CROI: Once-daily boosted atazanavir comparable to twice-daily Kaletra in treatment-naive patients, with better lipid profile

Once-daily atazanavir (Reyataz) boosted with ritonavir is as potent as twice-daily Kaletra in treatment-naive individuals, and appears to be better tolerated with a favourable lipid profile, according to 48-week data from the multi-centre CASTLE study presented to the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston on Monday.

Study background

Two years ago, the 045 study, sponsored by atazanavir’s manufacturer, Bristol-Myers Squibb (BMS), had found that once-daily atazanavir boosted with low dose ritonavir was as effective as twice-daily Kaletra (lopinavir/ritonavir) at suppressing viral load over two years when combined with tenofovir (Viread) and an NRTI in treatment-experienced patients.

The 045 study also suggested that atazanavir was better tolerated than Kaletra, and resulted in a better lipid profile. However, there has been no head-to-head study of the two protease inhibitor regimens in treatment-naive individuals.

Last year, however, data presented at last year’s IAS Conference in Sydney showed that atazanavir with or without ritonavir boosting was found to be safe and effective over two years in treatment-naïve individuals. Nevertheless, it was ritonavir-boosted atazanavir that showed a trend towards a higher rate of viral suppression, fewer virological rebounds and less protease inhibitor or nucleoside analogue resistance.

The CASTLE study

In Monday morning’s session on new antiretrovirals and clinical trials, Jean-Michel Molina of Hospital St Louis, Paris, presented 48-week data from the CASTLE study. This randomised, open-label, multi-centre 96-week study, also supported by BMS, assessed the non-inferiority of once-daily atazanavir (300mg) boosted with once-daily 100mg ritonavir compared with Kaletra Participants received the older, capsule formulation of Kaletra for the first 48 weeks of the study and were switched to the tablet formulation at the 48-week point. Both arms also received once daily Truvada (tenofovir 300 mg/FTC 200 mg).

Although designed as a 96-week trial, the study’s primary endpoint was the proportion of study participants with a viral load below 50 copies/ml at week 48. Non-inferiority was assessed with a 10% margin. Confirmed virologic response was based on an intention to treat (ITT) analysis where non-completer equalled failure. Two other analyses - an on-treatment and an ITT time to loss of virologic response (TLOVR) were also performed as supportive analyses.

Of 883 participants originally randomised, 878 were treated (438 in the atazanavir/ritonavir arm, and 440 in the Kaletra arm). Both arms were evenly matched at baseline: median CD4 counts were 206 and 204 cells/mm³ in the atazanavir and Kaletra arms respectively, median viral load 5.01 and 4.98log₁₀ copies/ml, median age 34 and 36 years, hepatitis B and/or C co-infection, 14% and 12%. Thirty-one percent of the participants in both arms were female.

At 48 weeks, 78% of participants in the atazanavir/ritonavir arm achieved a viral load below 50 copies/ml, compared with 76% in the Kaletra arm. This was a non-statistically significant difference of 1.7% (95% confidence interval [CI], -3.8% to 7.1%). The supporting ITT-TLOVR and on-treatment analyses also failed to show a statistically significant difference in response.

Responses in the two arms were also similar in participants who began with higher and with lower viral loads. Of the 435 participants with HIV RNA levels ≥ 100,000 copies/ml at baseline, 82% in the atazanavir/ritonavir arm and 81% in the Kaletra arm achieved suppression. Of the 448 with viral load

A post-hoc analysis showed a trend to poorer virologic responses in the Kaletra arm at lower CD4 counts. Of the 228 patients who began with CD4 counts ≥ 200 cells/mm³, 80% were suppressed. Response rates declined with baseline CD4 strata, to a rate of 63% with baseline counts 3 (p=.0085). No such trend was seen with atazanavir/ritonavir.

Mean CD4 increases from baseline were 203 cells/mm³ for atazanavir/ritonavir and 219 cells/mm³ for Kaletra.

Resistance data are still being analysed; the investigators hope to present findings at the International HIV Drug Resistance workshop in June.

Tolerability and side-effects

Atazanavir appeared to be better tolerated than Kaletra, with 2% experiencing grade 2-4 treatment-related diarrhoea and 4% experiencing nausea, compared with 11% and 8% on Kaletra, respectively. Grade 2-4 jaundice and rash were seen in 4% and 3% on atazanavir/ritonavir and 0% and 2% on Kaletra, respectively. Overall rates of serious adverse events (SAEs) were similar at 12% for atazanavir/ritonavir and 10% for Kaletra.

As expected, individuals in the atazanavir/ritonavir arm were much more likely to experience hyperbilirubinaemia, with bilirubin elevations more than 2.5 times the upper limit of normal (ULN) in 34% versus less than 1% on Kaletra. Atazanavir/ritonavir was less likely to lead to fasting lipid abnormalities than Kaletra. Triglyceride increases were markedly lower in the atazanavir/ritonavir arm, although relatively few patients in either arm reached extremely high triglyceride levels. There was a 25.2% greater change in triglycerides from baseline in the atazanavir/ritonavir arm (p<.0001 on="" patients="" with="">Kaletra reaching triglyceride levels ≥ 751 mg/dL, versus 2 (

Total cholesterol levels ≥ 240 mg/dl were seen in 7% on atazanavir/ritonavir and 18% on Kaletra. The change in total cholesterol (TC) levels was significantly (p<.0001 higher="" in="" on="" patients="">Kaletra, with a 9.5% greater increase than those on atazanavir/ritonavir; however, the changes in LDL and HDL cholesterol levels were not significantly different between the two arms, with the TC difference apparently driven by greater non-HDL cholesterol increases in the Kaletra arm.

Fewer patients on atazanavir (2%) than on Kaletra (8%) initiated lipid-lowering therapy during the study, and fewer than 2% in either of the arms experienced grade 3-4 ALT/AST elevations.

By week 48, although 9% in the atazanavir/ritonavir arm discontinued treatment (2% due to adverse events), 13% discontinued Kaletra, 3% of which were due to adverse events. Of note, three participants on atazanavir/ritonavir discontinued due to jaundice/hyperbilirubinaemia.

Conclusions

The investigators conclude that once-daily atazanavir/ritonavir is non-inferior to twice-daily Kaletra in treatment-naive individuals, with comparable antiviral efficacy when combined with tenofovir and FTC. Ritonavir-boosted atazanavir appears to be better tolerated with a favourable lipid profile, and constitutes "an appropriate therapeutic option for treatment-naive patients."