Once-daily therapy with the dual protease inhibitor (PI) combination of atazanavir and saquinavir alongside two nucleosides is better tolerated and results in an improvement in lipid profiles in antiretroviral-experienced people with advanced HIV disease when compared with twice daily ritonavir and saquinavir in combination with two nucleosides, according to the results of a small pilot 48 week study published in the current issue of AIDS. Preliminary 24 week results of the same study were reported as a late breaker at ICAAC, Chicago in 2001.
Whilst this is good news for those people who need a salvage regimen but are concerned about the increased cholesterol and triglyceride levels usually associated with PI-based HAART, the study was not large enough to detect a difference in efficacy between the two doses of atazanavir and ritonavir with saquinavir. In fact, more recent studies have suggested that atazanavir boosted with ritonavir is more effective than atazanavir and saquinavir, since resistance to atazanavir is likely in previously PI-treated patients. Balancing tolerability, side-effects and effectiveness continues to be a major sticking point in all HAART regimens, as noted in the latest BHIVA guidelines.
In this study, 85 PI-experienced patients (most had used indinavir and/or nelfinavir, and many had previously received ritonavir as their sole PI) failing their current therapy (but with more than 75 CD4s if they had no prior AIDS-defining illness or more than 100 CD4s if they had prior AIDS) were randomised to one of three arms: once daily 400 mg atazanavir plus 1200 mg saquinavir (soft gel capsules - SGC); once daily 600 mg atazanavir plus 1200 mg saquinavir SGC; and twice-daily ritonavir 400 mg plus 400 mg saquinavir SGC. Two nucleosides (to which the patients were phenotypically sensitive) were added to each regimen, most commonly stavudine (d4T) with didanosine (ddI) or lamivudine (3TC).
After 48 weeks, 41% (14 out of 34) of those on the 400 mg atazanavir regimen had a virological response to therapy - on average a viral load reduction of 1.44 log. This compared with the 29% (8 out of 28) on 600 mg atazanavir who responded to therapy - with an average viral load drop of 1.19 logs - and the 35% (8 out of 23) on the ritonavir regimen who responded to therapy with an average drop in viral load of 1.66 logs. However, since the number of people who were on therapy was so small, the difference was deemed not to be significant.
What the study did show, however, was that 52% of the people in the ritonavir arm discontinued therapy compared with 24% and 29% in the atazanavir 400 mg and 600 mg arms, respectively. Many dropped out because the therapy was not working for them (this was an open-label trial) but there was a significant difference in drop-out rates due to adverse events (26% in the ritonavir versus 12% and 11% respectively in the low and high dose atazanavir arms). Diarrhoea and nausea were more common in the ritonavir arm, although jaundice occurred only in the atazanavir arms. Interestingly, lipodystrophy was reported in two patients on 600 mg atazanavir and two patients on ritonavir, although no definition of lipodystrophy was given.
Where atazanavir really shone, however, was in blood lipid levels, notably triglycerides and LDL cholesterol. Whilst those in the ritonavir arm had a 93% increase in triglyceride levels and a 23.2% increase in fasting LDL cholesterol levels, those in the low and high dose atazanavir arms had reductions of 4.8% and 27.1% in triglycerides, respectively, and reductions of 0.6% and 6.7% in fasting LDL cholesterol, respectively. Total cholesterol was also improved in the atazanavir arms but there was no difference in HDL cholesterol.
The authors conclude that “the favorable effect of atazanavir plus saquinavir on plasma lipid profiles suggests that this combination may reduce the risk of future cardiovascular events in this population.”
Atazanavir is likely to be approved in the EU very soon, and is currently available on expanded-access. The drug received marketing approval in the United States on June 20th.
Further information on this site
Atazanavir in treatment-experienced people: boosted looks better
Atazanavir resistance: independent study finds high cross-resistance to atazanavir
Haas DW et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 17: 1339-1349, 2003.