Tenofovir/FTC backbone outperforms AZT/3TC (Combivir) with efavirenz in treatment naive patients; reduced toxicity drives ITT viral efficacy
Simon Collins, HIV i-Base
Results from a planned 24-week interim analysis of the Gilead 934 study were presented by Brian Gazzard from Chelsea and Westminster Hospital, London as a late-breaker. The bottom-line results had been press-released by Gilead several weeks before this meeting.
The study randomised 517 treatment naïve patients (from UK, Spain and the US) in a 1:1 ratio to background nucleosides of either tenofovir plus FTC taken once daily as separate pills or Combivir (AZT/3TC) taken twice-daily (Q12H). Efavirenz was the third drug for both arms. Primary endpoint is time to loss of virologic response at week 48, with follow up to 96 week. The study was designed with 85% power to show non-inferiority (13% difference). The intent-to-treat (ITT) analysis counted missing data, and patients switching treatment as failure.
This study had no entry restrictions based on CD4 count. Just over 40% of patients in each arm had baseline CD4 <200 cells/mm3, with 15% of TDF/FTC arm and 11% CBV arm having CD4 count <50 cells/mm3.
At 24 weeks, the time to loss of virologic response was significantly greater in the TDF/FTC arm using <400 and <50 copies/mL cut-off, and results are shown below.
Time to loss of virologic response at 24 weeks
|VL||TDF/FTC||CBV (AZT/3TC)||95% CI|
|<50 copies/mL||73%||65%||+0.5%, +16.2%|
Differences in the ITT analysis were largely driven by higher rates of discontinuations due to toxicity in the Combivir arm.
11% patients discontinued TDF/FTC. 3% of which was for toxicity, compared to 21% discontinuation in the Combivir arm, with 9% relating to toxicity. Renal safety was similar in each arm. A breakdown of grade 3/4 side effects is detailed below.
Summary of discontinuations due to adverse events
|Primary reason adverse event (n)||3% (24)||9% (38)|
|% discontinuations any side effect||3% (8)||9% (22)|
|aneamia (n)||0||5% (14)|
|neutropenia (n)||0||1% (2)|
|depression||<1% (1)||1% (2)|
CD4 responses were not statistically different, Mean CD4 increases were slightly higher in the TDF/FTC arm (+129 vs +111 cells/mm3), but baseline CD4 counts were also slightly lower.
The resistance profile of patients viral load >400 at week 24) were analysed but there were only 10 and 8 patients with virological failure in the TDF/FTC and CBV arms respectively. Although there were small percentage differences approximately half failed with wild-type and half with either NNRTI +/-3TC resistance. Neither K65R nor TAMS were detected. Although eleven patients in each arm were found to have NNRTI resistance at baseline (reinforcing the importance or resistance testing naïve patients prior to treatment) they were excluded from this analysis.
The difference between these two regimens was largely driven by discontinuations related to side effects in the Combivir arm. Although this was an interim 24-week analysis, results from tenofovir registrational studies do not suggest a level of later toxicity-related discontinuations, that is likely to reverse these results. The final analysis from this study is still likely to be needed before widespread prescription change occurs. Intolerability to AZT, for example, would be overcome with a switch to tenofovir.
However, the association of AZT-related mitochondrial toxicity on adipocyte differentiation and subsequent risk of lipoatrophy highlighted in the Lipodystrophy Workshop report above, is a clinical advantage for not including AZT in initial regimens.
In the UK, this is likely to become further complicated by cost of treatment, where patients may continue to use AZT on the basis of lower cost, despite lower efficacy and tolerability. The pressure for this will increase when AZT comes off-patent in 2006.
Further discussion of tenofovir plus ddI:
Gazzard B et al. The combinations of tenofovir DF (TDF), emtricitabine (FTC) and efavirenz (EFV) has significantly greater response vs fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral naïve patients: A 24 week preliminary analysis. 41st ICAAC, Washington, 2004. Late breaker abstract H-1137a.