only the add.
The study has significant limitations. First, while the authors concluded that there was no improvement in antiviral activity with hydroxyurea, there appears to be a statistically significant improvement in the data provided. Second, analysis of effects on CD4 total counts is confounded by the competing suppression of bone marrow by hydroxyurea and stimulation of white blood cell counts by prednisone; I would have liked to have seen better accounting of CD4 counts and percentages; perhaps an assessment of CD8 counts and percentages, too.
It is difficult to draw clinically relevant conclusions from this study; though one is tempted to conclude that the addition of nevirapine to Trizivir doesn't increase either virologic potency or immune reconstitution in a dramatic way. In both cases, addition of the fourth drug appears to only increase the pill burden and side effect profile, leading to more treatment discontinuations. Perhaps more is better; this study would argue against this point with regard to simple, three-drug treatments.
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