July 26, 2005
In this presentation, Damian J. McColl and colleagues presented antiretroviral resistance data from the Gilead 934 study. Gilead 934 was an open-label, randomized study comparing tenofovir (TDF, Viread) + emtricitabine (FTC, Emtriva) + efavirenz (EFV, Sustiva, Stocrin) to zidovudine/lamivudine (AZT/3TC, Combivir) + efavirenz in antiretroviral-naive patients. Five hundred seventeen patients were randomized evenly to 1 of the 2 arms and followed for 144 weeks. Inclusion criteria allowed any CD4+ cell count, but required a viral load greater than 10,000 copies/mL. The full clinical results from this study will be presented later at this conference; this particular presentation focused only on resistance data.
Patients were genotyped at baseline after enrollment. Genotyping was performed on all patients at post-baseline if they met the following resistance analysis criteria: viral load greater than 400 copies/mL at 48 weeks, or early discontinuation of the study.
Results from this genotyping indicated that 22 patients (11 in each arm) had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance at baseline. The majority of these patients had a reverse transcriptase gene K103N mutation. Because these 22 patients had baseline NNRTI resistance, they were not included in the modified intent-to-treat (mITT) analysis.
Five hundred nine patients were included in the full ITT analysis; 487 patients were included in the mITT analysis. The percentage of patients in each arm who demonstrated a viral load less than 400 copies/mL after 48 weeks is outlined in the chart below.
|Study Arm||Pts. With VL <400 (ITT)||Pts. With VL <400 (mITT)|
|tenofovir + emtricitabine||81%||84%|
Both the ITT and mITT analyses were statistically significant.
Of those patients with NNRTI resistance at baseline:
Of this last group of patients, most had developed an M184V mutation conferring lamivudine (3TC, Epivir) or emtricitabine resistance.
Thirteen patients in the study (7 on the tenofovir + emtricitabine arm and 6 on the zidovudine/lamivudine arm) were also found to have nucleoside reverse transcriptase inhibitor-resistant virus at baseline. All were thymidine-associated mutations (TAMs); there was no baseline evidence of reverse transcriptase K65R, the primary mutation for tenofovir. At week 48, all of these patients were still on their study medications, with 12 of the 13 patients achieving a viral load less than 400 copies/mL.
In terms of resistance development during the study, 12 patients (4%) developed resistance on the tenofovir + emtricitabine arm and 23 (7%) developed resistance on the zidovudine/lamivudine arm. The majority (9 of 12 on the tenofovir + emtricitabine arm; 16 of 23 on the zidovudine/lamivudine arm) developed efavirenz- or other NNRTI-associated mutations. An M184V mutation developed in 2 tenofovir + emtricitabine patients and 7 zidovudine/lamivudine patients. No patient in the tenofovir + emtricitabine arm developed a TAM, and only 1 patient did so in the zidovudine/lamivudine arm. No patient who experienced virologic failure developed a K65R mutation while on the study.
Data was also presented with respect to subtype; they indicated that about 8% of patients in each arm had non-subtype B virus. All non-B isolates were considered wild type at baseline. There was no significant difference in virologic response between subtype B and non-subtype B viruses. Only one study patient with non-subtype B virus, in the zidovudine/lamivudine arm, developed efavirenz and lamivudine resistance.
The major findings from this study are:
It remains to be determined whether the slightly increased frequency of resistance, and slightly decreased likelihood of achieving an undetectable viral load, in the zidovudine/lamivudine arm was associated with the twice-daily dosing of zidovudine/lamivudine, compared to the once-daily regimen of tenofovir + emtricitabine + efavirenz.
Finally, it was disturbing to see that, in this study of treatment-naive patients, so many trial participants had evidence of baseline NNRTI resistance. We were not told how long these people may have been infected prior to enrolling in the study; thus, we do not know whether they could have been infected with a resistant strain, had prior NNRTI experience or were subsequently infected with another NNRTI-resistant HIV strain. However, these data would indicate that perhaps all patients should have resistance testing performed prior to treatment initiation, in order to maximize the effectiveness of their initial regimen.
It was interesting to see that approximately equal numbers of patients with baseline NNRTI resistance were still able to achieve an undetectable viral load (as defined in this study) prior to discontinuation of the trial. Whether they had lower baseline viral loads, and thus could achieve this result with only 2 active drugs, was not stated.