February 25, 2005
This large, international study, known as the INITIO trial (for background on this study, click here), was designed so that all participants would receive stavudine (d4T, Zerit) + didanosine (ddI, Videx) with either efavirenz, nelfinavir or both efavirenz + nelfinavir. There were no CD4+ cell count or viral load restrictions to enter this study; the only requirement was that participants be antiviral naive.
|INITIO Trial Design|
|efavirenz + d4T + ddI||nelfinavir + d4T + ddI||efavirenz + nelfinavir + d4T + ddI|
|# of Patients in Each Study Arm||288||305||288|
Study participants were in follow-up for about 3 years. The primary endpoint focused on the percentage of people who had a viral load below 50 copies while on treatment. Switches were allowed for side effects, as well as for viral load rebound, and different analyses were done to explore which initial regimen was the most successful.
In all, 915 people were randomized from February 1999 to April 2002, while 881 actually started on the assigned treatment, and were followed for a median of 3.7 years. About 13% of the participants were lost to follow-up in the course of this study.
It is reasonable to note that these regimens, while popular at the time the study was launched in 1999, are no longer among those in the current Department of Health and Human Services guideline2 recommendations for initial treatment. This is largely because of the higher side effect rates seen with the regimen of stavudine + didanosine versus what we see with other nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) pairs. Not surprisingly, during this study, about 157 people overall switched from the combination of stavudine + didanosine to zidovudine (AZT, Retrovir)/lamivudine (3TC, Epivir).
Judging the primary endpoint (viral load below 50 copies at the end of year 3) confirms what was reported in ACTG 384. There was a 74% response seen in the efavirenz arm -- a significantly higher success rate compared to either the nelfinavir arm (62%) or the efavirenz + nelfinavir 4-drug arm (62%).
From another perspective, if all the participants who changed the nucleoside backbone were considered to be treatment failures, the overall results would be similar, with a 63% response rate noted on efavirenz, versus about a 50% response rate on the 2 other arms. Both of these achieved statistical significance favoring the efavirenz 3-drug arm. CD4+ cell counts were similarly increased in all 3 arms of the study. Overall, about 30% discontinued participation in the trial due to adverse events.
The study results confirmed that initiating treatment with 2 NRTIs plus efavirenz is superior to beginning treatment on either nelfinavir or the combination of efavirenz + nelfinavir. There remains no clear benefit to starting on 4 antivirals versus some of the most potent 3-drug options. These results are extremely similar to what was reported in ACTG 384, which documented that efavirenz was the best of these 3 choices.
However, ACTG 384 also confirmed what was seen here, which is the higher than desirable rate of side effects for participants on stavudine + didanosine. It was ACTG 384 that led to the conclusion that zidovudine + lamivudine is one of the standards of care for initial treatment.
It is important to note that since both the ACTG 384 and INITIO studies began, other critical studies regarding initial therapy have been presented. One trial presented at ICAAC3 in September 2004 by Gilead, called study 934, demonstrated that tenofovir (TDF, Viread)/emtricitabine (FTC, Emtriva) plus efavirenz has a significantly higher success rate then the combination of zidovudine/lamivudine at 48 weeks. Another study, by Edwin DeJesus, was presented at ICAAC in 2003.4 His study showed that the combination of abacavir (ABC, Ziagen)/lamivudine had results that are statistically similar in success rates to zidovudine/lamivudine at week 48.
INITIO now provides additional support for current treatment decision-making using 3 drugs and not 4 for initial therapy, and using efavirenz instead of nelfinavir for initial therapy.
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