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| Drs. Joseph J. Eron, Daniel R. Kuritzkes, and Pedro Cahn review lat |
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I learn a lot from this printed discussions of experts in clinical care options. I respect Dr Daniel Kuritzkes' opinion the most in the field of HIV. He usually says what he believes without being afraid of pharmaceuticals.
DUET-1 and -2: Assessment of Etravirine (TMC 125- a new non nucleoside) Plus Darunavir/Ritonavir (Prezista) -Based Regimens in Treatment-Experienced Patients
Daniel R. Kuritzkes, MD:
The DUET-1 and -2 studies are a pair of randomized, placebo-controlled, double-blind, phase III trials investigating the use of etravirine (formerly known as TMC125), a next-generation NNRTI, in highly treatment–experienced patients (Capsule Summary).[1,2] The 24-week results from these 2 trials were presented at the International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention and were also recently published in The Lancet.[3,4] To be enrolled in the studies, patients experiencing virologic failure on their current HAART regimen had to have evidence of at least 1 NNRTI resistance mutation either at screening or in a previous genotype, along with 3 or more primary PI resistance mutations at screening. These inclusion criteria ensured that this group of patients was highly treatment experienced. The DUET studies were unique in that all participants received darunavir/ritonavir as part of their optimized background regimen, which was also an investigational agent at the time the study was done. A total of 1203 participants in both DUET trials were randomized to receive etravirine or placebo, each combined with darunavir/ritonavir and optimized background regimen. The primary endpoint of both studies was HIV-1 RNA < 50 copies/mL at Week 24. The DUET-1 trial was conducted in Argentina, Brazil, Chile, France, Mexico, Panama, Puerto Rico, Thailand, and the United States, whereas DUET-2 was conducted in Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Portugal, Spain, the United Kingdom, and the United States.
The 24-week results of the studies showed that there was a substantial advantage to receiving etravirine in addition to darunavir/ritonavir and optimized background regimen. The rate of virologic suppression < 50 copies/mL for the etravirine arms vs the placebo arms was 56% vs 39% for patients in DUET-1 (P = .005) and 62% vs 44% for patients in DUET-2 (P = .0003). In addition, patients who received etravirine in DUET-1 demonstrated a significantly greater mean increase in CD4+ cell count from baseline compared with placebo recipients (+89 vs +64 cells/mm3, respectively; P = .0002). Etravirine was well tolerated, with a toxicity profile comparable to that of the placebo arms.
Some very interesting subanalyses assessed the relationship between the number of NNRTI mutations and activity, as well as how the use of enfuvirtide in the background regimen influenced activity. The investigators identified 13 etravirine resistance mutations, which were associated with a reduced response to etravirine. This group of mutations comprised V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Patients with no etravirine resistance–associated mutations at baseline had a virologic response rate (HIV-1 RNA < 50 copies/mL) that approached 80%. This response rate fell to approximately 60% in the presence of 1 or 2 etravirine resistance–associated mutations and fell further to 38%—a virologic response rate similar to the placebo arms—in the presence of 3 or more etravirine resistance–associated mutations. The relatively common Y181C mutation confers resistance to the first-generation NNRTIs but, by itself, had minimal impact on etravirine response rates as demonstrated in a focused subanalysis. A similar proportion of patients with only the Y181C resistance mutation achieved an undetectable HIV-1 RNA compared with the overall virologic response rate for the pooled etravirine arms (65% vs 62%, respectively). Finally, it is important to point out that the K103N mutation does not affect etravirine susceptibility and, as such, is not listed among the 13 etravirine resistance mutations.
Joseph J. Eron, Jr., MD:
Early findings raised concerns that Y181C might have a particularly important influence on etravirine susceptibility, but these data demonstrated that this is only true when Y181C is present together with several additional NNRTI resistance mutations. It was also reassuring to see the most common NNRTI mutation, K103N, did not affect the response to etravirine. The investigators presented data showing that patients who had no etravirine resistance–associated mutations at baseline attained the best virologic response at Week 24 (approximately 80% with HIV-1 RNA < 50 copies/mL), suggesting that the investigators have correctly identified the mutations that contribute to etravirine resistance.
Pedro Cahn, MD, PhD:
It is interesting to note that the placebo arm regimens also performed quite well, which speaks to the efficacy of darunavir/ritonavir in the background regimen. The proportion of patients in the placebo arms who achieved HIV-1 RNA < 50 copies/mL at Week 24 in DUET-1 and DUET-2 was 39% and 44%, respectively. Furthermore, 33% to 34% of patients in the placebo arm who did not receive enfuvirtide or who were not naive to enfuvirtide still achieved HIV-1 RNA < 50 copies/mL at Week 24. In comparison, placebo recipients who did receive enfuvirtide for the first time in combination with darunavir/ritonavir achieved virologic response rates of 56% and 68% in DUET-1 and DUET-2, respectively.
In my opinion, the difference in virologic outcomes between etravirine recipients and placebo recipients who had no active agents in their background regimens was a striking finding. In DUET-1, 47% of etravirine-treated patients with no active agents in their background regimen achieved HIV-1 RNA < 50 copies/mL at Week 24 compared with 9% of placebo-treated patients. In DUET-2, the respective proportions were similar at 44% vs 7%.
Joseph J. Eron, Jr., MD:
Indeed, the difference in response rates between etravirine-treated patients and placebo-treated patients who had no or only 1 active agent in their background regimen ranged from 27% to 38%. However, when there were 2 or more active drugs in the background regimen, there was only a modest difference in response rates between the 2 arms—approximately 7% to 12%. It is not clear to me why etravirine was so effective on its own or in combination with 1 other active agent, and yet it contributed only modest added efficacy once there were multiple active drugs in the regimen.
Another interesting aspect of this study is the adverse effect profile of etravirine compared with placebo. Rash was reported by patients in both study arms, but it was significantly more common in the etravirine arms (P < .0001). The incidence of rash in the etravirine and placebo arms was 20% vs 10% in DUET-1 and 14% vs 9% in DUET-2. However, the reported rashes were usually mild. Only 1% of patients had grade 3 rash, and none had grade 4 rash. A few patients had fever and rash, but there were no patients with fever, rash, and abnormal liver function test results. Of note, 34% of women in the etravirine arms experienced rash compared with only 18% of men (P = .0192). Aside from rash, there were no other noticeable differences between the placebo-treated patients and the etravirine-treated patients regarding the incidence of adverse events. The investigators specifically evaluated the incidence of central nervous system (CNS) events and psychiatric events (sleep disturbances, anxiety, depression) and observed very few differences between the study arms.
Pedro Cahn, MD, PhD:
There were also no significant differences between the etravirine and placebo arms regarding increases in lipid parameters, nor were there any significant differences in liver toxicity.
TMC278 ( another non nucleoside following TMC 125) Metabolic and Safety Substudies: Investigation of Rilpivirine (TMC 278) in Treatment-Naive Patients
Pedro Cahn, MD, PhD:
Rilpivirine, formally known as TMC278, is another next-generation NNRTI with activity against both wild-type and NNRTI-resistant HIV-1 that is currently being developed for use in first-line therapy. TMC278-C204 is an ongoing, randomized, controlled, partially blinded, dose-ranging phase IIb study comparing the efficacy and safety of 3 different doses of rilpivirine (25, 75, and 150 mg once daily) with that of efavirenz (600 mg once daily). According to the preliminary 48-week results of the TMC278-C204 study reported at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI), rilpivirine produced comparable virologic and immunologic activity to efavirenz when both agents were dosed with 2 NRTIs in treatment-naive individuals with no major baseline NNRTI mutations (Capsule Summary).[5] Approximately 80% of patients in the rilpivirine and efavirenz arms achieved HIV-1 RNA < 50 copies/mL at Week 48. In addition, the initial reports suggested that rilpivirine had a better adverse events profile, regarding both CNS effects and lipid abnormalities.
Two studies were presented at IAS that more rigorously compared the metabolic and adverse events profiles of rilpivirine vs efavirenz at 48 weeks in treatment-naive individuals participating in the TMC278-C204 study. Regarding metabolic parameters, rilpivirine was associated with minimal changes in lipid parameters, glucose levels, and insulin sensitivity after 48 weeks of treatment (Capsule Summary).[6] For the combined rilpivirine doses, the changes in total cholesterol (+5 vs +31 mg/dL [+0.13 vs +0.80 mmol/L]; P < .001), low density lipoprotein (LDL) cholesterol (+1 vs +15 mg/dL [+0.03 vs +0.39 mmol/L]; P < .001), triglycerides (-10 vs +18 mg/dL [-0.11 vs +0.20 mmol/L]; P < .05), and glucose (+1 vs +3 mg/dL [+0.05 vs +0.17 mmol/L]; P <.05) were all significantly more favorable in patients treated with rilpivirine vs efavirenz. Interestingly, changes in high density lipoprotein (HDL) cholesterol were significantly more favorable with efavirenz vs rilpivirine (+12 vs +5 mg/dL [+0.31 vs +0.13 mmol/L]; P < .001). The change in the ratio of total cholesterol-to-HDL cholesterol was not significantly different between the rilpivirine and efavirenz arms (-0.5 vs -0.3), nor was the log change in the homeostasis model assessment of insulin resistance (0.2 vs 0.1). In addition, the magnitude of the changes in all metabolic parameters was not related to the rilpivirine dose. Therefore, rilpivirine seemed to perform better than efavirenz regarding many metabolic parameters.
Regarding adverse events, rilpivirine had an adverse events profile very similar to that of efavirenz (Capsule Summary).[7] However, the data did suggest that rilpivirine was associated with fewer CNS adverse events (18% vs 40%; P < .001) and psychiatric adverse events (7% vs 15%; P < .05) than efavirenz. The major differences in CNS adverse events between the rilpivirine and efavirenz arms could be attributed to dizziness (5% vs 27%; P < .001) and somnolence (3% vs 10%; P < .05). There was no difference between the treatment arms in the incidence of headache (8% vs 8%). The difference in psychiatric adverse events between the rilpivirine and efavirenz arms could be attributed to the incidence of abnormal dreams (2% vs 10%; P < .01), as there was no significant difference between the arms in the incidence of insomnia (3% vs 5%) or depression (1% vs 1%).
Joseph J. Eron, Jr., MD:
I was surprised by these results because the data presented at CROI suggested that rilpivirine was generally associated with a lack of CNS adverse effects as was the case with etravirine in the DUET studies. However, in the current rilpivirine presentation, although there were lower rates of CNS and psychiatric adverse effects associated with rilpivirine than with efavirenz, the rates of headache, insomnia, and depression were all similar. Moreover, it is important to note that this was only a partially blinded study; the rilpivirine arms were blinded to dose, but the efavirenz arm was unblinded. Therefore, patients who knew they were receiving efavirenz might have been more likely to report CNS and psychiatric adverse events, as they should have been counseled about the possibility of developing these adverse effects. Therefore, some caution is warranted when interpreting these data.
In conclusion, these 2 substudies provide a little more information about the safety and tolerability of rilpivirine. For additional efficacy and safety data, we must await the results of the double-blind phase III studies of rilpivirine, which are supposed to begin in fall 2007. |
Comparable Antiviral Activity and Accelerated Viral Decay of Raltegravir (Isentress, an integrase inhibitor) vs Efavirenz (Sustiva) in Treatment-Naive Patients
Daniel R. Kuritzkes, MD:
Markowitz and colleagues[15] presented the 48-week results from a randomized study of the HIV integrase inhibitor raltegravir conducted in 198 treatment-naive individuals (Capsule Summary). Four different doses of raltegravir—100, 200, 400, and 600 mg twice daily—were compared with efavirenz 600 mg once daily, each combined with tenofovir and lamivudine.
The 24-week results of this study were presented at the 2006 International AIDS Conference and demonstrated that the various doses of raltegravir were associated with comparable virologic and immunologic outcomes to efavirenz (Capsule Summary).[16] For example, the proportion of patients in the raltegravir arms with HIV-1 RNA < 50 copies/mL at Week 24 ranged from 85% to 95%, which was similar to the virologic response rate of 92% observed in the efavirenz arm. At 48 weeks, the virologic responses appeared to be durable in all of the study arms. The proportion of patients with HIV-1 RNA < 50 copies/mL at Week 48 in the raltegravir arms ranged from 83% to 88% compared with a rate of 87% in the efavirenz arm.
An interesting observation in the 24-week data was the rapid decrease in HIV-1 RNA in the raltegravir arms compared with the efavirenz arm. For example, at Day 15, at least 30% of patients in each raltegravir arm had achieved HIV-1 RNA < 50 copies/mL compared with only 11% of patients in the efavirenz arm (all P values < .05). Given that observation, Murray and colleagues[17] performed modeling work, in which they assessed the first-phase viral decay rates and compared those with the decay rates for the efavirenz-containing arm (Capsule Summary). The investigators determined that the first-phase viral decay rate did not significantly differ between the raltegravir and efavirenz arms, and they reported that the half-life of first-phase viral decline across all raltegravir-treated patients was 1.2 days. From this information, the investigators extrapolated that the difference had to be in the second-phase decay rates, but they had difficulty measuring the second-phase decay rates because patients’ HIV-1 RNA had so quickly progressed below the limit of detection of their assays. All raltegravir arms showed a significant reduction in second-phase HIV-1 RNA decline compared with efavirenz, and HIV-1 RNA levels were 70% lower with raltegravir vs efavirenz at the start of the second phase of viral decay (P < .0001). However, it was noted that the half-life of second-phase viral decay was similar between the combined raltegravir arms and the efavirenz arm (15.5 vs 18.3 days, respectively; P = .2). Therefore, although their observations are intriguing, a more comprehensive assessment of the first-phase and second-phase decay rates needs to be performed using more sensitive virologic assays and also using more closely timed samples in the first 48 hours of treatment. In this way, the investigators might be able to tease apart whether there are any differences in virologic decay.
The investigators proposed a hypothetical model to explain these data that seems very plausible, even though there are no data yet to support it. Namely, these findings may be explained by the possibility that raltegravir may be blocking the integration of HIV-1 DNA in latently infected cells, which may allow for an additional day’s worth of virus production in patients receiving efavirenz or a PI, which do not block this integration step.
Irrespective of the mechanism of the accelerated viral dynamics, however, the bottom line is that the faster rate of viral decay associated with raltegravir may have no clinical relevance given that similar rates of undetectable HIV-1 RNA were eventually reached, regardless of whether patients received raltegravir or efavirenz.
Joseph J. Eron, Jr., MD:
The investigators also compared the incidence of adverse events between the efavirenz and raltegravir arms. In this open-label comparison, raltegravir was associated with a much lower incidence of the CNS adverse effects, such as dizziness, headache, and atypical dreams, that are associated with efavirenz. The investigators also compared the changes in lipid parameters between efavirenz-treated patients and raltegravir-treated patients from baseline to Week 48. Raltegravir produced no adverse changes in lipid parameters, whereas efavirenz was associated with significantly greater changes in total cholesterol (-2.3 vs +20.7 mg/dL [-0.06 vs +0.54 mmol/L]; P < .001) and LDL cholesterol (-7.5 vs +3.0 [-0.19 vs +0.08 mmol/L]; P = .016). There was a numeric difference in triglyceride changes (-1.0 vs +49.5; P = .068) and a modest decrease in the total cholesterol–to–HDL cholesterol ratio that did not significantly differ between the raltegravir and efavirenz arms (-0.59 vs -0.47; P = .52).
Daniel R. Kuritzkes, MD:
Data are also starting to accrue on the in vivo patterns of resistance and cross-resistance to raltegravir and elvitegravir, the other integrase inhibitor in late-stage development. In contrast with what was seen in the laboratory, the in vivo resistance patterns of elvitegravir and raltegravir look very similar, with the N155H and the Q148R/K/H mutations representing the predominant mutations for both drugs.[18] At IAS, DeJesus and colleagues[19] presented data from a pilot study designed to assess the response to raltegravir in patients who had failed on elvitegravir/ritonavir (Capsule Summary). They studied 2 patients who had either the N155H or Q148R mutation and who replaced elvitegravir/ritonavir with raltegravir while continuing the rest of their failing regimen. Little or no reduction in HIV-1 RNA was observed after 7 days, therefore reinforcing the impression that it will not be possible to use these 2 drugs sequentially. |
References
1. Mills A, Cahn P, Grinsztejn B, et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1. (Capsule Summary)
2. Katlama C, Campbell T, Clotet B, et al. DUET-2: 24-week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-2. (Capsule Summary)
3. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
4. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
5. Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 144LB. (Capsule Summary)
6. Ruxrungtham K, Bellos N, Morales-Ramirez J, et al. The metabolic profile of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB105. (Capsule Summary)
7. Pozniak A, Steyn D, Grinsztejn B, et al. Less frequent reporting of central nervous system and psychiatric adverse events with TMC278 than with efavirenz. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEA105. (Capsule Summary)
8. Fätkenheuer G, Staszewski S, Plettenburg A, et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV-infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS202. (Capsule Summary)
9. Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5 antagonist, maraviroc vs efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]), for the treatment of antiretroviral naive patients infected with R5 HIV 1: week 48 results of the MERIT study. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS104. (Capsule Summary)
10. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection: ACTG 5142. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0204. (Capsule Summary)
11. Gulick R et al. ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV+ treatment-experienced subjects: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB102. (Capsule Summary)
12. Gulick RM, Su Z, 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. J Infect Dis. 2007;196:304-312.
13. Cohen C, DeJesus E, Mills A, et al. Potent antiretroviral activity of the once-daily CCR5 antagonist INCB009471 over 14 days of monotherapy. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB106. (Capsule Summary)
14. Saag MS, Jacobson JM, Thompson M, et al. Antiviral effects and tolerability of the CCR5 monoclonal antibody PRO 140: a proof of concept study in HIV-infected individuals. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS201. (Capsule Summary)
15. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104. (Capsule Summary)
16. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0214. (Capsule Summary)
17. Murray JM, Emery S, Kelleher A, et al. The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB103. (Capsule Summary)
18. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). Program and abstracts of the 16th Drug Resistance Workshop; June 12-16, 2007; Barbados, West Indies. Abstract 9.
19. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032. (Capsule Summary)
20. Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS. 2006;20:1261-1268.
21. Cahn P, Altclas J, Martins M, Losso M, Cassetti I, Cooper D. Superior activity of apricitabine in treatment experienced HIV-1 infected patients with M184V and NRTI resistance. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS203. | |
Regards,
Nelson Vergel
powerusa dot org
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