Introduction
Efavirenz (EFV) has been a recommended component of initial combination antiretroviral therapy in all major treatment guidelines and has been used to treat millions of people worldwide
Aim
The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir (TDF) and emtricitabine (FTC) as first-line treatment for HIV infection
Patient Profile
- HIV-1-infected antiretroviral-naive adults
Methods
- ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries
- 96-week double-blind, placebo controlled, non-inferiority trial
- 630 patients were randomly assigned to receive tenofovir plus emtricitabine with either
- reduced EFV daily dose 400 mg (n=321) or
- standard dose of efavirenz 600 mg (n=309)
Endpoints
- The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks
- Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than –10% by modified intention-to-treat analysis
- Adverse events were summarised by treatment
Results
- The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL
- Proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg
- The lower 95% CI did not cross –10%; therefore, efavirenz 400 was non-inferior to efavirenz 600
- The mean change from baseline to week 48 for 400 mg group was −3・00 and in the 600 mg group was −2・94 log10 copies per mL
- No significant difference in time to loss of virological response was reported between study groups (n per 100 participant years, efavirenz 400=0・24, efavirenz 600=0・35, HR 1・42; p=0・12)
- There was no difference in the primary endpoint stratified by baseline BMI or ethnic origin
- At week 48, CD4 T-cell counts were significantly higher for efavirenz 400 compared with efavirenz 600 at week 48 (mean difference 25 cells per μL; p=0·01) than with efavirenz 600 (28 cells per μL; p=0·01)
- No difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%; p=0·77)
- Significantly more frequent drug-related adverse events were reported in the 600 mg group than in the 400 mg group (146% vs 118%; p=0·01)
- Significantly fewer patients with these events stopped treatment (400 mg=6 , 600 mg=18 , p=0·01)
- No difference between randomised groups in quality of life, depression, anxiety and stress, and efavirenz-related symptoms over 48 weeks
|
|
Efavirenz 400 mg, n (%) |
Efavirenz 600 mg, n (%) |
Total n (%) |
p value |
|
Number of adverse events |
49·8% |
50·2% |
100 |
·· |
|
Grade 1 |
72·9% |
73·1% |
73·0 |
·· |
|
Grade 2 |
22·5% |
21·5% |
22·0 |
·· |
|
Grade 3 |
4·1% |
5·0% |
4·5 |
·· |
|
Grade 4 |
0·4% |
0·4% |
0·4 |
·· |
|
Patients reporting adverse events |
89·1% |
88·4% |
·· |
·· |
|
Median time to first adverse event |
1 week |
1 week |
·· |
·· |
|
Serious adverse events |
|
|
|
|
|
Total number of serious adverse events |
46·2% |
53·7% |
·· |
·· |
|
Number with serious adverse events |
7·17% |
7·12% |
·· |
0·98 |
|
Number with serious adverse events related to study drug |
0·93% |
1·29% |
·· |
0·67 |
|
Adverse events definitely or probably related to study drug |
|
|
|
|
|
Patients with adverse event related to study drug |
36·8% |
47·2% |
·· |
0·01 |
|
Patients stopping drug due to drug-related adverse event |
1·9% |
5·8% |
·· |
0·01 |
Conclusion
- Reduced dose of 400 mg efavirenz demonstrated non-inferiority to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection
- Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg
- Lower dose efavirenz should be recommended as part of routine care
Reference
Lancet 2014; 383: 1474–82