Switching from nelfinavir-based HAART to atazanavir (Reyataz) returns lipids to pre-treatment levels after three months and maintains viral suppression for at least 36 weeks after the switch, according to the results of a Bristol-Myers Squibb-sponsored study published in the June 1st issue of The Journal of Acquired Immune Deficiency Syndromes.
BMS-AI424-008 was a randomised, controlled, dose-blinded trial of two doses of atazanavir (400mg or 600mg once daily) versus 1250mg nelfinavir twice daily in treatment-naïve patients. All participants also received 150mg 3TC (lamivudine) and either 30mg or 40mg d4T (stavudine) twice daily, depending on body weight. Patients who had viral loads of below 10,000 copies/ml after at least 48 weeks were eligible to switch to BMS-AI424-044, a rollover/crossover study designed to assess the longer-term efficacy and safety of atazanavir, as well as the virological, immunological and lipid effects of switching from nelfinavir to atazanavir. Patients from the nelfinavir arm were switched to 400 mg atazanavir once daily, while the remaining arms continued with the same dose of atazanavir. The median cumulative time on therapy in both studies was approximately 108 weeks (>72 weeks in 008 and >36 weeks in 044).
All three arms had similar baseline characteristics, with a mean age of 37 years, 37% females, 53% Caucasians, a median viral load of 1.73 log10 copies/ml and a median CD4 count of 495 cells/mm3. After 24 weeks of rollover/crossover, 83% of individuals in the atazanavir 400mg arm, 85% of individuals in the atazanavir 600mg arm, and 87% of individuals in the nelfinavir-to-atazanavir switch arm had HIV viral load measurements below 400 copies/ml. The percentage with viral loads below 50 copies/ml was 60%, 56% and 60% in the three arms, respectively.
In all arms, across both studies, the percentage of individuals with viral load measurements below 400 or 50 copies/ml either remained stable or increased by week 108, compared with week 48. Mean CD4 counts at week 24 were also comparable across all three groups, suggesting that both doses of atazanavir and switching from nelfinavir to atazanavir effectively control viral load and increase CD4 cell counts for two years or more in the majority of the individuals on treatment.
Total cholesterol, fasting LDL and fasting triglyceride remained at levels consistent with the National Cholesterol Education Programme (NCEP) guidelines for the majority of those on either dose of atazanavir after 24 weeks of the rollover study. Interestingly, those who switched from nelfinavir to atazanavir had statistically significant reductions in total cholesterol (-16%; p
There were some discontinuations during the crossover/rollover study, including four individuals who withdrew from the 400mg atazanavir arm due to treatment failure/lack of efficacy, compared with none in either of the other arms. Adverse events were comparable across all three arms. The most frequent lab abnormality was grade 3 (2.6 - 5 times the upper limit of normal) or grade 4 (>5 times the upper limit of normal) elevations in total bilirubin, predominantly the indirect, unconjugated type associated with jaundice, although the elevations were asymptomatic and no-one stopped therapy.
The bilirubin elevations were seen more often in the individuals in the two atazanavir arms (400mg, 26%; 600mg, 44%) than in those who switched (13%). It makes sense, then, that jaundice was reported more frequently in the 600mg atazanavir arm than the 400mg atazanavir arm (22% versus 13%). Grade 4 bilirubin levels were seen only transiently, and only in five individuals, although three of the four receiving 600mg atazanavir reduced their dose to 400mg.
Unboosted atazanavir has not yet been granted a European license, and is currently only approved in the EU for once daily dosing as two capsules with food, together with a single ritonavir capsule (300mg/100mg). The US-approved dose is 400mg once daily without any restrictions on its use. The results of this study may well persuade the European Agency for the Evaluation of Medicinal Products to approve atazanavir to be dosed without ritonavir, since it shows that atazanavir continues to have good long-term results, particularly regarding lipid levels.
Although it is unknown exactly why atazanavir does not raise lipid levels like other currently approved protease inhibitors (PIs), the authors hypothesise that it may be because the drug doesn’t interfere with triglyceride production in the liver as strongly as ritonavir or nelfinavir, and/or because it interferes less with lipogenesis and proteasome function than other PIs.
Atazanavir is also a competitive inhibitor of the uridine diphosphate-glucoronosyl transferase 1A1 enzyme that can lead to elevations in unconjugated bilirubin in a significant number of individuals. The authors note, however, that “these elevations were asymptomatic, reversible, and not associated with hepatotoxicity,” concluding that “atazanavir is a potent, safe and effective PI for the long-term treatment of HIV.”
Further information on this website
Can atazanavir reverse body fat changes? - news story
Atazanavir, once daily protease inhibitor, now available in UK - news story
Atazanavir - overview of the drug
Wood R et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr 36: 684 - 692, 2004.