What is the future of nucleoside reverse transcriptase inhibitor (NRTI)-only regimens? While abacavir (ABC, Ziagen)/lamivudine (3TC, Epivir)/zidovudine (AZT, Retrovir) (i.e., Trizivir, TZV) is a compact, well-tolerated regimen with good antiviral activity, it has been bested by efavirenz (EFV, Sustiva, Stocrin)-containing regimens in ACTG 5095,¹ and always was somewhat suspect in patients with high baseline HIV RNA.

In addition, those taking novel NRTI combinations, such as abacavir/lamivudine/tenofovir (TDF, Viread) or didanosine (ddI, Videx)/lamivudine/tenofovir, have had unacceptably high rates of virologic failure, considerably higher than with abacavir/lamivudine/zidovudine. In the two small studies presented here -- plus a larger comparative study² -- favorable results of a quadruple-NRTI regimen of abacavir/lamivudine/zidovudine plus tenofovir are presented.

DeJesus, et al reported on the 24-week outcome of an open-label, single-arm pilot study of abacavir/lamivudine/zidovudine plus tenofovir, all given once daily. Results of an unscheduled safety review (prompted by the poor response to abacavir/lamivudine/tenofovir) have been presented previously.³ There were 123 participants; at baseline, HIV RNA was 5.08 log (approximately 100,000 copies/mL) and the CD4+ cell count was 221 cells/mm³. Fifty-eight percent of the subjects had a baseline HIV RNA of >100,000 copies.

Twenty-four week results demonstrated that 67% and 54% of the subjects achieved an HIV RNA <400 and <50, respectively, by intention-to-treat analysis. Eight patients discontinued due to abacavir hypersensitivity; 3 other treatment discontinuations for adverse events occurred. Fasting lipid values improved on the study. Out of the 8 patients with virologic failure, 2 had pre-treatment resistance not detected prior to entering the study. Resistance testing of these patients with virologic failure found thymidine analog-associated mutations (TAMs) in 6 of the 8, with 3 of these patients also having M184V. The TAM pathway was exclusively the more benign 67, 70, 215 pattern. The study authors noted that response rates in this study were lower than that in a twice-daily abacavir/lamivudine/zidovudine plus tenofovir study; in addition, excellent results compared with zidovudine/lamivudine plus efavirenz are reported at this conference.²

The second study of this combination (Rodriguez, et al) looks at a abacavir/lamivudine/zidovudine plus tenofovir regimen in treatment-experienced patients. Importantly, these were patients with low-level virologic failure (HIV RNA 400-10,000) on their initial antiretroviral treatment.

Fifty-one subjects were enrolled from 23 sites in the United States. (The study initially intended to enroll 100, but accrual was slower than expected, and the study stopped at approximately 50% of enrollment.)

By protocol definition, all had received either zidovudine/lamivudine or stavudine (d4T, Zerit)/lamivudine as their initial NRTIs, plus either a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI). The median baseline CD4+ cell count was 436, with a median viral load of 3.3 log, or approximately 2,000 copies.

At entry, the most common mutation was M184V (seen in 80% of the subjects); TAMs were found in approximately 20% of the subjects, NNRTI mutations were found in 35% and primary PI mutations in 42%.

At the end of 24 weeks, 80% of the subjects had an HIV RNA <50 copies/mL on an on-treatment basis; 65% had <50 copies/mL by intention to treat. Three subjects overall withdrew from the study for adverse events (nausea and fatigue); notably, no subjects experienced a hypersensitivity reaction to abacavir.

The results of this study suggest that patients with early virologic failure on their first regimen can have successful salvage treatment using this quadruple-NRTI approach. The major benefits of this strategy are that it does not introduce a new drug class, and that this particular treatment can be given with relatively low pill burden (3 pills daily).

Both of these studies demonstrate our improved understanding of NRTI resistance: It is now apparent that the high rates of failure seen with abacavir/lamivudine/tenofovir and didanosine/lamivudine/tenofovir were most likely due to the strong selective pressure towards both M184V and K65R, a phenomenon which reduced activity of all 3 drugs in the regimen. By contrast, using abacavir/lamivudine/zidovudine plus tenofovir has zidovudine selecting the gradual accumulation of TAMs, and tenofovir selecting the slow development of K65R. As these mutations are almost mutually-exclusive, the regimen has an extremely high barrier to resistance. Whether the promising results from these two studies (and the comparative study H-1131) will be durable and have favorable long-term toxicity await further follow-up.

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. Moyle G, Nelson M, Higgs C, et al. A randomised open label comparative study of Combivir + efavirenz (2 class triple therapy) versus Trizivir + tenofovir (single class quadruple therapy) in initial therapy for HIV-1 infection. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30 - November 2, 2004; Washington, D.C. Abstract H-1131.

3. Elion R, Cohen C, DeJesus E, et al, for the COL40263 Study Team. COL40263: resistance and efficacy of once-daily Trizivir and tenofovir DF in antiretroviral naive subjects. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Abstract 53.