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Atazanavir+saquinavir once daily vs RTV/SQV twice daily
Report from Jules Levin
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David Haas (University of Vanderbilt) and Bristol Myers reported on a 48-week study BMS-009 which compared the safety and efficacy of atazanavir and saquinavir taken once per day with ritonavir+saquinavir taken twice per day. This study was conducted in patients with prior PI experience, and looks at safety, tolerability, and antiviral activity.
Atazanavir (TAZ) is a protease inhibitor in phase 3 human studies that is taken once per day and has a low pill burden (2 capsules). In early small preliminary studies, atazanavir did not raise cholesterl and triglycerides and appeared about equal in efficacy to nelfinavir. From early in vitro (test tube) studies, the TAZ resistance profile is favorable. Early in vitro resistance studies suggest that TAZ ought to reduce viral load for personıs with limited PI resistance but not for patientıs with extensive PI resistance to for example 5 protease inhibitors.
65 patients were randomized equally to 1 of 3 treatment regimens. Each regimen included 2 NRTIs:
- atazanavir 400 mg once per day + saquinavir 1200 mg once per day
- atazanavir 600 mg once daily + saquinavir 1200 mg once daily
- ritonavir 400 mg + saquinavir 400 mg twice daily
Age was about 38 years across all 3 arms; There were 22% female in RTV/SQV arm, 32% in 600mg TAZ arm, and 18% female in 400 mg TAZ arm. About 65% of patients across all 3 arms were white. IVDUs: 9% in RTV/SQV, and 18% in each of the TAZ arms. AIDS diagnosis: 13% in RTV/SQV, 25% in 600 mg TAZ, 32% in 400mg TAZ. Average viral load was about the same in all 3 study groups: 31,000 copies/ml in the TAZ 400mg arm, 14,000 in the 600mg TAZ arm, and 14,000 in RTV/SQV Arm. Average CD4 count was about the same in all 3 study groups: 290-330.
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Baseline values were about the same in each of the 3 study groups and the values were not high. So, this in general was a group of patients that did not have high lipids.
PRIOR PI & NNRTI EXPERIENCE OF PATIENTS
About 86% of all study patients, equal in each arm, had prior PI experience. In the 400mg TAZ arm, 50% had used indinavir and 38% nelfinavir. In the 600mg TAZ arm, 26% used indinavir and 67% nelfinavir. In the RTV/SQV arm, 65% used nelfinavir and 22% indinavir.
19% used NNRTIs previuosly in the 400mg TAZ arm; 22% in the 600mg TAZ arm; and 30% in the RTV/SQV arm.
RESULTS
DISCONTINUATIONS
There were more discontinuations in the RTV/SQV group (52% vs 24% in 400mg & 29% in 600mg TAZ groups). There were more discontinuations due to adverse events in the RTV/SQV arm: 30% vs 9-11% in the 2 TAZ groups. Discontinuations related to the study drugs were higher in the RTV/SQV arm: 26% vs 6-9%.
The adverse events experienced in the RTV arm were: 2 cardiovascular (presumably lipid elevations), 1 headache, 1 diarrhea, 2 abdomen pain, 1 hepatitis and 1 urogenital system. In the 400 mg TAZ arm only 2 adverse events were reported: 1 fever, 1 dermatrophytosis. In the 600 mg TAZ arm, there was 1 fever, 1 vomiting, 1 enteritis, 1 hypothyroidism, 1 peripheral nuerology (probably neuropathy), and 1 sex drive decrease.
At week 48, the viral load reductions were about 1.7 log in the RTV arm (n=11), -1.5 log in the 400 mg TAZ arm (n=22), and -1.1 log in the TAZ 600mg arm (n=18). Not much diference between the arms.
About 40% had >1 log viral load decrease or <400 copies/ml in the RTV/SQV arm (n=23). This compared to about 30% in the 600mg arm (n=28) and 45% in the TAZ 400 mg arm (n=34). These are rough estimates based on visual observation of the graphs shown by Haas in his slide show.
CD4 increase was about 150 in RTV group, 100 in 400 TAZ group, and 50 in 600 TAZ group.
LIPIDS AT WEEK 48
The mean total cholesterol increased in the RTV group by 10-15 mg/dL; and baseline total cholesterol was 200. Total cholesterol remained the same or went down a little in the 2 TAZ groups.
The mean fasting LDL (bad cholesterol) increased in the RTV group by about 20 mg/dL, and at baseline the value was 122. Again, fasting LDL did not increase in the 2 TAZ groups.
The mean fasting triglycerides increased by about 90 mg/dL in the RTV group, from the baseline value of 190. But triglycerides remained the same as it was at baseline for the TAZ groups.
SELECTED LAB ABNORMALITIES
Grade 1-4 bilirubin increases were seen in both TAZ groups with higher incidence in the 600mg dose group. The percent of grade 3/4 bilirubin in the 600 mg arm was 33% and 44% for grade 1-4. This compared to 16% grade 3/4 events in the 400 mg TAZ arm, and 22% grade 1-4 events. In the RTV/SQV arm there were 9% grade 3/4 events and 13% grade 1-4.
The incidence of grade 1-4 and 3/4 increases in ALT and AST (liver enzymes) were higher in the RTV and 600mg TAZ arms than in the 400mg TAZ arms. The incidence of grade 1-4 and 3/4 AST & ALT elevations in the 400mg TAZ arm was 3%. In the 600mg arm the range was 4%-11%; and in the RTV arm the range of incidence was 9%-13%. Increased GGT incidence was about the same in the 3 groups. Haas concluded that the bilirubin elevations were isolated and not associated with ALT, AST & GGT elevations. Switching failing regimen to TAZ/SQV was associated with superior lipid profiles compared to RTV/SQV.
Larger phase 3 studies of atazanavir are ongoing comparing it to efavirenz and Kaletra. The study reported above is small and we need to see the results from the larger phase 3 studies to confirm the observations seen so far with TAZ. But, so far it does appear promising that we might have a once per day PI with low pill burden that nay not increase cholesterol and triglycerides. This might have positive implications for risk of heart disease and perhaps lipodystrophy, if the cause of lipodystrophy is associated with elevations in cholesterol & triglycerides. Insulin resistance and abnormalities in glucose handling by the body may also play a role in causing lipodystrophy. As well, immune dysfunction caused by HIV and immune reconstitution from HAART may play roles in causing lipodystrophy.
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