This is the case in a study comparing Trizivir and Sustiva. In this instance a communication was mailed to all HIV practitioners; investigators studying Trizivir vs. Sustiva (efavirenz) felt there to be a significant difference in effectiveness of one treatment arm and one inferior arm was terminated. Let's dissect the information to investigate the possibility of any existing drama in ACTG A5095 (AIDS Clinical Trials Group).
Trizivir consists of Retrovir (AZT), Epivir (3TC) and Ziagen (abacavir). Combivir consists of Retrovir and Epivir.
1,147 patients were followed for an average of 32 weeks. The mean (average) CD4 T-cell count at baseline (start of study) was 238 cells and HIV RNA was 78,825. However, 43% of study patients had viral loads greater than 100,000 copies vs. 57% had HIV RNA below 100,000 at start of study.
Since the National Institutes of Health sponsors and funds all ACTG studies, they sent a letter to physicians informing them of the interim results. They reported that 21% of the patients on Trizivir only had been considered virologic failures vs. 10% in the other two groups (both Sustiva arms) combined. It is worthy to note that this study considers and deems virologic failures for viral loads greater than 200 copies at least four months after starting treatment.
With these results in hand, an independent panel, the Data Safety Monitoring Board (DSMB), recommended stopping the Trizivir arm and is providing the volunteers with the option of an alternative regimen, whether they were failing (viral loads above 200 copies) or still at undetectable levels. It is common to have an independent panel of experts review studies during the ongoing trial, they would intercede for the benefit of the patients. Additionally, the remaining patients of the two other treatment arms who were administered Sustiva were told they were taking Sustiva but still blinded as to which nucleosides were their background treatment.
According to sources familiar with this study, 74% of patients randomized to Trizivir arm and 89% of the pooled Sustiva arms still maintained viral loads undetectable at an average at week 48 (Intent-to-Treat analysis). Approximately 50% of patients had CD4 counts less than 200 and the median CD4 count was 214 cells in this study. In fact, 17% of patients randomized to the Trizivir arm and 20% in the pooled Sustiva arms had CD4 counts between 0-50 cells.
Particularly, another study, DMP-006, was completed several years ago and ran for more than three years. It was historically important because of several significant findings and it led to the quick approval of Sustiva by the FDA. Here patients were randomized to either Sustiva or Crixivan, each with Combivir (vs. Crixivan + Sustiva alone). Sustiva was shown to be superior over Crixivan, and a sub-analysis in this trial demonstrated patients with CD4 count below 100 or high viral RNA at baseline were also successfully treated with Sustiva.
Moreover, other studies showed the benefit of administering dual protease inhibitor regimens in these immune-suppressed patients as being more advantageous for durability (longer time to treatment failure), than a triple therapy regimen. With this in mind, many physicians do not offer a simplified regimen of Trizivir for the patient considered very advanced or in a late stage of disease.
One wonders the rationale for designing a study that potentially places the immune-devastated patient on Trizivir alone. Alternatively, the results of a Sustiva-based treatment (not to mention a quadruple therapy arm containing Sustiva) in this advanced disease population beating out Trizivir was not a revelation nor a shock to us.
Daniel S. Berger, M.D., is Medical Director of Chicago's largest private HIV treatment and research center, NorthStar Healthcare, and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago and editor of AIDSInfosource (www.aidsinfosource.com). He also serves as medical consultant and columnist for Positively Aware. Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.