THIS GREAT INFORMATION WAS PROVIDED BY CLINICAL CARE OPTIONS. THESE ARE COMMENTS ABOUT CLINICAL STUDY DESIGN ISSUES THAT I FOLLOW VERY CLOSELY AS AN ACTIVIST. IT IS VERY INTERESTING TO ME HOW SOME COMPANIES CHOSE TO SHOW THEIR DATA AND HURRY THEIR STUDY ENROLLMENT AT THE EXPENSE OF PATIENT VOLUNTEERS.
THE NEXT HIV DRUG TO BE APPROVED : MARAVIROC – COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT MOTIVATE 1/2 STUDIES AND PFIZER’S EXCLUSION OF FUZEON DATA IN ITS ANALYSIS…
One interesting aspect of this study was that there was no discernable increase in the rate of virologic suppression among maraviroc patients who also received enfuvirtide. This contrasts with data from the A4001029 study, which evaluated the use of maraviroc in patients with dual/mixed-tropic virus; in this study, a similar reduction in HIV-1 RNA was observed with maraviroc vs placebo, but there was a slightly greater reduction in HIV-1 RNA when enfuvirtide was coadministered with maraviroc
One possible interpretation of why enfuvirtide had no discernable benefit in the MOTIVATE studies is that the background regimen may already have been so potent that the use of enfuvirtide did not result in any additional HIV-1 RNA reduction. Moreover, the virologic response data did not differentiate between enfuvirtide recipients who were using enfuvirtide for the first time from those with previous enfuvirtide experience. Overall, approximately 60% of the study population was enfuvirtide naive at baseline, and 40% was enfuvirtide experienced. This suggests that perhaps one fourth to one third of the patients initiated enfuvirtide for the first time with maraviroc; this may be too small a proportion to have a discernable impact in the subgroup analysis.
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THE NEXT DRUG TO BE APPROVED AFTER MARAVIROC: MK 518 (RALTEGRAVIR, MERCK’S INTEGRASE INHIBITOR) – COMMENTS FROM Daniel R. Kuritzkes, MD ABOUT THE BENCHMRK STUDY AND ITS OBR (OPTIMIZED BACKGROUND THERAPY)
Baseline resistance scores showed that approximately two thirds of patients had a genotypic susceptibility score of either 0 or 1 for the background regimen. It is worth noting that patients were considered to be resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry; in the case that enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was assigned to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive; this approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR; this is probably the major difference between the trials.
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COMMENTS ABOUT GILEAD’S INTEGRASE INHIBITOR (ELVITEGRAVIR) STUDY AND ITS HURRIED IMPLEMENTATION THAT EXPOSED PATIENTS TO VIRTUAL MONOTHERAPY
Daniel R. Kuritzkes, MD:I agree that the failure kinetics of elvitegravir appear to resemble that of lamivudine or an NNRTI, with which a single-point mutation confers resistance and is associated with rapid viral rebound, whereas failure with raltegravir appears similar to failure with a PI, that is, resistance requires mutations at multiple loci and rebound is more gradual. Whether similar failure kinetics would have been observed with raltegravir if PIs had been excluded from the BENCHMRK studies is a matter of speculation.
Development of elvitegravir has been complicated somewhat by the fact that it has many drug-drug interactions. The manufacturer had to decide whether to elucidate all those interactions first, so that studies could allow the concomitant use of as many other drugs as possible, or to proceed with studies more rapidly but restrict the drugs that could be combined with elvitegravir. The consequences of choosing the latter approach was that in this treatment-experienced patient population, there were insufficient drugs available to provide an effective background regimen to support the integrase inhibitor. Most patients received NRTIs only, and approximately one half of them contributed no activity, meaning that those patients received de facto monotherapy with elvitegravir.
Joseph J. Eron, Jr, MD:Although I agree about the limitations of the current study, the goal of a phase IIb study is to identify the best dose to take forward into phase III development, and it does seems likely that the right dose of elvitegravir was identified.
Daniel R. Kuritzkes, MD:You are correct. However, if the investigators had chosen to perform a 14‑day study of different doses in treatment‑experienced patients, they might have come up with the same result. Unfortunately, the patients who received up to 16 weeks of treatment with the lowest dose (20 mg) before that arm was discontinued—as well as the patients who experienced virologic failure in the other arms because of the lack of an effective OBR—are now likely resistant to this integrase inhibitor and may or may not be cross‑resistant to other drugs in the class. The challenge for all investigational drugs is how to generate the key data that are essential for drug development while minimizing the risk to the patients enrolled in early studies.
Joseph J. Eron, Jr, MD:I agree. Patients in the elvitegravir study had an even higher median CD4+ cell count than those in the maraviroc and raltegravir trials, so most were not in urgent need of a new regimen, yet some of these patients may now have restricted future options because they received elvitegravir combined with NRTIs only.
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COMMENTS ABOUT RELPIVIRINE (TMC 278- A NON NUCLEOSIDE) FROM TIBOTEC:
William G. Powderly, MD:The lipid data from this study were intriguing. Results in the efavirenz arm were as expected: a mean 31 mg/dL (0.80 mmol/L) increase in total cholesterol, a 16 mg/dL (0.41 mmol/L) increase in low density lipoprotein (LDL) cholesterol, and a 12 mg/dL (0.31 mmol/L) increase in high density lipoprotein (HDL) cholesterol. Triglyceride levels also increased in the efavirenz arm by a mean of 18 mg/dL (0.20 mmol/L). By contrast, there were virtually no significant lipid changes in the rilpivirine arms: a 5 mg/dL (0.13 mmol/L) median increase in total cholesterol, no change in LDL cholesterol, a 5 mg/dL (0.13 mmol/L) increase in HDL cholesterol, and a 10 mg/dL (0.11 mmol/L) decrease in triglycerides. This is a potential advantage to rilpivirine over efavirenz, although it is not clear how these changes might translate into differences in cardiovascular risk, since the larger increase in HDL cholesterol in the efavirenz arm might counterbalance the larger increase in LDL cholesterol and triglycerides also seen in that arm.
This is the second time that a study of a novel agent in treatment-naive patients has demonstrated fewer lipid effects than efavirenz. The first was a phase II study in which raltegravir was associated with significantly smaller changes in cholesterol and triglycerides than those observed with efavirenz (P < .05 for 200-mg, 400-mg, and 600-mg doses of raltegravir) . This type of result challenges the notion that a proportion of the lipid changes observed in treatment-naive patients who start antiretroviral therapy represent a “return to normal” in the form of a reversal of the effects of unchecked HIV replication. The results of these studies question that hypothesis and raise the possibility that lipid changes may indeed be a form of drug toxicity in the majority of patients. ******************************************************** COMMENTS ABOUT THE X4 INHIBITOR AMD 11070:
Daniel R. Kuritzkes, MD: There were very few reports on agents in the early stages of development. Two pilot studies of AMD 11070, a CXCR4 inhibitor, were presented at this meeting. The ACTG 5210 trial was an open-label dose-escalating 10-day monotherapy study in patients who had been off therapy for ≥ 14 days and who had X4 or dual/mixed virus detected 18] A total of 6 patients in the first cohort were treated with AMD 11070 200 mg every 12 hours for 10 days (20 doses). Three of the 6 patients had ≥ 1 log10 reduction in the X4 virus population by Day 10 as measured by luciferase assay. Five of the 6 subjects had dual/mixed virus at Day 10, and the sixth had R5 virus. However, none of the patients experienced a ≥ 1 log10 copies/mL reduction in HIV-1 RNA.
The XACT study had similar results. This was a 10-day monotherapy study in treatment-naive and treatment-experienced patients with X4 virus detected (N = 10; 8 received 200 mg twice daily and 2 received 100 mg twice daily). One patient was unevaluable based on discrepancies in tropism assay results. Four of the remaining 9 patients had ≥ 1 log10 reduction in the X4 virus population by luciferase assay by Day 10, and 3 of these 4 had only R5 virus detected at Day 10. However, there were no changes in HIV-1 RNA or CD4+ cell count among the 4 responders.
The fact that reduction in X4 virus was not associated with an overall reduction in HIV-1 RNA would present a huge challenge for subsequent development of an X4 inhibitor because one is unable to demonstrate an impact on what are considered traditional endpoints—decrease in HIV-1 RNA and increase in CD4+ cell count. Development of AMD 11070 is now on hold because of serious toxicity demonstrated in animal models.
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COMMENTS ABOUT RACIVIR
Joseph J. Eron, Jr, MD: Clinical data were also presented on racivir, a racemic mixture of enantiomers of an emtricitabine-like molecule.[20] In this study, patients failing therapy with M184V on a lamivudine-containing regimen were randomized 2 to 1 to substitute racivir for lamivudine (n = 26) or continue lamivudine (n = 16) in a double-blind fashion. Among those receiving racivir, the mean HIV-1 RNA change after 28 days was a decrease of 0.4 log10 copies/mL, whereas those on lamivudine experienced a 0.13 log10 copies/mL increase (P = .0004). In a subgroup analysis of patients with M184V < 3 thymidine analogue mutations with or without NNRTI or PI mutations (n = 14), the HIV-1 RNA decreased 0.7 log10 copies/mL over same period (P = .0002)
The lack of clinical data on drugs at early stages of development highlights an important concern. Within the next year, 3 new drugs may be approved. However, in the next few years beyond that, very few new drugs are likely to become available. Those that do become approved will most likely be second or third in class and therefore more likely to be of incremental benefit, as opposed to the potentially dramatic benefit that may be associated with the first agent in an entirely new class, to which even the most experienced patient is likely to remain fully susceptible. This underscores once again the critical importance of using the current batch of new agents optimally—in combination with other active agents and with the goal of achieving undetectable HIV-1 RNA—in the hope that today’s treatment-experienced patients can achieve durable responses.