ACTG 241 was a phase II randomized multicenter, double-blind clinical trial designed to compare the three drug combination of nevirapine (NVP, 400mg/day), zidovudine (ZDV, 600mg/day) and didanosine (ddI, 400mg/day) to the two drug combination of ZDV (600mg/day) and ddI (400mg/day). The 398 subjects who started study treatment had CD4 cell counts <=350/mm3 and >=6 months of prior nucleoside therapy (median 25 months) with ZDV, ddI or zalcitabine (ddC). Primary measures for comparing the two treatment arms were long-term changes (from pre-treatment to 48 weeks) in absolute CD4 cell count, viral infectivity in peripheral blood mononuclear cells (PBMC), p24 antigenemia, time to HIV disease progression or death, and adverse experiences. Changes in percent CD4 cells and plasma HIV-1 RNA copy number are also considered in this report. Viral infectivity in PBMC and plasma viral load were assessed in a subset of 198 subjects.
At 48 weeks, absolute CD4 cell counts were higher by 25% for subjects assigned to ZDV+ddI+NVP compared with those assigned to ZDV+ddI (95% confidence interval: 9% to 45%; p=0.002). There was a similar benefit of ZDV+ddI+NVP in raising percent CD4 cells. ZDV+ddI+NVP also lowered viral infectivity in PBMC over the long-term by 50% more than did ZDV+ddI (95% c.i.: 8% to 73%; p=0.027). These differences between treatments were established within eight weeks and were sustained thereafter over the 48 week study period. For plasma HIV-1 RNA copy number, there was also a statistically significant difference (p=0.006 in area under the curve analysis) favoring ZDV+ddI+NVP established within eight weeks although this diminished with time and the difference in long-term changes was not significant. Only 66 subjects had detectable p24 antigen levels at study entry and completed the evaluation for long-term change; no significant difference was found. Thirty-four subjects (17%) assigned to ZDV+ddI+NVP and 27 (14%) assigned to ZDV+ddI died or experienced a study-defined HIV disease progression (relative hazard=1.24, 95% c.i. 0.75 to 2.06; p=0.40).
There was an excess of severe rashes (grade 3 or 4) affecting 16 subjects (8%) assigned to ZDV+ddI+NVP compared with 3 subjects (2%) assigned to ZDV+ddI (p=0.004). However, there was not a significant difference in the overall rates of severe or worse adverse experiences: neither for signs and symptoms (30% for ZDV+ddI+NVP, 24% for ZDV+ddI; p=0.16) nor for hematology and chemistry abnormalities (30% versus 26%, respectively; p=0.38).
In summary, the addition of NVP to ZDV+ddI gave moderate benefits on both CD4 cell count and viral infectivity in PBMC which were sustained over 48 weeks. Benefit of adding NVP to ZDV+ddI was also seen in plasma HIV-1 RNA levels. No clinical benefit was noted over 48 weeks though the study was not designed to have high power to detect differences in clinical progression between treatments. Ongoing analyses hope to define virologic and/or pharmacologic factors associated with a sustained antiviral response to triple therapy with ZDV+ddI+NVP.
ACTG 241: Questions and Answers
1. What was the purpose of Study ACTG 241?
ACTG 241 was a randomized, double-blind clinical trial that compared the triple combination of nevirapine (a non-nucleoside reverse transcriptase inhibitor), zidovudine (ZDV) and didanosine (ddI) with the two drug combination of ZDV and ddI in patients with CD4+ counts of 350 or less who had received prior nucleoside therapy for at least 6 months.
The main purpose of ACTG 241 was to learn if there was a difference in biological activity (i.e., effect of CD4 cell counts or viral burden), clinical activity, and toxicity among the two different antiretroviral combinations.
2. Where and when was the study conducted?
Study enrollment opened in May 1993 and ended in July 1993. The study was conducted at 16 sites of the AIDS Clinical Trials Group (ACTG).
3. How many patients were enrolled in the study?
A total of 400 patients were enrolled. Data from 398 patients were analyzed.
4. How long did the study last?
The duration of therapy was originally scheduled to be 48 weeks. The study was later extended to allow patients to receive drug until the study was unblinded in November 1994. The data for the first 48 weeks of therapy have been analyzed.
5. Who sponsored the study?
ACTG 241 was sponsored collaboratively by the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases and by Boehringer Ingelheim, Bristol-Myers Squibb, and Burroughs Wellcome, the companies that manufacture nevirapine, ddI and ZDV.
6. Who participated in the study?
The study was open to persons with HIV infection with CD4+ cell counts of 350 or less who had received at least 6 months of prior cumulative nucleoside treatment.
7. What happened to the CD4+ cell counts of study participants?
On average, after 48 weeks, the CD4+ cell counts in patients who received triple drug therapy (ZDV+ddI+NVP) were 25% higher than the CD4+ cell counts of patients who took ZDV+ddI. The differences between treatment arms began within eight weeks after starting therapy with ZDV/ddI/NVP and continued over the 48 week study period.
8. What happened to the viral burden in study participants?
Two different ways of measuring the amount of HIV in the blood were used. By both of these measures, the patients who received ZDV/ddI/NVP had greater decreases in the amount of HIV in the blood during the first weeks of study. This difference was maintained until 48 weeks by one of these measures but may have been lost by 48 weeks using the other way of measuring virus in the blood.
9. Was there any difference in toxicity among the different regimens?
Overall, there was no significant difference in the rates of side effects due to the study drugs. However, there were significantly more severe rashes in the group of patients receiving ZDV/ddI/NVP therapy than in patients receiving ZDV/ddI. The increased number of rashes occurring in the triple drug therapy arm was felt to be due to the use of nevirapine.
10. Was there a difference in clinical progression or death among study participants?
There was no significant difference in HIV disease progression or survival of patients who received either ZDV/ddI/NVP or ZDV/ddI. However, the study was not designed with enough power to detect a difference in clinical progression between the two treatment groups. This study was intended to be an exploratory study of the biological effects of nevirapine in combination with nucleosides. There may be clinical benefits or risks from the addition of nevirapine to ZDV and ddI which were not detected in the study.
11. Are the results of this study going to affect patient management?
At the present time, standard clinical patient management should not be affected by this study. ACTG 241 was intended to be an exploratory study. The study suggests that additional immunologic and virologic activity was obtained with the addition of a third agent (nevirapine). A potentially serious side effect, rash, was also associated with the addition of nevirapine. The clinical effect of the triple combination, however, remains to be determined in future studies.