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Report from the XVI International HIV Drug Resistance Workshop
An expert’s take on the most clinically relevant findings from this year’s resistance meeting
Many new agents from novel drug classes are now available through expanded access and are expected to gain FDA approval within the next year. Having so many new agents available at the same time means that clinicians can finally construct salvage regimens that maximize the likelihood of full virologic suppression while minimizing further resistance. Still, resistance to these new agents is inevitable, as indicated by many presentations at this year’s International HIV Drug Resistance Workshop, which took place in mid-June in Barbados. The findings described herein are all from industry-supported studies.
CCR5 Antagonists
Two CCR5 antagonists are currently in the late stages of clinical development: Maraviroc is available through expanded-access programs, with FDA approval seemingly imminent, and vicriviroc is entering phase III investigation. Because these drugs bind to host receptors rather than to the virus itself, patterns of efficacy and resistance will likely differ from those of other antiretrovirals.
Tsibris and colleagues analyzed the characteristics of a virus that developed resistance to vicriviroc in ACTG 5211, a phase IIb trial in highly treatment-experienced patients (ACC Jul 9 2007) [Abstract 13]. Similarly, Mori and colleagues characterized four viruses that developed resistance to maraviroc in the phase III MOTIVATE trials [Abstract 10]. Several findings from these studies were notable.
First, the mutations responsible for CCR5-antagonist resistance were in the V3 loop, but their positions and specific amino-acid substitutions varied from one virus to the next. Consequently, clinicians will need to rely on phenotypic testing, rather than genotypic testing, to identify viruses that are resistant to this drug class.
Second, phenotypic tests did not reveal the classic pattern of resistance: The 50% inhibitory concentration did not change, as it does with resistance to other antiretroviral drug classes. Instead, a plateau effect was seen, such that no amount of drug could maximally suppress the virus. This unusual pattern complicates the definition of drug resistance, even with phenotypic testing.
Finally, the mutations observed in the V3 loop seemed to reduce viral fitness in the absence of the drug, such that wild-type virus had the advantage when the drug was withdrawn. Interestingly, the virus that showed the greatest degree of resistance to vicriviroc grew better when the drug was present rather than absent, indicating that the resistant virus had developed a degree of dependence on the drug for optimal replication.
In another analysis from the MOTIVATE trials, Lewis and colleagues explored the development of CXCR4-using virus during treatment [Abstract 56]. Surprisingly, they found that viruses that started using CXCR4 receptors during treatment were often phylogenetically unrelated to the predominant viruses present at baseline. In some cases, the virus found during treatment was a minor variant in the starting population. These findings suggest that, in some patients, the baseline virus is not evolving into a dual/mixed CXCR4-using virus through the accumulation of mutations; instead, a pre-existing dual/mixed or CXCR4-using virus might be present at baseline that goes undetected by the phenotypic assay and then gets selected by CCR5 antagonists during treatment. This pathway of viral escape seems to be fairly common, accounting for two thirds of virologic failures with maraviroc and 40% of failures with vicriviroc. Thus, the emergence of true resistance (in which mutations accumulate and render the drug ineffective) appears to be relatively less common.
Integrase Inhibitors
The integrase inhibitors furthest along in clinical development are raltegravir, which is available through expanded-access programs, and elvitegravir, which is being investigated in phase II studies. In separate presentations, Hazuda and McColl described resistance patterns in patients who experienced virologic failure in phase II trials of these two drugs [Abstracts 8 and 9]. Both reports implicated the same set of mutations (at positions 148 and 155 of the integrase) and demonstrated that a mutation at either position could confer cross-resistance to both compounds. These findings underscore the importance of using integrase inhibitors in combination with other active drugs.
Etravirine
The novel NNRTI etravirine (formerly TMC125) has been studied in the phase III DUET trials (Lancet 2007; 370:29, 39) and is available by expanded access. Vingerhoets and colleagues reported on resistance patterns among DUET participants, all of whom had NNRTI-resistant virus and were randomized to receive optimized background regimens, the new PI darunavir, and either etravirine or placebo [Abstract 32]. The likelihood of virologic response to etravirine was inversely related to the number of NNRTI mutations present at baseline. Notably, when present alone, the 181C mutation did not confer resistance to etravirine; only when it was combined with at least three other NNRTI mutations did it have any major detrimental effect on virologic response to etravirine.
Lopinavir
Resistance to lopinavir is fairly uncommon in patients who receive the drug as part of a first PI-containing regimen. Two research groups documented a new pathway to such resistance, involving the L76V mutation [Abstracts 127 and 75]. This mutation emerged most commonly in people who had nonsubtype-B virus (predominantly African immigrants to Europe).
Additional information about lopinavir resistance came from a report on ACTG 5142, a large randomized trial that compared three regimens: an efavirenz-based regimen (with 2 NRTIs), a lopinavir/ritonavir-based regimen (with 2 NRTIs), and a nucleoside-sparing regimen (with efavirenz + lopinavir/r). As previously reported, the efavirenz-based regimen performed slightly better than the lopinavir-based regimen, and the nucleoside-sparing arm did about as well as the efavirenz-based arm (ACC Sep 18 2006). Now, Haubrich and colleagues have analyzed the prevalence and patterns of resistance in 180 of the trial participants who experienced virologic failure [Abstract 57]. Seventy percent of these patients demonstrated evidence of resistance to one or more drugs, with distinct patterns seen in each treatment arm. Among patients who experienced failure on efavirenz-based regimens, 44% had evidence of resistance to efavirenz, and 30% had evidence of resistance to an NRTI, mainly 3TC. In contrast, among patients who experienced failure on lopinavir-based regimens, only 19% had resistance to NRTIs, and none had resistance to lopinavir. In the nucleoside-sparing arm, two thirds of patients with treatment failure had evidence of efavirenz resistance, but only 4% had evidence of lopinavir resistance. Overall, these findings highlight an important trade-off between efavirenz and lopinavir: Efavirenz-based regimens are slightly more successful in terms of maintaining virologic suppression, but when these regimens fail, the chances of resistance are greater than those seen with lopinavir-based regimens. The reason for the difference in performance of the efavirenz- and lopinavir-based regimens is not clear but may be related to minor differences in tolerability of the two regimens (patients in this study used the older gel formulation of lopinavir/r, which has since been replaced by a tablet formulation that may be better tolerated).
— Daniel R. Kuritzkes, MD
Dr. Kuritzkes is a Professor of Medicine at Harvard Medical School and Director of AIDS Research at Brigham and Women’s Hospital in Boston. He was co-chair of ACTG 5211 and directed the related analysis described in Abstract 13. He is a consultant to and has received honoraria and/or research support from Abbott, Gilead, Merck, Pfizer, Schering-Plough, and Tibotec, all of which produce drugs discussed in this report.
Published in AIDS Clinical Care July 9, 2007