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CCR5 Antagonists, Tropism Assays: Entry and Entry Inhibitors at 15th Conference on Retroviruses and Opportunistic Infections 2008
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CROI Feb 3-6, 2008, Boston
Eric S. Daar, M.D.
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
There were several important studies related to entry and tropism presented at the 15th Conference on Retroviruses and Opportunistic Infections. This included efficacy trials as well as issues surrounding assays to assess tropism and the emergence of drug resistance. In addition, there was early data presented with new CCR5 antagonists in development.
Maraviroc: Treatment-experienced patients and resistance
The first in class CCR5 antagonist maraviroc (MVC) was recently approved by the FDA for the management of treatment-experienced patients with R5 only virus. Approval was based upon the results of the MOTIVATE 1 and 2 studies, two virtually identical trials performed in different parts of the world that enrolled this patient population in a 1:2:2 ratio to optimized background regimen (OBR), which at the time did not include darunavir, with placebo versus either once or twice daily MVC (1). MVC was dosed at 300 mg unless it was given with ritonavir (RTV)-containing protease inhibitor (PI) other than tipranavir or delavirdine, in which case it was given as 150 mg once or twice-daily. At this meeting the 48-week follow-up data was presented as a combined analysis. This included a total of 840 patients receiving MVC with the mean change in plasma HIV-1 RNA at 48-weeks being -0.78 log10 copies/mL for placebo versus -1.68 and -1.84 log10 copies/mL for once and twice daily MVC, respectively. The details of the virologic response overall as well as by baseline plasma HIV-1 RNA and CD4+ T-cell strata are further summarized in Table 1, with the treatment arms outperforming the placebo group in all cases. Safety data is also derived from combining the large studies with 48-week follow-up. These types of analyses are always complicated by the fact that patients are on a wide range of OBR and the follow-up on the investigational drug tends to be longer than in the placebo group due to higher rates of discontinuation for virologic failure in the latter. Nevertheless, despite the fact that there was considerably more exposure to the study treatment in those given MVC compared to placebo, it was reported that there were no clinically relevant differences in safety. This included no differences in the rate of discontinuation for adverse events, serious adverse events or progression to Category C events. There was particular interest in the number of malignancies since earlier data with another CCR5 antagonist raised this issue as a potential concern. This analysis provided data on AIDS-related and non-AIDS related malignancies demonstrating no suggestion of a higher rate in those treated with MVC than placebo. Finally, there was considerable interest in defining the effect on liver enzymes due to the experience with a CCR5 antagonist that was dropped from development, aplaviroc, and a few select cases in those previously treated with MVC which led to a black box warning in the package insert. The reported data is consistent with earlier analyses showing that Grade 3 or 4 transaminase elevation was rare in all groups with grade 3 and 4 alanine transaminase occurring in 23 (2.7%) and 6 (0.7%) of the 840 MVC-treated patients, respectively, compared to 6 (2.0%) and 1 (0.5%) of the 209 placebo treated subjects, respectively. Importantly, this analysis was not adjusted for study treatment exposure which was nearly 3 times longer for MVC than placebo-treated patients.
Previous analyses of MOTIVATE 1 and 2 have demonstrated that just over half of the patients who experienced virologic failure on MVC had detectable CXCR4-utlizing virus. While this appears to be a major pathway to virologic failure for this drug a careful analysis was performed to define the frequency in which true CCR5 antagonist resistance emerged. In this case the virus does not use an alternative receptor but adapts to use the CCR5 receptor that is bound to the antagonist. Lewis and colleagues analyzed viral clones from patients experiencing virologic failure and defined clones that were likely to be CXCR4 versus CCR5-utilizing by sequence of the V3 loop, a major determinant of tropism (2). These clones were further evaluated in the tropism assay for both tropism and susceptibility to MVC. They found changes within the V3 loop were associated with the ability of resistant virus to interact with the MVC-bound CCR5 receptor. This preliminary data provides further evidence for the emergence of resistance in select MVC-treated patients. The frequency and clinical relevance of these observations remains to be seen. Moreover, assays for CCR5 resistance are not yet available. The clinical implications for this observation may impact how patients who experience virologic failure on a CCR5 antagonist should be managed. For example, it remains unknown whether those experiencing virologic failure on this class of drugs should have repeat tropism assay performed. If done and CXCR4-utilizing virus is present a case could be made for the patient not being a candidate for continued treatment with MVC or other CCR5 antagonists in development. If such viruses are not present it is not possible to know whether true resistance has emerged and therefore if this drug would be an active part of a subsequent regimen.
Vicriviroc (VCV): Treatment-experienced patients
VCV is a CCR5 antagonist that was previously shown to be efficacious in ACTG 5211, a phase 2b study of OBR with placebo versus one of several doses of the investigational drug in patients without detectable CXCR4-utlizing virus at screening (3). At this meeting data from the VICTOR-E1 Trial, a similar study using different doses of this drug were reported (4, 5). This was a multinational, randomized, double-blind, placebo-controlled trial of OBR with placebo or VCV given as 20 or 30 mg once daily. Patients were all treatment-experienced and did not have detectable CXCR4-utilizing virus at screening. OBR included at least 3 drugs along with at least 100 mg of RTV to pharmacologically boost VCV. Overall there were 116 subjects randomized 1:1:1 between the groups with a primary efficacy analysis being change from baseline in plasma HIV-1 RNA. The virologic and immunologic responses are summarized in Table 2 with significantly better responses at 48-weeks in those given either dose of VCV compared with placebo. While the data set for this drug is much smaller than that for MVC the overall responses are quite similar and suggest this is a promising once-daily CCR5 antagonist. Although not significantly different, median Cmin drug levels were approximately 30% higher with the 30 mg than 20 mg dose and overall responses tended to favor the 30 mg dose, particularly in those with higher plasma HIV-1 RNA levels. There were no apparent differences in adverse events, no serious adverse events attributed to study drug and no deaths during the study. In ACTG 5211 there were several cases of malignancies that led to considerable discussion of the potential role of VCV (3). Ultimately it was determined that there was no conclusive evidence of a relationship between the investigational drug and this outcome. Consistent with this, it was reported in VICTOR-E1 that there was only one lymphoma and it developed in a study subject during follow-up after completion of the 48 week study. It was stated that the 30 mg once-daily dose in a ritonavir-containing regimen is currently in phase 3 clinical trials.
Maraviroc (MVC) in antiretroviral-na•ve patients
The MERIT study was a phase III trial of zidovudine/lamivudine (ZDV/3TC) given with MVC at 300 mg once or twice daily compared to efavirenz (EFV) in treatment-na•ve patients without detectable CXCR4-utilizing virus at screening. As previously reported (6), the once daily arm was discontinued prematurely due to lower response rate and at 48 weeks the twice-daily MVC demonstrating that the twice-daily MVC was noninferior to EFV for the proportion with plasma HIV-1 RNA <400 copies/mL but was not noninferior for the proportion less than 50 copies/mL. The difference between the groups was 4% with the lower 97.5% confidence interval reaching -10.9%, crossing the pre-defined noninferiority cutoff of 10% (6). At this meeting the investigators attempted to determine how much of this difference might have driven by the inclusion of those with low level CXCR4-utlizing virus missed at screening. The rationale for evaluating this is that it has been seen in virtually all trials of CCR5 antagonists that while patients enter after screening negative by the Trofile assay (Monogram Biosciences) for CXCR4-utlizing virus approximately 5-10% will have these viruses detected at entry, prior to receiving the drug. In the current analysis (7), the investigators retrospectively reviewed the data and found that 25 of those who screened into the study had CXCR4-utilizing viruses present at entry, 11 given EFV and 14 MVC twice-daily. In assessing the outcome in these patients they found that those without CXCR4-utilizing virus at screen or entry had 69.3 compared to 68% in the EFV and MVC group, respectively, achieving less than 50 copies/mL at 48 weeks. In contrast, those with CXCR4-utlizing virus present at entry had attenuated responses regardless of which drug they received, although it was much lower amongst the 14 given MVC (7.6%) than the 11 given EFV (54.6%). This data is entirely consistent with the fact that the main difference in outcome between the arms may relate to a small but important number of individuals entering the study that had CXCR4-using virus that would not be inhibited by a CCR5 antagonist. It further emphasizes a limitation of the current assay that is widely used to screen subjects for treatment with this class of drugs.
While efficacy and safety remain key endpoints for clinical trials of novel agents, there is increasing interest in the impact of new drugs on metabolic parameters. These endpoints are often difficult to define in current trials of treatment-experienced patients due to the heterogeneity of the patient population and the drugs used in the OBR. The MERIT trial allowed for a careful assessment of the effect of MVC relative to EFV, both given with ZDV/3TC on lipid parameters. DeJesus and colleagues presented the lipid data from this study comparing maximum change from baseline for total cholesterol, HDL, LDL and triglycerides between the groups (Table 3) (8). Overall changes were modest but were greater in those given EFV than MVC for all parameters with modest but significantly greater decrease in the total cholesterol to HDL ratio in the MVC than EFV group (-0.54 versus -0.43, respectively; p=0.005).
Tropism assays
Recognition that low level CXCR4-utilizing virus can be missed with the currently validated Trofile assay, Monogram Biosciences is developing an assay with enhanced sensitivity for detecting these viruses. They previously reported that the new assay had greater than 10-fold increased sensitivity for detecting CXCR4-utlizing virus (9). At the current meeting there were several studies that used the new assay on clinical specimens to assess the potential utility in clinical practice. Reeves and colleagues reanalyzed samples at screening and entry for those enrolled in ACTG 5211 (10). The enhanced assay was used on stored plasma from the screening visit of all study subjects and demonstrated the potential to increase the ability to identify people with low level CXCR4-utlizing virus who are at risk for virologic failure. By the currently available assay 12 subjects at screening that did not have detectable CXCR4-utlizing virus had them detected by the same assay at baseline. Of these, 7 (58%) had these viruses detected by the enhanced assay in stored samples from the screening. In addition, they demonstrated that CXCR4-using virus was identified by the enhanced assay in 9 of 18 (50%) subjects that did not have them detected at either screen or baseline by the standard assay but went on to fail with these viruses. Based upon these data it appears likely that the increased sensitivity of the enhanced assay may improve outcomes when CCR5 antagonists are used in the clinic. To assess the specificity of the new test the group studied stored samples from screening for all 116 enrolled subjects, all of whom had no detectable CXCR4-using virus present by the standard assay. They found that 25 of the 116 subjects who screened in by the standard assay did have CXCR4-utlizing virus present in the screening sample by the enhanced assay. Of these, 15 were ultimately treated with VCV, 12 of which ultimately failed with viruses that could use the CXCR4 receptor. An additional 3 (20%) would have been screened out by the enhanced assay for this treatment despite the fact that they did not fail. While this could suggest that the new assay is too sensitive and might exclude those that might otherwise benefit, it may also reflect the fact that all patients received OBR which in some cases may have been sufficiently potent to result in virologic suppression alone. Overall, this study suggests that the enhanced tropism assay may improve the utility of CCR5 antagonists and provide reassurance that this class of drugs will be fully active in those without detectable CXCR4-utilizing virus. The enhanced assay remains in development and is not yet available for clinical purposes. In the interim, clinicians will need to use the standard assay or others that may be available, although not validated to the extent of the Trofile assay, in order to determine which patients are the best candidates for CCR5 antagonist therapy.
There is considerable interest in developing other genotypic and phenotypic methods for assessing viral tropism on clinical samples in the clinic. The SensiTrop test (Pathway Diagnostics) uses a heteroduplex tracking assay and has been available through select laboratories. Since this assay is more rapid and potentially less expensive than the Trofile assay there was interest in defining its relative sensitivity for detecting CXCR4-utlizing virus. Tressler and colleagues submitted 100 plasma samples from patients screened for MCV use in the expanded access program (11). Screening by the Trofile assay found that 52 did, and 39 did not have detectable CXCR4-utilizing virus. The remaining 9 samples were non reportable by the assay. Of the 39 with dual/mixed or X4 virus by Trofile 19 were R5 only and 6 nonreportable by the SensiTrop assay. Based upon this data the authors reported the specificity of the SensiTrop assay for detecting CXCR4-using virus to be 92.5% (95% CI: 84.3-100.7) with a poor sensitivity of 42.5% (95% CI: 25.6-59.3%). This is vital in order to determine whether CCR5 antagonist can be counted upon as one of the active drugs in a new regimen.
Another study was reported by Pathway Diagnostics demonstrating the increased sensitivity of the SensiTrop assay when selectively combined with sequencing (12). In study they used the heteroduplex assay first and if no CXCR4-utlizing virus is detected it is followed by DNA sequencing. They showed that this method increased the overall concordance between their assay and Trofile from 72% to 89%. Although this group and others should be commended for their efforts to develop new tropism assays, the experience emphasizes the importance of using assays that have been carefully validated to ensure that treatment is optimized for the given patient.
CCR5 Antagonists in Earlier Stages of Development
There are several CCR5 antagonists in development, including SCH532706 (13). This drug is 80% protein bound, is a substrate for cytochrome P450 and has a dissociation half life of approximately 78 hours. The study was a fixed-sequence, open label, non-randomized study of 10 days of monotherapy in patients not on treatment and had no detectable CXCR4-utilizing virus present by the ViroTest assay at screening. The primary endpoint was change from baseline in plasma HIV-1 RNA at day 10 of treatment. The drug was dosed at 60 mg twice daily with 100 mg once-daily of ritonavir. There were 12 subjects enrolled with a mean change in plasma HIV-1 RNA of -1.3 log10 copies/mL at day 10 and a mean peak change of -1.6 log10 copies/mL at day 15. 83% had greater than 1 log10 reduction in viral load at day 10. Other than diarrhea in 33% the drug was generally well tolerated with no QTC prolongation or serious adverse events. They did report a single patient with self-limiting pericarditis that developed 13 days after drug was stopped. The authors proposed that the long half-life of the drug should make it possible to be developed as a once-daily therapy.
Clinical data was also presented from a 14-day monotherapy study of the CCR5 antagonist INCB9471. Once again, this study included patients not on antiretroviral therapy who had no detectable CXCR4-utlizing virus at screening by the Trofile assay (14). Patients received placebo (n=9), 100 mg (n=9), 200 mg (n=19) or 300 mg (n=12) once-daily for 14-days. Of the 39 treated with drug, 30 achieved a greater than 1.5 log10 copy/mL decline in plasma HIV-1 RNA from baseline with 4 having detectable CXCR4-utlizing virus after the initiation of therapy. As seen in other related analyses, preliminary data suggested that the emergent CXCR4-using viruses pre-existed at low levels prior to the initiation of therapy. Moreover, often these viruses returned to minority species that were undetectable with current assays after the CCR5 antagonist was discontinued.
REFERENCES
1. Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 792.
2. Lewis M, Mori J, Simpson P, et al. Changes in V3 loop sequence associated with failure of maraviroc treatment in patients enrolled in the MOTIVATE 1 and 2 trials. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 871.
3. Gulick RM, Zu S, Flexner C, et al. Phase 2 Study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS Clinical Trials Group 5211. Journal of Infectious Diseases. 2007;196:304-12.
4. Zingman B, Suleiman J, DeJuesus E, et al. Vicriviroc, a next generation CCR5 antagonist, exhibits potent, sustained suppression of viral replication in treatment-experienced adults: VICTOR-E1 48-week Results. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 39LB.
5. Zingman B, Suleiman J, DeJesus E, et al. Vicriviroc in combination therapy with an optimized ART regimen for treatment-experienced subjects: VICTOR-E1. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 795.
6. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine/lamivudine), for the treatment of antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Abstract WESS104.
7. Heera J, Saag M, Ive P, et al. Virological correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-na•ve patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 40LB.
8. DeJesus E, Walmsley S, Cohen C, et al. Fasted lipid changes after administration of maraviroc or efavirenz in combination with zidovudine and lamivudine for 48 weeks to treatment-na•ve HIV-infected patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 929.
9. Reeves JD, Han D, Liu Y, et al. Enhancements to the Trofile HIV coreceptor tropism assay enable reliable detection of CXCR4-using subpopulations at less than 1%. 47th ICAAC 2007, Chicago, IL, Abstract H-1026.
10. Reeves J, Han D, Wilkin T, et al. An enhanced version of the Trofile HIV co-receptor tropism assay predicts emergence of CXCR4 use in ACTG5211 vicriviroc trial samples. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 869.
11. Tressler R, Valdez H, van der Ryst E, et al. Comparison of results from the SensiTrop vs Trofile assays on 100 samples from the maraviroc expanded access program. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 920a.
12. Li W, Webb E, Nary L, Robins T. SensiTrop QT: A novel molecular diagnostic assay for the detection and quantification of HIV co-receptor tropism. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 919.
13. Pett S, Emery S, MacRae K, et al. Safety and Activity of SCH532706, a Small Molecule Chemokine Receptor 5 Antagonist in HIV-1-infected Individuals. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 38.
14. Erickson-Viitanen S, Abremski K, Solomon K, et al. Co-receptor tropism, ENV genotype, and in vitro susceptibility to CCR5 antagonists during a 14-day monotherapy study with INCB9471. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Abstract 862.
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