US label changes for rilpivirine and Eviplera follows EU caution on high baseline viral load: new summary on drug resistance
Simon Collins, HIV i-Base
On 7 December 2012, the US FDA approved changes to the rilpivirine (Edurant) package insert that included restricting the indication to treatment-naïve adult patients with HIV viral load less than 100,000 copies/mL.
Previously, the FDA had only highlighted the poorer responses in patients with baseline viral load >100,000 copies/mL. This brings the US indication in line with the label indication originally granted by the EU. On 25 January, a similar change occured for the Fixed Dose Combination of Eviplera that contains rilpivirine/tenofovir/FTC.
Of note, the FDA review included a different summary of data relating to the risk of resistance based on baseline viral load and CD4 count, that appears to be different to the analysis of the 96 week pooled phase 3 data in the EU Summary of Product Characteristics, see Table 1 and 2.
This showed that in people failing virologically, there were disproportionately higher rates of resistance when stratified by both baseline viral load (above vs below 100,000 copies/mL) and baseline CD4 count (above vs below 200 cells/mm3).
|VL <100,000 copies/mL||VL >100,000 copies/mL|
|NNRTI||26% (14/54)||74% (40/54)|
|NRTI||22% (11/50)||78% (39/50)|
|M184V||23% (11/50)||77% (36/47)|
|K65N/R||0 (0/8)||100% (8/8)|
|CD4 >200 cells/mm3CD4 <200 cells/mm3|
|NNRTI||37% (20/54)||63% (34/54)|
|NRTI||28% (14/50)||72% (36/50)|
The virologic outcome of randomised treatment of the two phase 3 registrational studies TMC278-C209 and TMC278-C215 at Week 96 is summarised in Table 10 in the full US SPC (not reproduced here).
Several changes were made in the label changes relating to side effects including the importance of hepatic monitoring, especially in patients with HBV or HCV coinfection. Nephrolithiasis was added as a “Less common” side effect and nephrotic syndrome was added to the post marketing experience subsection.
Troleandomycin was removed from the table of drug interactions and telithromycin was added with the clinical comment that telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
These results highlight the lower response rates for people with the most advanced HIV disease, defined by baseline viral load, due to the higher potential for clincially important drug resistance.
A recent meta-analysis of over 12,000 patients from 21 studies originally presented at the IAS2012 conference and recently published in HIV Medicine (albeit, Janssen sponsored) suggested that lower reponses at high viral appears to be an underlying trend across all ARV studies in all classes. [3, 4]
The focus on CD4 count, while plausible, is not supported by statistical values, and appears to be based on low patient numbers and wide confidence intervals. Non-inferiority conclusions from sub-group analyses similarly need to be interpreted cautiously as these studies are under-powered for such comparisons.
What appears different with rilpivirine is that these response rates were also significantly lower compared to the efavirenz-based control group, and that this was independent of the choice of background nukes.
For full details see the new product label. 
- FDA list serve. Labeling updates for Edurant (rilpivirine). (7 December 2012).
- Rilpivirine Summary of Product Characteristics. (EMA website assessed 28 January 2013).
- Stephan C et al. Effects of baseline HIV-1 RNA levels on the 48 week efficacy of first-line antiretroviral treatment for HIV: a meta-analysis of 10,962 patients in 19 randomised clinical trials. AIDS 2012, Washington 2012. Poster abstract TUPE085.
- Stephan C et al. Impact of baseline HIV-1 RNA levels on initial highly active antiretroviral therapy outcome: a meta-analysis of 12,370 patients in 21 clinical trials. HIV Medicine. Article first published online: 22 NOV 2012 DOI: 10.1111/hiv.12004.