Regimens containing 3 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been found to neither achieve nor maintain virologic control as well as regimens containing drugs from 2 different drug classes. The best example of this is the ACTG 5095 study, which demonstrated the inferiority of zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) when compared with an efavirenz (EFV, Sustiva, Stocrin)-based regimen. For this reason, triple-NRTI regimens are not considered optimal first-line therapy by DHHS guidelines.^1,2 Hence the hesitation to experiment with quadruple-NRTI regimens.

However, quadruple-NRTI therapy remains attractive for several reasons: there is a low potential for drug interactions, this regimen has an alternative adverse event profile compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) and, finally, a quadruple regimen of NRTIs provides the opportunity to save a drug class for future salvage therapy.

This study sought to examine the efficacy and possible toxicity of adding a fourth NRTI to a triple-NRTI regimen as first-line therapy. Graeme Moyle from Chelsea and Westminster Hospital in London presented 48-week data from the study which compared a single-class, quadruple regimen of zidovudine/lamivudine/abacavir plus tenofovir (TDF, Viread) to a traditional 2-class regimen of zidovudine/lamivudine (AZT/3TC, Combivir) plus efavirenz for initial therapy of HIV-1 infection.

One hundred fourteen treatment-naive patients were randomized 1:1 to receive 48 weeks of zidovudine/lamivudine (1 tablet twice a day) plus efavirenz (600 mg once a day) versus zidovudine/lamivudine/abacavir (1 tablet twice daily) plus tenofovir (300 mg once a day) -- hereafter called triple- vs. quadruple-therapy arms -- in this open-label, comparative trial. Patients were stratified by plasma HIV RNA > vs. <100,000 copies/mL. Both regimens were 3 pills per day by mouth without regard to food.

There were no significant differences in baseline demographics between the 2 study arms. Patients in both arms were primarily male, 39-40 years of age, with a mean viral load just below 100,000 copies/mL. The 56 patients in the triple-therapy arm had a mean CD4+ cell count of 193 cells/mm³, while the 57 in the quadruple-therapy arm had a mean CD4+ cell count of 153.

In terms of discontinuations, 29% in the triple-therapy arm vs. 30% of the patients in the quadruple-therapy arm discontinued the study, with 11% in the triple- vs. 5% in the quadruple-therapy arms lost to follow-up. Only 1 death occurred, a myocardial infarction in the quadruple-therapy arm, considered unrelated to study drug.

Adverse events were higher in the quadruple-therapy arm -- 16% vs. 11% in the triple-therapy arm, primarily due to possible abacavir hypersensitivity reactions (6/57 patients -- 10.5%).

Dr. Moyle noted that the statistical effect of a single adverse event may be magnified here by the small group size. The triple-therapy arm had 2 patients (4%) who developed efavirenz-related rashes. Virologic failure at week 48 was 0 vs. 1% in the triple vs. quadruple arms. Zidovudine-related adverse events, primarily anemia, occurred in 7 vs. 6% of patients in the triple vs. quadruple arms.

The primary efficacy endpoint was the time-weighted change in average log viral load (DAVG) from baseline through week 48. At day 14 there was no difference in the time weighted average decrease in viral load (-2.14 vs. -2.05 log) in the triple vs. quadruple arms. Throughout the study and at the end of week 48, there was no statistically significant difference in viral load between groups, with a drop of almost 3.5 logs in viral load seen.

Sixty-eight percent of the patients in the triple-therapy arm vs. 67% of the patients in the quadruple-therapy arm reached a viral load less than 50 copies/mL by intent-to-treat analysis with missing/switch of any regimen component equaling failure.

On-therapy analysis showed 100% vs. 97% of patients (triple vs. quadruple, respectively) reached viral loads under 50 copies/mL at 48 weeks. The absolute change in CD4+ cell count was +119 cells/mm³ in the triple-therapy arm vs. +165 cells/mm³ in the quadruple arm, with both arms finishing with around the same total absolute CD4+ cell count, since patients in the triple arm had a higher baseline CD4+ cell count (190 vs. 153 cells/mm³).

Response stratified by baseline CD4+ cell count > or <100 cells/mm³ and viral load >100,000 or <100,000 copies/mL failed to reveal any significant difference.

There was only 1 virologic failure, and this occurred in the quadruple arm. Baseline genotyping showed no reverse transcriptase (RT) mutations, but showed protease mutations 20I and 36I in the protease gene. This patient had a great response to therapy, with a 4-log viral load drop at 4 weeks and a concomitant 180-cell CD4 rise. The researchers reported that this patient's compliance with scheduled medication doses was questionable during this time period, with multiple new RT gene mutations occurring by week 24 (67N, 70R, 184V, 215F, 219E) with a viral load of 63,100 copies/mL. With a regimen change to didanosine (ddI, Videx), tenofovir and lopinavir/ritonavir (LPV/r, Kaletra) at week 24, the patient's viral load rapidly became undetectable.

Fasting triglycerides were different at multiple points and favored the quadruple-therapy arm, although these small differences were not clinically meaningful. The change in cholesterol, however, was significant, with a 25% increase from week 4 to 48 in the triple-therapy arm and no change in the quadruple-therapy arm.

This study explores the intriguing alternative of a single-class, quadruple-nucleoside regimen providing similar efficacy and tolerability to a 2-class triple regimen at 48 weeks of follow-up in treatment-naive patients. While larger, multi-center studies need to be conducted to verify this data and to explore issues such as lipid effects and adherence, these initial data support a 3-pill-a-day single-class all-nucleoside regimen as a viable alternative to the currently recommended 2-class regimens. Dr. Moyle's long-term plan is to continue this study as the Trizivir Induction Maintenance Study (TIMS) -- so we can expect more interesting data on simplified single-class regimens to come.

Footnotes

1. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. April 29, 2004;350(18):1850-1861.

2. Panel on Clinical Practices for Treatment of HIV convened by the Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. October 29, 2004. Available at: http://aidsinfo.nih.gov. Accessed November 1, 2004.