Reyataz vs Kaletra

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Is Atazanavir/Ritonavir as Effective as Lopinavir/Ritonavir? In a prior issue of the journal AIDS [1], M. and colleagues presented results from a clinical trial of atazanavir/ritonavir (ATV/r; Reyataz), lopinavir/ritonavir (LPV/r; Kaletra) and atazanavir/saquinavir (Reyataz/Invirase) in a total of 358 treatment-experienced HIV patients.

The conclusion, that ATV/r is as effective as LPV/r, does not seem to be supported by further analysis of the trial data, according to Hill, whose rebuttal to the et al. article appears in the current issue of AIDS (November 18, 2005) [2].

“The most common primary efficacy analysis of HIV clinical trials,†writes Hill, “is the proportion of patients with HIV RNA under 50 copies/ml, using an intent-to-treat population, in which patients discontinuing randomized medication or with missing data are classified as treatment failures.

Hill points out that antiretroviral drug approval trials are normally powered, using this HIV RNA endpoint, to detect differences of at least 10-12% between treatment arms, or to show equivalence or non-inferiority within these limits [3].

“A normal regulatory trial powered within these limits would have 250-400 patients per arm,†writes Hill. He asserts that because the ATV/r vs LPV/r study [bMS-045] enrolled only about 120 patients per arm, it is “clearly underpowered†to evaluate effectiveness using the standard endpoint of HIV RNA 50 copies/ml.

According to Hill, in the BMS-045 trial, the intent-to-treat analysis of the 50 copy HIV-RNA endpoint showed responses of 38% for ATV/r and 46% for LPV/r at week 48; the ATV/r arm was 8% inferior to LPV/r at week 48, with 95% confidence intervals of -20.4% to +4.4%.

“These 95% confidence intervals fall outside the 10-12% limits that would normally be used to define equivalent or non-inferior efficacy,†writes Hill.

He maintains that intent-to-treat analyses in open-label trials typically include only those patients who receive at least one dose of study drug: “Patients who are randomly assigned but are never treated are normally excluded from this type of analysis (intent-to-treat exposed method).â€

“Of the patients randomly assigned to the BMS-045 trial, five patients in the LPV/r arm but only one patient in the ATV/r arm were assigned but never treated. Those untreated patients had been included as non-responders in the published results.â€If an intent-to-treat exposed analysis is conducted, including only patients who received study medication, the percentage with HIV RNA less than 50 copies/ml at week 48 would be 38% for the ATV/r arm versus 48% for LPV/r, a difference of 9.6% (95% confidence intervals -22.1 to +2.8%).

“Differences in efficacy between arms in the region of 8-10% have been found to be statistically significant in larger randomized clinical trials…

“Although the results from the as-treated analyses show more similar findings for the two arms, the discontinuation rate in the ATV/r arm (22%) is higher than for the LPV/r arm (11%), and it is not clear what proportion of patients withdrew with detectable versus undetectable HIV-RNA levels across the treatment arms.

“The primary efficacy endpoint for the BMS-045 trial was the log10 reduction in HIV RNA using a time-averaged difference (TAD) method. This method has been used for the analysis of other trials in treatment-experienced patients in which rates of HIV-RNA undetectability are expected to be low (for example the TORO clinical trials of enfuvirtide).

“However, for more recent Food and Drug Administration product labels, the log10 reduction in HIV RNA by TAD is no longer included in the summary of treatment efficacy [4].

“There are two main problems with using log10 reductions in HIV RNA to compare treatment groups. First, when a significant proportion of treated patients show HIV-RNA reductions under the assay detection limit, the log10 reduction cannot easily be measured because the lower detection limit has already been achieved: this will tend to make treatment groups appear more similar.

“Second, there are not standardized methods for including data from early withdrawals. With the TAD method quoted in the report, it is not apparent what assumptions are made for patients who withdraw prematurely or have missing data. A patient who withdraws with undetectable HIV-RNA levels might have these values carried forward, censored, or reset at a zero change from baseline.

“In summary, the question remains whether the study's conclusion that ATV/r is as effective as LPV/r is truly describing the overall efficacy of the treatment arms, or is the conclusion rather a result of the chosen statistical analysis in conjunction with a relatively small sample size for a study of this type?â€

11/07/05

Source

A Hill. Atazanavir/ritonavir versus lopinavir/ritonavir: equivalent or different efficacy profiles? AIDS 19(17): 2054-2055. November 18, 2005.

References

1. M, Grinszstejn B, C, Coco J, DeJesus E, Lazzarin A, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 2005; 19:685-694.

2. Hill A. Atazanavir/ritonavir versus lopinavir/ritonavir: equivalent or different efficacy profiles? AIDS 19(17): 2054-2055. November 18, 2005.

3. Food and Drug Administration. Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements - clinical considerations for accelerated and traditional approval. US Department of Health and Human Services, Center for Drug Evaluation and Research (CDER), Clinical Medical, October 2002. Available at: http://www.fda.gov/cder/guidance/index.htm

4. Enfuvirtide (Fuzeon). US prescribing information. Nutley, NJ, USA: Roche Pharmaceuticals/Trimeris, revised October 2004.

Regards, VergelProgram for Wellness Restoration

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