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CROI Resistance Report 4: Certain, But Not All, Triple Nuke Regimens Have High Viral Failure Rate
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Written for NATAP by Andrew Zolopa, MD
Stanford University
Resistance Associated with Certain "all Nuc" ARV Therapy
Over the past year, we have seen several studies demonstrating relatively poor virologic responses associated with certain 'triple nuc" regimens. As a result, certain triple nucleoside/tide regimens are no longer recommended as regimens of first choice in most settings. However, Trizivir has not been shown to be associated with these poor responses; Trizivir is one pill taken twice daily and consists of abacavir (Ziagen), AZT, and 3TC in each pill. At the conference this year we heard additional reports of all nuc regimens and the resistance patterns seen with failure. We will focus on the resistance aspects of these studies.
Late last year, a "Dear Doctor" letter was widely circulated to practitioners regarding poor virologic responses in a small pilot study of once daily DDI, 3TC and TDF (tenofovir, a/k/a Viread). Jemsek presented the results of the study that was the basis of this letter. The open label uncontrolled study included 24 treatment naïve patients who received DDI EC 250 mg, TDF 300 mg and 3TC 300 mg all dose qday (once daily). [abstract 51] The study was terminated early given the poor responses seen. The average viral load change at 24 weeks was --0.49 log and apparently no patients achieved <50 copies/ml while on this combination. Of the 24 subjects enrolled, genotypes were available on 20, all had 184V or I mutations and 10 had the 65R mutation (7 of the 10 were present as mixtures with wildtype at codon 65). No NNRTI or PI mutations were detected. No PK data was available and adherence was not systematically evaluated.
The Tonus study was the third study evaluating the combination of ABC, 3TC and TDF as a once daily regimen for treatment naïve subjects. [abstract 52] This open label study was also terminated early like the previous studies given the reports of poor response. This study had the advantage over the prior two studies of this combination in that plasma and intracellular PK evaluation was performed to evaluate potential antagonistic drug-drug interactions that might have explained the poor responses observed. Virologic failure (never achieved <500 copies or a 0.7 log rebound) was observed in 12/36 subjects at week 24 - 8/12 failed to suppress and 4 rebounded. Failure was clearly associated with higher baseline viral loads, in fact all failures were seen in the group with baseline viral loads of >100,000.
In the 12 failures, 11 had genotypes available at failure and 9 had both K65R and M184V/I mutations detected. The other 2 had the 184V mutation only. In 10 subjects who did not meet failure criteria but had ongoing viremia, genotype revealed that 7/10 had 65R and 184V and 2 had the 184V alone. The PK analysis revealed adequate trough concentrations of all drugs in 32/37 subjects evaluated, 5 subjects had low Cmins for at least one drug in the regimen. In a subgroup of 14 subjects with intracellular tri/di phosphate levels evaluated all had detected levels but were not quantified.
Rick Elion presented interim results from an open label uncontrolled pilot study, COL 40263 another all nuc regimen. [abstract 53] In this case, unlike the other studies, the regimen used could be called a "quad nuc" regimen, consisting of Trizivir and TDF dosed q day (once daily). In this interim analysis, the investigators used the virologic failure criteria that were developed for another GSK sponsored study of ABC/3TC/TDF (ESS 30009). This endpoint termed early virologic non-response (EVNR) is defined as: <2 log decline and >50 copies by week 8 or >1 log rebound from nadir by week 8, in addition, failure was defined as >400 copies at week 24 or later. In the 123 subjects enrolled in the study, 88 had at least 8 weeks of evaluation and 54 had >24 weeks of evaluation. Over all, 24% met the EVNR definitions (17% in the group with baseline HIV RNA of <100,000 and 29% in those with >100,000 copies at baseline). On treatment analysis at 24 weeks, revealed 78% of subjects had viral loads of <400 copies and 67% were <50 copies. The investigators compared this response rate to that seen in ESS30009 and this cross study comparison favored the quad nuc regimen.
In terms of the resistance patterns seen in this study, genotypes were available on 8 subjects of 54 that experienced virologic failure after completing 24 weeks on study. Thymidine-analog mutations (TAM's) were present in 5 of the 8, 3 of these subjects had 184V in addition to the TAM's and only 1 subject had the K65R mutation.
The theme of higher failure rates with these particular triple nuc regimens continues with these studies but the response rates seen with the quad nuc regimen appears to be better. However, controlled trials are required to fully assess the efficacy of this treatment regimen. In terms of the resistance themes that emerge from these studies, it is clear that triple nuc regimens that contain 2 or more drugs that select for the 65R mutation show relatively high rates of that mutation at failure. The clinical implications of the K65R mutation on subsequent response to ARV therapy has not been fully explored but in the Tonus trial, good responses were achieved in patients who failed with the 65R. None-the-less there is concern since K65R is associated with reduced susceptibility on phenotype tests to all of the nucleosides/tides except for AZT (in which it causes hypersusceptibility) and possibly D4T. Since 65R makes viruses more susceptible to AZT, there is the suggestion that AZT-containing regimens may help prevent the emergence of 65R. Certainly there were fewer subjects with 65R at failure in the COL 40263 study compared triple nuc regimens of ABC/3TC/TDF or DDI/3TC/TDF. In the next section we will explore the prevalence of 65R, mechanisms of resistance and mutational interactions and the clinical implications of these observations.
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