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TRIZAL: a randomized comparative study of switch to Trixivir compared to HAART in patients successfully treated with HAART
Reported by Jules Levin
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Christine Katlama of France reported on this open-label randomized study of patients on a HAART regimen who were randomized to stay on their HAART regimen or switch to Trizivir (one pill of abacavir, 3TC, AZT twice daily). Patients had to be <400 copies/ml for 6 months or longer on their current regimen and <50 copies/ml at screening for this study. The duration of the study was 48 weeks and the primary endpoint of the study was treatment failure defined as virologic failure (2 consecutive viral loads >400 c/ml) or premature discontinuation of the randomized treatment by 48 weeks.
A brief summary of the study: fasting cholesterol and triglycerides decreased more for the patients who switched to TZV compared to those who stayed on HAART. Although it wasnıt looked at in this study results from other studies have suggested that glucose may not increase or may have less of tendency to increase on TZV compared to being on a PI regimen. Patients reported TZV was more convenient and easier to take and adhere to. There were, however, 5 viral rebounds among the patients who switched to TZV compared to none who stayed on HAART. The study authors said 2 of these 5 resuppressed their viral load within the 48 weeks of the study while staying on their TZV regimen. And a third patient resuppressed their viral load by adding efavirenz. The transient increases could be due to underlying NRTI resistance and could lead to earlier viral rebound over time. Other studies have shown that viral rebound can occur after making the switch to an abacavir regimen, although in a small number of patients. This appears to be a particular concern if the patient had prior NRTI experience and resistance. The presence of AZT/d4T and/or 3TC mutations may be a risk for viral rebound after switching to TZV or an abacavir triple NRTI regimen.
106 patients were randomized to the Trizivir (TZV) arm and 103 to comtinue their current regimen. About 80% were men, age 38 yrs, median CD4 was about 490, median triglycerides were 1.6 mmol/l in both arms and cholesterol was 5.9 mmol/l in the TZV arm and 5.6 mmol/l in the HAART arm. 74% of patients were Classification A by the CDC (less advanced HIV), and 12% B, 15% C.
The information or data on the study participants prior ART is interesting. Patients who switched to TAZ had 27 (8-129 range) prior months on ART. Patients who stayed on HAART regimen had an average of 24 (8-44) prior months on ART. About 62% in each arm were last on (before the study) a PI+2 NRTI regimen. 19% were on a NNRTI+2 NRTI regimen. But interestingly, 17% in both arms were previously on a triple NRTI regimen. In other words, 17% had <50 c/ml on 3 NRTIs and then switched to TZV. There is no reason for them not to remain undetectable. This could favor viral outcome in the TZV arm. Of note, was the prior ART experience among the patients. 15% in each arm had prior mono- or dual NRTI therapy. But, in the TZV arm 13% had prior dual NRTIs and 2% had prior monotherapy. While in the HAART regimen 8% had prior dual NRTIs and 7% had prior monotherapy.
Katlama reported 22% in each arm discontinued before the 48-week study was completed. 16 in each arm discontinued due to adverse events. Premature study drug discontinuations occurred in 18 taking TZV (10 patients [11%] with possible hypersensitivity), compared to 22 who discontinued from HAART. 5 patients in the TZV arm switched therapy due to a viral load rebound. While none of the patients in the HAART arm had a viral load rebound. Katlama said 3 of the 5 viral failures on TZV regained undetectable viral load: 2 remained on TZV (presumably viral load went down on the same regimenperhaps transient viral load increases or lab variance) and 1 added efavirenz to TZV. Nonetheless, the viral load increases, even if transient, suggests to me that perhaps NRTI resistance may be present and causing the transient increase; and perhaps over time these patients may tend to have viral rebound sooner. Katlama reported 1 of the 5 patients had the 3TC 184 mutation and 3 AZT (67, 210, 215) mutations. The TZV viral load failures could be due to pre-existing NRTI resistance. In previously reported studies of patients with a viral rebound after switching to an abacavir-based triple NRTI regimen from a fully suppressive HAART regimen, NRTI resistance was found and the viral rebound may have been due to the NRTI resistance. Thus, for patients with prior NRTI experience and resistance switching to a TZV can lead to viral rebound.
At week 48, 75% had <50 copies/ml in the TZV arm and 69% in the HAART arm (in an ITT analysis). 4% in the TZV regimen reported lipodystrophy and 9% in the HAART arm. This difference may not be significant.
Statistically significant (p<0.001) higher reductions in average fasting cholesterol occurred by week 48 in the TZV group compared to the HAART group (-0.80 mmol/l vs 0.44 mmol/l). But, cholesterol fell in the HAART arm as well as in the TZV arm. Fasting triglycerides (TG) fell in the TZV arm (-0.17 mmol/l, while TG in the HAART arm remained about the same (+0.01 mmol/l).
Adherence reported by the patients was better in the TZV arm, although the difference was not statistically significant (74% vs 62%, p=0.07). Interestingly, adherence here was defined as self-reported 100% intake of ARTs by completed questionaires. Patients taking TZV reported they found TZV more convenient to take compared to the patients taking HAART (p<0.001), and the TZV patients reported fewer treatment-related barriers to adherence than those on HAART (p<0.01).
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