Sustiva is a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) which has demonstrated efficacy when used combination with either a protease inhibitor, NRTI or both in ARV naïve NRTI extreme patients. The antiretroviral activity of NNRTI drug class in patients with high baseline HIV-1 RNA levels has been questioned. The authors thus re-analyzed the data from three clinical trials using EFV to investigate whether the efficacy demonstrated with the entire cohorts were similar to those of patients with baseline viral loads above 100,000 copies/mL. The data were evaluated from DMP 266 studies, 003 (EFV plus IDV), 006 (EFV plus IDV or EFV plus 3TC), and 020 (EFV plus IDV plus NRTI). HIV-1 RNA was assessed by Roche Amplicor primary end point was the percentage of patients below quantifiable levels (below 400 copies) by on-treatment data analysis. Additional data information will be presented as it comes available to the authors. The authors feel that their data demonstrates that ARV combinations containing EFV (with or without a PI) have similarly high levels of efficacy in individuals with baseline plasma HIV-1 RNA levels above 100,000 when compared to the general study population, and thus support the use of EFV containing regimens in patients with high baseline viral loads. The authors hope that this data will help make available otherwise scarce information to help guide therapeutic decision making regarding the use of these agents in this setting.
What is valuable in this study is that the authors have very large cohorts, allowing for greater stratification based on baseline viral load (i.e., 0 - 50,000, 50,000 - 100,000, 100,00 - 300,000, and greater than 300,000). The authors also use fairly stringent criteria; for instance, non-completers were considered failures, meaning that dropouts and missing data were imputed as a failure. All arms of the studies analyzed have similar demographics, ranging from 75% to 90% males, and thus 25% to 10% females. On average, roughly 60% caucasian, 20% black, 20% hispanic and 3-75 other. The mean age was about 36 years. Risk factors include IVDU at 8%, homosexual sexual practices in about 70%, heterosexual sexual practices in 12-30%, transfusion 2% and unknown risk varied anywhere from 3% to 20%. The mean CD4 counts in three of the arms was roughly 350 and in one of the arms 282. Log HIV-1 RNA's at the start ranged from 4.2 to 6.2, with the geometric mean of roughly 60,000.
Conclusions: 1) Similar efficacy results were demonstrated for Efavirenz (EFV) containing regimens for patients with high baseline plasma viral loads (defined as >100,000 copies/mL) as the entire population or those with baseline viral loads below 100,000 copies. 2) This observation was noted by all three analytical methods performed: observed or on treatment analysis, etc.. This finding was seen for both the percentage of patients achieving plasma HIV-1 RNA levels below 400 copies as well as <50 copies/mL. In study 006, similar trends were seen in the subgroup of patients with high baseline viral loads in the population as a whole, favoring the Efavirenz + AZT + 3TC arm over Indinavir + AZT + 3TC. 3) Lastly, study 006 showed similar results for all viral load strata but the peak response rates of the subgroup with the higher baseline viral loads were delayed by several weeks when compared with those patients who had viral loads at baseline.
Where precisely and in what patients precisely EFV should be used remains an open question. Although initially reserved for salvage therapy, over the course of the past year, I think this position has evolved; many will use this as a drug in the first switch, in a situation where there has been a failure of the first regimen. While I think the jury is out, I think this data lends significant support to using NNRTI's as a first line drug, even in patients who have high viral loads. This decision is based not only on the results of this sort of data which is interesting, although I do not think conclusive, but also, taking into account a more specific regimen that the patient might be compliant with. Indeed, given the setting of high viral loads, a slightly less effective regimen that is taken properly is much more effective than a more effective regimen that is not taken. By that I don't mean to imply that this regimen is necessarily less effective, but only that compliance is of equal importance as the power of chemotherapeutic agents. Accumulating data and the improvement of comfort level that many clinicians may have with EFV as an initial regimen continues to expand the therapeutic armamentaria. Further data concerning the use of Efavirenz in a non-PI containing regimen in patient with >100,000 copies/mL HIV RNA should be available soon.