During the past 2 years, there have been quite a few studies of triple-nucleoside regimens that have failed. But perhaps one of the most surprising results occurred in a recent study called GSK 30009 which pitted the triple-nucleoside arm of tenofovir (TDF, Viread) plus abacavir/lamivudine (ABC/3TC, Epzicom) against efavirenz (EFV, Sustiva, Stocrin) and abacavir/lamivudine.

Based on previous studies that compared triple-nuke regimens to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, one might have predicted that the efavirenz-based regimen would prevail in this matchup. But few would have predicted the colossal failure of the tenofovir plus abacavir/lamivudine regimen. Approximately 50% of the study participants manifested early virologic failure and the trial was halted prematurely.

The stoppage of the 30009 trial coincided with several other high-profile flops of triple-nucleoside regimens. The most famous, of course, was the AIDS Clinical Trial Group's (ACTG) 5095 trial, which compared zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) to efavirenz-based regimens. The zidovudine/lamivudine/abacavir arm was brought to an early close by the data safety and monitoring board because of its relative underperformance.¹

Not long after the 5095 study was halted, more than half (11 of 19) of the study participants experienced virologic failure by week 8 in a pilot study utilizing tenofovir, lamivudine (3TC, Epivir) and abacavir (ABC, Ziagen).²

Finally, another triple-nucleoside study looked at the combination of didanosine (ddI, Videx), tenofovir and lamivudine³ and this one also had dismal results; 20 of the 22 subjects failed therapy in this pilot.

The underperformance of zidovudine/lamivudine/abacavir versus efavirenz-based therapy in the ACTG 5095 trial was not all that unexpected, since there had been prior studies that questioned the potency of zidovudine/lamivudine/abacavir, particularly in patients with high viral loads.

Tenofovir was the drug of choice in many new triple-nucleoside trials because in early monotherapy trials it had been shown to be significantly more potent than zidovudine (AZT, Retrovir). It thus seemed logical to use it in place of zidovudine along with lamivudine and abacavir. The hope was that this triple-nucleoside, tenofovir-based cocktail would be compact, class sparing, well tolerated and, of course, effective. These research results demolished any such illusions.

An additional observation common to these trials of tenofovir-based triple-nucleoside therapy was the high rate of resistance mutations accompanying the virologic failures. Most of the trial participants who experienced virologic failure developed the M184V mutation that confers resistance to lamivudine. Many participants had a double whammy, with the development of not 1 but 2 resistance mutations -- the K65R mutation associated with tenofovir resistance was also found. One of the natural questions that arose concerning this failed arm of the trial was how to handle these participants with virologic failure. What salvage regimens would be effective for patients who had the combination of M184V and K65R? This follow-up study was designed to gather information on subsequent treatment outcomes for these patients.

Study

The 30009 study compared fixed-dose abacavir/lamivudine with either tenofovir or efavirenz. As mentioned, the tenofovir portion of the study was prematurely stopped, but the subjects randomized to efavirenz continue on study. This report provided details on the 24-week outcomes of these efavirenz-treated subjects and also some follow-up data on some of the unlucky abacavir/lamivudine and tenofovir recipients.

There were 169 study participants randomized to efavirenz in this trial. The week 24 intention-to-treat results were as follows: 77% of the participants reached a viral load of less than 400 copies/mL and 69% reached an HIV RNA of less than 50 copies/mL. These results are consistent with findings from other studies of efavirenz plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

When the abacavir/lamivudine plus tenofovir arm of this trial was terminated, study participants were given the opportunity to remain in the trial with an investigator-chosen, second-line regimen. One hundred and thirty of the original 171 tenofovir-treated patients remained in the trial on second-line therapy and 12-week interim data were presented for this group.

Of the 130 study participants who were switched, 40% had an HIV RNA of less than 50 copies/mL at the time of the switch. Over the next 12 weeks, approximately 80% of the 130 patients suppressed to less than 50 copies/mL on the "intention to treat" analysis and 90% reached less than 50 copies/mL on the "as treated" analysis.

At the time of this presentation, data was not yet available on the impact of resistance mutations on the response of these subjects to second-line therapy.

Comment

This interim analysis represents important data because it helps to clarify treatment options for patients who have failed the ill-fated tenofovir-based triple-nuke initial regimen. The reassuring news was that even though most patients were switched to an NNRTI-based regimen, there was evidence of a favorable early virologic response.

Since one of the concerns was that an M184V and K65R pattern would make NNRTI-based salvage difficult and necessitate early use of protease inhibitors (PIs) it will be interesting to see the actual outcomes for these patients once this data is fully analyzed. Most of the previous literature regarding second-line therapy in this situation has involved the use of boosted-PI therapy, and optimal management tactics for these patients with dual mutations remains an unanswered question.

Footnotes

1. Gulick RM, Ribaudo HJ, Shikama 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. Farthing C, Khanlou H, Yeh V. Early virologic failure in a pilot study evaluating the efficacy of abacavir, lamivudine and tenofovir in the treatment naive HIV-infected patients. In: Program and abstracts of the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 43.

3. Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Abstract 51.