Ritonavir reduces virological failure and resistance in treatment naive patients treated with atazanavir
3 August 2006. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 15 Sitges 2006.
Simon Collins, HIV i-Base
Atazanavir was licensed in the US in June 2003 as a treatment for naive or experienced patients, and in Europe it was licensed in March 2004 for use in treatment-experienced patients only. In practice, especially when once-daily combinations are important, and when there is a caution against using efavirenz, atazanavir is becoming used off-label in the UK as first line treatment. Its lack of effect on lipids and good tolerability, also contributes to this use.
The licensing indication is further complicated by recommendations for ritonavir boosting. Although the US product specifications specify that a daily dose of 300mg ritonavir, boosted with 100mg ritonavir is the preferred dose, unboosted atazanavir (400mg once-daily) is still included in recommendations. In Europe atazanavir was approved as a boosted PI.
At the Resistance Workshop, Donna McGrath and colleagues from Bristol-Myers Squibb presented an evaluation of resistance in treatment naive patients randomised to either boosted (ATV300/RTV100mg; n=95) or unboosted (ATV400; n=105) atazanavir, as part of first line therapy. Background nucleosides for both regimens were 3TC plus d4T extended release (once-daily).
Virological failure occurred in approximately 10% of patients using unboosted atazanavir compared to 3% in patients using ritonavir boosting, and is detailed in Table 1.
Table 1: Virological response and resistance in patients receiving atanazavir +/- ritonavir
| ATV 400mg | ATV 300mg/RTV 100mg | |
|---|---|---|
| N | 105 | 95 |
| Virological failure | 10 (10%) | 3 (3%) |
| Never supressed & on-study wk 48 | 2/10 | 0/3 |
| Viral rebound | 6/10 | 3/3 |
| D/c due to poor VL response | 2/10 | 0/3 |
| No. of isolates for Rx testing | 8/10 | 2/3 |
| New emergent mutations | 4/8 | 0/2 |
| PI: I50L, I50I/L | 3/8 | 0/2 |
| PI: 63A/P/S, 63P, 63P/S | 1/8 | 0/2 |
| RT: M184V at failure | 7/8 | 1/2 |
New PI resistance was seen in 4/8 patients (3 with I50L or mixed I50I/L, with emergent E34E/Q, and one with G73G/S plus T74T/A substitutions, respectively) vs 0/2 patients in the unboosted vs boosted groups respectively. Baseline genotype showed 1 to 3 protease substitutions at L10, K20, M36, L63 and A71 in all patients who subsequently failed treatment. No data was provided for patients who successfully responded to treatment.
Only one of the failing patients (on unboosted atazanavir) showed phenotypic resistance (28-fold change) but retained phenotypic sensitivity to other PIs. The other 7 patients not using ritonavir, also retained phenotypic sensitivity to other PIs. The M184V substitution and phenotypic resistance to 3TC developed in 1/2 and 7/8 patients whose treatment failed in the ATV300mg/RTV100mg and ATV400mg groups respectively.
The study concluded that these data suggested a protective benefit from ritonavir boosting for naive patients in both reduced risk of virological failure and that, if failure occurs, a reduced risk of resistant mutations.
Reference:
McGrath D et al. Evaluation of resistance patterns in treatment-naive subjects with virological failure on atazanavir- or atazanavir/ritonavir containing regimens. XV International Drug Resistance Workshop, 13-17 June 2006, Sitges, Spain Abstract 87.