Atanazavir and saquinavir in salvage therapy: reduced effect on lipids shown in pilot study

1 July 2003. Related: Antiretrovirals.

Simon Collins HIV i-Base

Atazanavir is the most recently licensed protease inhibitor in the US, and is already available in an expanded access programme in the UK, with full European licensing expected shortly. This pilot dose-ranging atazanavir study shows the potential for atazanavir to boost levels of saquinavir to allow once daily dosing of saquinavir (at 1200mg/day). In addition to reduced dosing, similar efficacy and reduced side effects were obtained compared to the more established twice-daily use of ritonavir/saquinavir (400mg/400mg).

This multinational, randomised 48-week study presented 24-week data at the 41st ICAAC 18 months ago and 48-week results are published in the June issue of AIDS. The study randomised 85 treatment experienced adults from North America, South America and Europe (approx: mean age 39 years, 20% women and 65% white) whose previously undetectable viral load had rebounded >1000 copies/ml. Previous use of ritonavir or saquinavir for >30 days was exclusion criteria, as was use of >2 nucleosides or >1 NNRTI. This was an experienced but not highly experienced group.

Primary endpoints were to assess safety and tolerability of 400mg and 600mg doses of ATZ, each with 1200mg saquinavir plus two physician-selected nucleosides. Secondary endpoints included virological and immunological comparisons of the three arms. Only ATZ dose was blinded and Fortovase formulation of saquinavir was used throughout.

Although fairly well matched, the 400mg ATZ group had statistically a higher proportion of subjects with baseline viral load >30,000 copies/ml

Toxicity management included ensuring that episodes of grade 4 hyperbilirubinemia (bilirubin >5-10xULN) resulted in discontinuation of ATZ until levels of grade 3 or less were reached, and ATZ was then restarted at dose reduced by 200mg. An elevation to >10xULN resulted in permanent discontinuation.

Baseline characteristics and results are shown below:

Virological response, defined as either viral load reduction >1log or viral load <400 copies at week 48 (neither of which is particularly associated with durable benefit) was achieved by 41%, 29% and 35% of the ATZ 400mg, ATZ 600mg and RTV groups respectively, and none of the efficacy differences between the arms achieved significance (P=NS).

Lipid profiles improved on the atazanavir arms with total cholesterol, fasting LDL-cholesterol, and fasting triglyceride levels were similar or below baseline levels at 48 weeks. In the ritonavir/saquinavir treatment group clinically significant increases in these parameters were observed of +10%, +23% and +95% respectively.

Reference:

Haas DW, Zala C, Schrader S et al – Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 2003; 17(9):1339-1349

Comment

The patient population in this study were those in early treatment failure who had ability to put together a supported salvage regimen. NRTIs were selected based on being </=2.5 times EC50, which may not have been sufficiently sensitive (for d4T and ddI). The lack of adverse effects on lipid profiles clarifies one of the circumstances where this may be a preferred option, but there are concerns about the potency of this combination.

The most stringent comparison for efficacy is likely to be lopinavir/r-based combinations but early results of the BMS-045 study comparing atazanavir+ritonavir, atazanavir+saquinavir and lopinavir/r in more highly treated individuals showed the saquinavir arm to be virologically significantly less effective.

Phase 3 studies of atazanavir used 400mg doses for treatment naïve patients and atazanavir boosted by ritonavir (300/100mg) for treatment experienced patients.

Use of Invirase may produce better absorption, fewer side effects and adherence benefits (smaller capsules, no refrigeration) over Fortovase. The study did not collect or present data on drug absorption, but as with all combinations not formally studied in larger trials that involve drug interactions for which there are little data, confirming adequate drug trough levels using TDM on an individual patient basis is both recommended and readily available in the UK.

This was highlighted by the results from the a sub-study of the French Puzzle-2 trial that showed that drug levels of atazanavir and ritonavir dropped when treatment experienced patients using atazanavir/ritonavir-based regimens added tenofovir to their combination.