Boosted fosamprenavir and atazanavir show comparable potency, tolerability in treatment-naive

Once daily dosing of fosamprenavir or atazanavir boosted with 100mg of ritonavir appear to be equally effective and tolerable in treatment-naive patients, according to interim 24-week results from a 48-week comparative study presented as a late breaker at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco on Friday.

The ALERT study is a 48-week ‘head-to-head’ comparison of two recently licensed protease inhibitors: fosamprenavir (Lexiva in the United States, Telzir in Europe) and atazanavir (Reyataz), each boosted with ritonavir and combined with a dual-nucleoside combination of tenofovir and emtricitabine (FTC). All study drugs were given once daily: tenofovir and FTC at the standard doses of 300mg and 200mg respectively. This study is testing a novel unlicensed once-daily dose of fosamprenavir: 1400mg, combined with 100mg of ritonavir (the current US product license requires 200mg of ritonavir); atazanavir was dose at 300mg once daily, with 100mg of ritonavir.

Kimberly Smith presented results of a 24-week planned interim analysis.

All 106 participants were treatment-naïve, mostly male, with a median baseline viral load of approximately 79,000 copies/ml (4.88 log), and a median CD4 cell count of 172 cells/mm³. Participants were evenly divided (53 each) between the fosamprenavir (‘FPV/r’) and atazanavir (‘ATV/r’) treatment arms. Seven discontinued before the 24th week (four in the fosamprenavir arm, three in the atazanavir arm).

At the end of the 24 weeks, virologic results were similar in both groups, with a high percentage of each group achieving undetectable viral load. Using a missing data equals failure, intent to treat analysis, 89% in each arm had viral load below 400 copies/ml at week 24, and 79% in the fosamprenavir group and 83% in the atazanavir group had viral load below 50 copies/ml.

Increases in CD4 counts were also similar: 126 cells/mm³ in the FPV/r group; 156 cells/mm³ in the ATV/r group. Increases in fasting plasma total cholesterol, LDL and HDL cholesterol were very modest and comparable, but triglycerides increased more substantially in the fosamprenavir arm (from 116mg/dL to 160mg/dL, compared to an increase of 6mg/dL in the atazanavir group).

One patient discontinued fosamprenavir after experiencing a grade 3 rash, and there were two discontinuations due to a protocol-defined decline in kidney function (as measured by glomerular filtration rate) of 25% below baseline or below 50ml/min. This decline in kidney function was attributed to tenofovir treatment, but investigator Kimberly Smith highlighted the fact that 61% of participants had abnormal renal function on entry to the trial, defined as a creatinine clearance between 50 and 90ml/min.

Forty-one per cent of the atazanavir group experienced grade 2-4 bilirubin elevations, although no patients discontinued treatment as a result of this toxicity. No bilirubin elevations were seen in the fosamprenavir group. No other significant differences in adverse events were noted. Diarrhoea occurred in 6% of fosamprenavir-treated patients and 2% of the atazanavir group.

Three participants experienced virologic failure. In the first case FTC resistance was detected after virologic rebound at week 20, coupled with protease inhibitor resistance mutations and a thirteen-fold loss of susceptibility to fosamprenavir. This patient was subsequently found to have already had fourfold amprenavir resistance at baseline, together with some NRTI resistance mutations.

In the second case virologic rebound occurred after week twelve, and tenofovir resistance (K65R mutation) was detected at week 24. No protease inhibitor resistance was detected. In the third case rebound occurred after week twelve, but no drug resistance mutations or loss of drug susceptibility could be detected at week 24.