March 10, 2003
The purpose of this letter is to inform you of the interim results from the Adult AIDS Clinical Trials Group (ACTG) study known as A5095. A recent review of the study by the National Institute of Allergy and Infectious Diseases (NIAID) Data and Safety Monitoring Board (DSMB) found that in antiretroviral treatment-naive patients, a combination preparation of three nucleoside analogues, Trizivir®, was inferior to two other efavirenz-containing treatment regimens being evaluated in the study. The data met pre-specified guidelines for stopping this one arm of the study based on virologic failure. There were no concerns about the toxicity of the study drugs.
Antiretroviral-naive patients randomized to receive a combination of abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV) (ABC/3TC/ZDV, Trizivir®) experienced virologic failure earlier and more frequently than patients who were randomized to receive either of the two other treatment regimens being evaluated in the study. The two other treatment regimens are: 1) a combination of 3TC and ZDV (Combivir) plus efavirenz (EFV, Sustiva), and 2) the combination ABC/3TC/ZDV plus EFV. Study drugs were given in a double-blind, placebo-matched manner.
A total of 1,147 antiretroviral-naive patients were followed for changes in their viral load and CD4+ T-cell counts. Virologic failure was defined as having an HIV RNA level in plasma above 200 copies/ml (measured by the Roche Amplicor® HIV-1 test) at least 4 months after starting study treatment.
As a result of these data, the DSMB recommended that the ABC/3TC/ZDV treatment arm be stopped. Therefore, the study volunteers receiving ABC/3TC/ZDV have been unblinded as to what treatment they were taking, and they have been asked to remain in the study for continued follow-up. These volunteers have been offered several alternatives to the use of ABC/3TC/ZDV alone. GlaxoSmithKline, one of the pharmaceutical companies involved with this study, is also working with DAIDS and the A5095 study team to provide ABC/3TC/ZDV outside the study for patients who choose this option.
Study volunteers originally given one of the other two drug treatments will continue on the study as planned and will not yet be unblinded. They will, however, be told that they are receiving a combination treatment that contains efavirenz. All study volunteers, will continue to be followed for approximately 2 years after the last subject is enrolled -- until approximately September 2004. This follow-up period will allow a comparison of the 3TC/ZDV + EFV and ABC/3TC/ZDV + EFV groups. It also will allow more information to be collected from all three groups about how to use antiretroviral drugs.
Although we are confident of these findings, they have not been presented at a scientific meeting, peer reviewed, or published. These results will be submitted to the upcoming International AIDS Society meeting in Paris (July 2003), and further analyses (e.g., CD4+ T-cell count and adherence data) will be forthcoming. A manuscript is in preparation.
It is important to consider this interim study finding in the context of published results, particularly those from prior studies that investigated either triple nucleoside regimens or EFV-based regimens. The risk of virologic failure is clearly an important factor in selecting an initial antiretroviral regimen. Other factors such as safety, toxicity, adherence, preservation of future treatment options, access, cost, and other issues also remain important in selecting the optimal first regimen for an individual patient.
Additional information about the study design and interim analysis is available on the National Library of Medicine Web site at www.nlm.nih.gov/databases/alerts/clinical_alerts.html, and on NIAID?s Division of AIDS Web site at www.niaid.nih.gov/daids/default.htm.
A5095 is a Phase III, randomized, placebo-matched, multicenter study of three antiretroviral drug combinations as initial treatment of HIV infection.
|Study Drug Treatments||Abbreviations||Trade Names|
|(1) lamivudine/zidovudine + efavirenz (5 active pills and 2 placebos)||3TC/ZDV* + EFV||Combivir® + Sustiva®|
|(2) abacavir/lamivudine/zidovudine (2 active pills and 5 placebos)||ABC/3TC/ZDV*||Trizivir®|
|(3) abacavir/lamivudine/zidovudine + efavirenz (5 active pills and 2 placebos)||ABC/3TC/ZDV* + EFV||Trizivir® + Sustiva®|
|* Also known as AZT.|
To assure double-blinding of all study drugs, each subject took two pills each morning and five pills each evening.
Changing study drugs for treatment-limiting toxicity (in the opinion of the investigator) is allowed during the study (for example, stavudine [d4T, Zerit®] for ZDV, didanosine [ddI, Videx®] for ABC, and/or nevirapine [NVP, Viramune®] for EFV).
The primary objectives of the study are: (1) to compare the ability of the drug combinations to decrease viral load (HIV-1 RNA level) to less than 200 copies per milliliter (c/mL); and (2) to describe the safety and tolerability of the drug combinations.
The study enrolled HIV-positive subjects who were antiretroviral therapy-naive with HIV RNA >400 c/mL and any CD4 + T-cell count. Study subjects were randomized 1:1:1 to one of the three antiretroviral drug combinations listed above.
As defined by the study, virologic treatment failure occurs when HIV RNA is confirmed >200 c/mL at least 16 weeks after starting the study treatment.
Subjects who stopped study medications early continue to be followed on the study. The length of the study is planned for about 2 years after the last subject entered the study (until September 2004).
On February 6, 2003, the DSMB conducted its second annual review of this study. After reviewing pair-wise comparisons of the virologic failure data on each of the regimens, the DSMB concluded that some of the pre-specified guidelines to stop the study early had been met. Based on their review of this (and other) information, the DSMB made several recommendations that may be summarized as follows:
The DSMB recommended that the ABC/3TC/ZDV arm be discontinued, the study volunteers enrolled in this arm be unblinded, and the data be released with this arm compared to the pooled data from the other two arms.
Because the other two EFV-containing treatments being studied in A5095 will continue unchanged, study results for these two treatment groups cannot be described separately at this time. Instead, the results from these two groups are being pooled together as the "EFV-containing arms," and are being compared to the results with the ABC/3TC/ZDV drug combination.
At baseline, the median CD4+ T-cell count was 238/mm3, and the median viral load was 78,825 c/mL, with 57% of subjects having HIV-1 RNA <100,000 c/mL and 43% >100,000 c/mL. Study volunteers had completed 16 weeks on study and were followed for a median of 32 weeks when the results were given to the DSMB.
At the time of analysis, 1,064 (93%) study volunteers were still in active study follow-up, and 940 (82%) remained on the initial study regimens (allowing for substitutions). A total of 34 (9%) of those receiving ABC/ZDV/3TC and 57 (8%) of those receiving one of the other EFV-containing treatments permanently discontinued all study medications, for a variety of reasons. Regarding substitutions for treatment-related toxicities, 94 of 1,147 (8%) substituted d4T for ZDV, 40 of 765 (5%) substituted ddI for ABC, and 46 of 765 (6%) substituted NVP for EFV.
Grade 3 and 4 signs and symptoms were observed in 37 (10%) and 9 (2%) of those receiving ABC/ZDV/3TC and in 95 (13%) and 17 (2%) of those in one of the other treatment groups, respectively. Grade 3 and 4 laboratory toxicities were observed in 70 (19%) and 32 (8%) of those receiving ABC/ZDV/3TC and in 132 (17%) and 78 (10%) of those in either of the other two treatment groups, respectively. Typical signs, symptoms, and laboratory abnormalities previously described with these drug regimens were observed.
Overall, a total of 167 study volunteers reached virologic treatment failure (had confirmed HIV RNA >200 c/mL at or after week 16): 82 of 382 (21%) were in the ABC/3TC/ZDV group and a total of 85 of 765 (10%) were in the combined EFV-containing groups. Virologic failure occurred significantly earlier, on average, in the ABC/3TC/ZDV group compared to the combined EFV-containing groups (p<0.001). This held true for those study volunteers with baseline HIV RNA <100,000 or >100,000 c/mL (p<0.001for both groups). The percentage of those with HIV RNA <200 c/mL at 48 weeks on the study was 74% in the ABC/3TC/ZDV group (N=88) and 89% in the combined EFV groups (N=217) (intent-to-treat analysis).