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Switch Study From Nelfinavir to Atazanavir
Reported by Jules Levin
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Rob Murphy from Northwestern University reported 12 weeks data from a study in which patients on nelfinavir switched to atazanavir to study the differences in cholesterol and triglycerides. Atazanavir is a protease inhibitor taken 2 pills once daily. Studies of about 1 year in length have shown that this drug does not appear to cause abnormalities in cholesterol and triglycerides. A study reported at this Workshop showed that atazanavir did not raise fasting insulin or glucose after 24 weeks of treatment. Atazanavir appears to have benefit for patients with up to just a few PI-related mutations but with additional mutations atazanavir does not appear to be very active. So it does not appear to be a deep salvage PI like tipranavir promises to be but the appeal of atazanavir appears to lie in its effect on lipids and glucose, and hopefully on the potential premature risk for heart disease.
Murphy reported on BMS A1424-044, a study to determine improvement in total cholesterol for subjects who switched from nelfinavir/d4T/3TC (from BMS A1424-008) to atazanavir (ATV) 400 mg/d4T/3TC. BMS A1424-008 is a 48 week randomized blinded trial of 2 doses of ATV (400mg or 600mg) plus d4T/3TC vs nelfinavir 1250mg every 12 hours plus d4T/3TC. In this study nelfinavir and ATV showed comparable antiviral efficacy. But the patients receiving atazanavir had slight increases in lipids and the patients receiving nelfinavir had higher increases. After 48 weeks on study drugs, patients receiving ATV had 5-6% increases in total cholesterol and patients on nelfinavir had on average 24% increases in total cholesterol. LDL-C, the bad cholesterol increased on average 5-7% for patients taking ATV and 23% for patients taking nelfinavir. Similarly, triglycerides also increased about 7% on average for patients taking ATV and 49% for patients on nelfinavir.
At the ICAAC meeting in a few days in San Diego, 48 week data will be reported on a large phase III study comparing efavirenz and ATV, both in combination with combivir. Yesterday, at the Lipodystrophy Workshop Michael Sension reported preliminary 24 week data on glucose as well as cholesterol and triglycerides responses for study patients in this study. That report can be read at
www.natap.org/2002/lipoWorkshop/day2.htm
RESULTS
63 patients were enrolled and treated in the switch study. Their average age was 37; 59% male; 51% white; HIV viral load 1.73 log; 70% had <400 copies; CD4s were on average 541. 3 patients (5%) of the 63 discontinued ATV after the switch from nelfinavir: 2 due to adverse events not mentioned by Murphy.
Murphy reported that the average total cholesterol was 213 when patients switched from nelfinavir and after 12 weeks on ATV therapy total cholesterol was 175 mg/dL. Fasting LDL-C (bad cholesterol) was 138 mg/dL and 104 after 12 weeks on ATV. HDL-C (good cholesterol) was 46 mg/dL when switching from nelfinavir and 48 after 12 weeks on ATV. Fasting triglycerides were 156 when switching off nelfinavir and 109 after 12 weeks on ATV. About 30% or perhaps more of patients on nelfinavir had >240 mg/dL total cholesterol, which is considered high by NCEP Guidelines, and about 10% had >240 after 12 weeks on ATV. Similarly, about 55% of patients had >130 mg/dL LDL-C, considered high by NCEP Guidelines, before switching off nelfinavir and about 20% had <130 after 12 weeks on ATV. 3 patients of the 63 who switched were also on statins as treatment for high lipids.
Adverse Events
4 patients (6%) reported lipodystrophy but we don't know the cause since the patients were on nelfinavir first. 2 reported diarrhea. 5 patients reported rash (8%). And 3 patients reported jaundice. In speaking with Murphy I think he told me this passes quickly and is not serious.
42 (67%) of patients experienced elevated total bilirubin. 6 patients (10%) experienced grade 3/4 lab abnormalities in bilirubin. Murphy reported that about 80% of study patients originally randomized to ATV experienced some elevation in total bilirubin, and about 23% of patients taking the 400 mg dose of ATV had grade 3/4 elevations of total bilirubin. I'm not sure but it did not appear as though there were discontinuations due to this. There were no grade 3/4 LFT elevations. Murphy reported there was no loss of virologic suppression during the 12 weeks follow-up. He also commented that grade 3/4 elevations in total bilirubin were transient. He concluded that lipid improvements seen in this study may ultimately translate into reduced risk for cardiovascular disease.
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