Atazanavir, the new protease inhibitor recommended for approval yesterday by the US Food and Drug Administration's Antiviral Advisory Committee, is likely to be best used in treatment-experienced patients when boosted with ritonavir, according to data unveiled at yesterday's hearing. The drug shows comparable activity to lopinavir/ritonavir when dosed as atazanavir/ritonavir 300/100mg, but results in less triglyceride and cholesterol elevation. (Click here to view main report on atazanavir approval).
Once again the transparency of the US system of drug approval allows European clinicians and treatment advocates full access to the deliberations that took place around the licensing of a new antiretroviral, in stark contrast to the almost papal European system which privileges commercial confidentiality over patient safety.
Of particular interest are findings from two studies in treatment-experienced patients, previously unreported at international meetings, which will guide the FDA and the EMEA in their decisions on how to license atazanavir. These data are also relevant to the use of atazanavir obtained through the Early Access Programme now operating in some European countries, which makes the drug available for treatment-experienced patients.
043 – moderately PI-experienced patients
The FDA review includes a summary of findings from study 043, which compared atazanavir 400mg once daily with lopinavir/ritonavir in patients who had experienced failure of one or two protease inhibitors. All participants received a nucleoside backbone chosen after a resistance test had identified which drugs they might be sensitive to. Tenofovir was not included in the list of permitted nucleoside analogues in this study.
Participants had an average of three years prior treatment experience, and a median CD4 count of 264 cells/mm3 at baseline, and median viral load of 4.22 log10 copies/ml (approximately 16,000 copies/ml). The study recruited 229 participants, 81% male, 53% Hispanic, 28% with a prior AIDS diagnosis, 62% with viral load below 30,000 copies/ml.
At baseline 74% of subjects were fully susceptible to atazanavir, whilst 88% were fully susceptible to lopinavir/ritonavir. Thirty one per cent were highly resistant to nelfinavir (greater than tenfold loss of susceptibility).
Data were available on 197 participants at week 24, of whom 95 received atazanavir and 102 lopinavir/ritonavir. The average viral load reduction was –1.73 log10 copies/ml in the ATV group, and –2.16 log10 copies/ml in the lopinavir/ritonavir group. The time-averaged difference in viral load reduction showed a statistically significant advantage to lopinavir/ritonavir treatment over the first 24 weeks (0.31 (0.06, 0.55, 97.5% CI).
81% of the lopinavir/ritonavir group had viral load below 400 copies/ml at week 24, compared to 61% of the atazanavir group (52% vs 41% below 50 copies/ml). A larger number of atazanavir-treated individuals experienced virologic failure before week 24, mainly due to failure to achieve a viral load below 400 copies/ml rather than viral rebound.
Even when the data were analysed for baseline treatment experience and protease inhibitor susceptibility, lopinavir-ritonavir continued to demonstrate a trend towards superiority.
Atazanavir-treated individuals experienced a mean decrease of 6% in LDL cholesterol, whereas lopinavir/ritonavir-treated individuals experienced a mean increase of 8% by week 24. Triglycerides also fell slightly in the atazanavir group (-2%), but rose by 57% in the lopinavir/ritonavir group (p
Lipid differences became observable within four weeks of starting the regimen, and by week 24, 18% of the lopinavir-treated patients were receiving lipid-lowering medication, compared to 5% of atazanavir-treated patients.
The FDA review panel concluded:
“In a registrational study of treatment-experienced subjects, atazanavir was inferior to lopinavir/ritonavir both in terms of viral load reduction and percentage of patients with viral load below limits of quantification”
“In registrational study 043 of treatment-experienced patients, atazanavir subjects experienced more grade 3-4 LFT abnormalities than lopinavir/ritonavir subjects. Although there was an imbalance in hepatitis B or C co-infection between treatment arms (ATV 20%, LPV/RTV 12%), this did not explain the differences.“
045 – Highly treatment experienced patients
The most intriguing data from the registration package come from the 045 study, which compared atazanavir/ritonavir 300/100mg once daily with lopinavir/ritonavir 400/100mg twice daily and atazanavir/saquinavir 400/1200mg once daily.
People were eligible to join 045 if they had experienced failure of at least two prior regimens and had been exposed to all three classes of antiretrovirals. 74% were susceptible to atazanavir, 75% to lopinavir and 83% to saquinavir. However, only 34% were taking a PI at baseline, so resistance may have been underestimated owing to lack of selective pressure. This means that resistance mutations would disappear in the absence of a drug, only to be selected again if a drug with a similar resistance pattern were introduced.
The FDA considered data on all patients who had completed 16 weeks of treatment, and 24 week results from this study will be formally presented at the International AIDS Society conference in Paris in July.
Week 24 results on all randomised participants show that atazanavir/ritonavir has similar efficacy to lopinavir/ritonavir (64%
Lipid changes at week 16 appeared to favour atazanavir/ritonavir, with an 8% reduction in LDL cholesterol and 7% reduction in total cholesterol, compared to 1% and 5% increases in the lopinavir/ritonavir group. Both measures fell by 10% among atazanavir/saquinavir-treated patients. Fasting triglyceride changes did not fall among atazanavir/ritonavir-treated patients, but increased by 34% among lopinavir/ritonavir-treated patients. The atazanavir/saquinavir group experienced an average reduction of 15%. These analyses excluded any patient who initiated lipid-lowering therapy during the study.
Lipodystrophy
Some clinicians have suggested that because atazanavir is associated with minimal triglyceride elevation in treatment-naïve patients, its use is likely to result in a lower incidence of lipodystrophy. FDA and BMS documents provided before the hearing were contradictory, with the FDA reviewers not able to address a DEXA sub-study of body fat distribution in the 034 study (atazanavir versus efavirenz + AZT/3Tc), which showed no significant increase in central fat and a small gain in appendicular fat (limb fat) after 48 weeks of treatment. This study was reported in a document supplied by BMS before the hearing.
This finding does not necessarily prove that fat loss or fat gain is unlikely with atazanavir treatment, since the ACTG 384 study, which included an AZT/3TC /efavirenz arm, did not show a decline in limb fat below baseline until recipients of that combination were into their second year of treatment. Unfortunately, longer-term randomised follow-up of the 034 study which might shed light on longer term changes is not possible, because the study ceased after 48 weeks of treatment for all patients.
Lipodystrophy monitoring relied on clinician reporting in other studies where different atazanavir doses or where the drug was compared with nelfinavir on a backbone of ddI/d4T. These figures probably do not provide a reliable guide to what might be expected to occur in people who start treatment with atazanavir now.
Further information
FDA advisory committee webscast and report
Further information on this website
Atazanavir – data from previously presented studies and drug overview