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Integrating Integrase Inhibitors and other antiretroviral stories
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CROI 2011 Boston MA
Joe Eron MD
Professor of Medicine; UNC Chapel Hill
Raltegravir Once Daily -
When Bernard Hirschel introduced the presentation of the results of the QDMRCK Study, (Eron et al QDMRK, A Phase III Study of the Safety & Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV-Infected Patients (Pts) # 150LB) he described it as the "late breaker that broke". What did he mean by this statement and is it in fact true? The results of the study have been summarized already several times on NATAP and by other conference summaries but the bottom line is that in the primary analysis, despite the fact that 83% of the patients treated with once daily raltegravir plus TDF/FTC had plasma HIV RNA < 50 c/mL at 48 weeks in a non-completer = failure (NC=F) analysis, the QD arm did not meet non-inferiority and in fact was inferior to the twice daily arm in which 89% of all patients randomized and dosed had HIV RNA levels < 50 c/mL at 48 weeks (treatment delta was -5.7% with 95% CI of -10.7 to -0.83). Numerically more patients on the QD arm also developed raltegravir and FTC resistance mutations (9 vs. 2 for raltegravir plus FTC mutations and 11 vs. 4 for FTC mutations alone).
Many of us looked for evidence that once daily raltegravir might be "ok" for some treatment naïve patients. For example if one looked at the patients who had HIV RNA < 100,000 c/mL at baseline the two arms were similar (QD 89% vs. BID 92% < 50c/mL at 48 weeks NC=F) and the time to loss of virologic failure comparison (which takes advantage of the fact that many patients had more than 48 weeks of follow-up) was not statistically different between the two arms in the lower viral load stratum. So perhaps QD raltegravir would be reasonable with lower baseline viral load? But if you looked harder at the data, all the numbers favored twice daily. Even with a baseline < 100,000 c/mL, twice daily was numerically better in proportion < 50 c/mL at 48 weeks and if you looked at the number of virologic failures (with a pretty strict definition: HIV RNA >50 copies/mL at Week 24 confirmed or confirmed HIV RNA>50 copies/mL after initial response to <50 copies/mL ) in the lower viral load group there were twice as many VF in the QD arm (N=16) as there were in the BID arm (N=8). Also 2 subjects with BL VL < 100,000 on the QD arm developed integrase inhibitor and FTC resistance, though admittedly their BL VL were 70,000 and 90,000, while no patient on BID raltegravir with in the lower baseline RNA group did.
What about patients who achieved suppression to < 50 c/mL, perhaps they were OK staying on QD? This question was addressed on a back-up slide that was shown during the presentation. In patients who had a VL < 50 c/mL at 24 weeks an analysis was performed comparing the two arms to see if there were differences in virologic rebound to > 50 c/mL (confirmed) between QD and BID. Here the numbers were smaller and it is important to remember that this in no longer a randomized comparison and a statistical analysis was not done. However, once again the numbers favored BID raltegravir treatment. Sixteen out of 340 QD patients rebounded to > 50 c/mL (4.7%) compared to 10 out of 364 (2.7%) on BID raltegravir. These data do not address what would happen if twice daily raltegravir or another first line TDF/FTC containing regimen were switched to once daily raltegravir after a patient had been suppressed to < 50 c/mL for a much longer period of time and perhaps there are investigators out there who will do this study. Given the QD MRK data one would have to carefully consider what the advantages and disadvantages of such a switch would be on an individual patient basis.
So was Dr.Hirschel right? Was QD MRK broke? The study was stopped based on recommendations from the data monitoring committee and clearly the primary endpoint as not met. However one could take a glass half-full approach to these data also by focusing on the raltegravir BID arm. Remember this is not a small study. Over 760 patients were randomized and 386 received twice daily raltegravir. So in this large phase III multisite study 89% (actually 88.9%) of patients treated with raltegravir BID, TDF/FTC had HIV RNA < 50 c/mL at 48 weeks in a NC=F analysis. Cross study comparisons can be misleading but this is the highest success rate for a treatment arm in any large phase III study to date. Two (not 2% but 2 patients) out of 386 developed integrase inhibitor resistance (0.52%), which would suggest that when given BID the combined pharmacologic plus genetic barrier to resistance for raltegravir is actually high. In addition when looking at both arms, 7 total patients discontinued due to an adverse even (< 1.0%) and 4 total patients (2 on each arm) discontinued due to a drug-related AE (0.5%). Clearly once daily raltegravir did not make it but BID raltegravir remains a remarkably successful, well tolerated regimen with limited resistance consequences. These results coupled with the 3 year STARTMRK data (presented by JŸrgen Rockstroh) in which twice daily raltegravir showed durable, comparable efficacy to efavirenz (both combined with TDF/FTC), solidify twice daily raltegravir as a preferred initial therapy regimen with clear advantages (and some disadvantages - like BID dosing) compared to the other preferred regimens.
A final point about the QD MRK study was that for the first time there was a relationship established between raltegravir PK and outcome in the once daily arm. There are likely to be a lot more details provided in future conferences but there are two important points about the PK data. The first is that in the BID arm there was no relationship between any PK parameter and outcome (as has been see in the previous BID studies). In the QD arms each of the PK parameters were associated (as a trend) with virologic failures but each of the parameters were averages of multiple determinations from each patient. No single determination was predictive of treatment outcome.
CROI: QDMRK, A Phase III Study of the Safety & Efficacy of Once Daily (QD) Versus Twice Daily (BID) Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV-Infected Patients (Pts) - (03/9/11)
CROI: Raltegravir (RAL) Demonstrates Durable Virologic Suppression and Superior Immunologic Response with a Favorable Metabolic Profile Through 3 Years of Treatment (Tx): 156 Week (Wk) Results from STARTMRK - (03/7/11)
More ECHO and THRIVE data
Though perhaps not obvious on first look there are some similarities between the QD MRK data and the ECHO and THRIVE data which looked at the comparison of rilpivirine vs. efavirenz (both combined with 2 NRTI). The big difference between the QD raltegravir and the rilpivirine studies is, of course, that the primary endpoint of non-inferiority was achieved in both ECHO and THRIVE. In the combined data from the two studies rilpivirine was superior to efavirenz in the strata with baseline viral load < 100,000 c/mL in a ITT-TLOVR analysis in which virologic failures and discontinuations receive similar weight (similar to NC=F or missing = failure). When one looks carefully at the data from these studies there is similarity to QD MRK. There are substantially more virologic failures with rilpivirine in the higher viral load stratum in the combined studies and even numerically more in the lower viral load strata (Rimsky L et al. ICAAC 2010 H1810). In addition there is a difference in the emergence of NNRTI resistance and in NRTI resistance that favors the efavirenz treatment arms. There was one major advantage to rilpivirine that could not be seen when raltegravir was compared to itself (QD vs. BID), which is rilpivirine was substantially better tolerated than efavirenz and there were more treatment discontinuations in the efavirenz arms that made up for (and in the low viral load strata more than made up for) differences in the virologic failure numbers. At CROI there were several presentations that gave further detail on the comparison between rilpivirine and efavirenz in the ECHO and THRIVE studies. One compared neurologic and psychiatric adverse events (Mills et al, Neurologic and Psychiatric Safety Profile of TMC278 Compared with EFV in Treatment-naive HIV-1+ Patients: ECHO and THRIVE Trials at 48 Weeks #420) and while there were significantly fewer of these adverse events in rilpivirine treated patients, the proportion that led to discontinuation of treatment were quite low (1.6% vs. 2.9%; rilprivine vs. efavirenz respectively). These types of AE's predominantly occurred early and there was little difference between the two treatment groups after the first 12 weeks. Not surprisingly these adverse events were more common in both treatment groups in patients with a history of neurologic or psychiatric illness. Another poster (Arribas et al Lipid Profiles of TMC278 and EFV in Treatment-naïve HIV-1+ Patients: Pooled Week-48 Data from the Randomized Double-blind Phase III ECHO and THRIVE Trials #819) demonstrated that most lipid parameters worsened more substantially with efavirenz-based treatment though the change from baseline in Framingham risk score was not significant. Finally in a late breaker David Wohl presented data on changes in vitamin D levels in patients treated with rilpivirine vs. efavirenz in the ECHO trial (Wohl et al Change in Vitamin D Levels Smaller and Risk of Development of Severe Vitamin D Deficiency Lower among HIV-1-infected, Treatment-naïve Adults Receiving TMC278 Compared with EFV: 48-Week Results from the Phase III ECHO Trial #79LB). Over 48 weeks there was not a significant change in 25 (OH) Vit D levels with rilpivirine but the mean decline in 25(OH)VitD levels on efavirenz was significant. In addition patients with insufficient levels pre-therapy were at risk for severe deficiency if they were on the efavirenz arm. The question is whether, in the minds of clinicians, the combination of these and other factors (tolerability, lipids, vitamin D levels, rash) will counter balance the increased risk of virologic failure and the greater likelihood of FTC/3TC resistance with rilpivirine/TDF/FTC therapy. This calculation may be different when the patient has a viral load < 100,000 c/mL compared to when a patient has a higher viral load. The decision of the clinician and patient may be quite different if the patient is a woman of child bearing potential.
CROI: Lipid profiles of TMC278 and efavirenz in treatment-naïve, HIV-1-infected patients: pooled Week 48 datafrom the randomized, double-blind, Phase III ECHO and THRIVE trials (03/12/11)
CROI: Neurologic and psychiatric safety profile of TMC278 compared with efavirenz in treatment-naïve, HIV-1-infected patients: pooled analysis from the randomized, double-blind, Phase III ECHO and THRIVE trials at 48 weeks (03/12/11)
CROI: Change in Vitamin D Levels Smaller and Risk of Development of Severe Vitamin D Deficiency Lower Among HIV-1-Infected, Treatment-naïve Adults Receiving TMC278 Compared with Efavirenz: 48-week Results from the Phase III ECHO Trial - (03/7/11)
An active integrase inhibitor for patients with resistance to raltegravir?
In the summer in Vienna we presented activity data on S/GSK 572 (now known as dolutegravir), given as 50 mg once daily, in patients with raltegravir resistant virus who received 11 days of functional monotherapy. In cohort 1 of the Viking study 572 demonstrated consistent activity against RAL resistant viruses that had mutations along the 155 and 143 pathways. However, activity against viruses that contained the 148 and 140 pattern (with or without additional mutations) was not consistent and enrollment of patients with that pattern of resistance was stopped. Overall activity of 572 against resistant virus was well correlated with baseline fold-change to 572. Concentration activity curves suggested that a higher dose of dolutegravir may result in better activity against more resistant variants. Pharmacokinetic data on 100 mg once daily did not show dose proportional increases in dolutegravir concentrations, which was likely due to absorption issues. Therefore in the Viking study cohort 2, which we presented at CROI, patient who had documented raltegravir resistance received functional monotherapy with 50 mg twice daily of dolutegravir along with their failing background therapy for 11 days (Eron et al DTG in Subjects with HIV Exhibiting RAL Resistance: Functional Monotherapy Results of VIKING Study Cohort II #151LB). The design was the same as cohort 1 except all patients had to have at least one fully active agent available to them that they could start at day 11 when their background therapy was optimized. Once again the patients were divided into two groups those with the 148 plus one or more mutations and those who RAL resistant virus went down another pathway (usually 143 or 155). At baseline cohort 2 patients were similar to cohort 1 patients, including having variants with very high levels of RAL resistance, except that fewer cohort 2 patients had darunavir and etravirine experience and fewer cohort 2 patients had advanced HIV disease (lower proportion with class C disease and modestly higher median baseline CD4 cell count). The mean baseline fold change to dolutegravir was very similar between the two cohorts though in cohort 1 there were more patients with variants at the extremes (FC > 15 and FC < 1).
In Cohort 2, 23 of 24 patients achieved the primary outcome of at least a 5-fold (0.7 log10) decline in HIV RNA or a viral load < 400 c/mL including all 11 patients that had viral variants with the 148 + 1 or more mutations. 54% of patients had VL < 400 c/mL at day 11. Dolutegravir concentrations were substantially higher than in cohort 1 in which 50 mg QD was given. The one patient that did not make the primary endpoint had a 0.5 log10 decline in HIV RNA and was reported to subsequently suppress when his/her regimen was optimized after day 11. No unexpected adverse events were observed though this was a short term study.
These results are highly suggestive that there will be an effective "second generation" integrase inhibitor for raltegravir (and likely elvitegravir) failures. Practically it probably won't have a huge clinical impact though for the small but real number of highly experienced patients with limited treatment options here is a new drug that probably can be counted on to have substantial activity even if the patient has variants with raltegravir resistance.
Unfortunately, for some patients there may be little else new coming through the pipeline if they don't have one or two other active agents to pull together a fully active regimen. Some patients with resistant virus and very advanced disease may not be able to wait. A phase III study for patients with raltegravir resistant virus is planned (Viking 3) and will likely not involve a randomization but instead would be similar to the phase II Viking study.
Further information about an expanded access or compassionate use program should be forth coming. Dolutegravir is likely to get substantial attention as a first line agent or one used earlier in therapy in integrase naïve patients given that in those scenarios it is a once daily regimen that does not require a boosting agent.
CROI: GSK1349572 Integrase in Raltegravir Resistant Patients - (03/2/11)
Nuc-sparing: To be or not to be?
Nucleoside-sparing regimens (usually 2-drug combinations) have been hypothesized as a way to avoid some of the long term toxicity associated with nucleosides. These combinations may also benefit patients in whom NRTI may not be the best initial choice for therapy. However, despite a lot of talk about this concept there is not a single NRTI-sparing regimen listed in all the tiers of the DHHS guidelines. One combination that would seem to be highly potent and well tolerated is the combination of darunavir/ritonavir plus raltegravir. Both are very potent therapies that have been successfully paired with TDF/FTC to produced potent, well tolerated initial regimens. [1, 2]. The ACTG tested raltegravir plus darunavir/r in 112 treatment naïve patients in a single arms study that allowed patients with renal dysfunction and NRTI and NNRTI TDR into the study (Taiwo et al Results from a Single Arm Study of Darunavir/Ritonavir Plus Raltegravir in Treatment-Naïve HIV-1-Infected Patients (ACTG A5262) #551) .
Surprisingly there were 28 virologic failures in this study (25% of the 112 enrolled and treated patients). High viral load and low CD4 significantly increased the risk for virologic failure. An additional 15 patients discontinued prematurely (mostly due to administrative reasons - 13 were lost to follow-up or withdrew consent). Though the ACTG does not typically combine endpoints, given that virologic failure and lost to follow-up have different consequences, if one did a missing = failure analysis on this group the success rate would be around 62%. This proportion was way below what the team anticipated. Only 5 subjects developed variants with integrase inhibitor resistance and many of the virologic failures were low level; 46% confirmed failure between 50-200 c/mL. Only two of these patients re-suppressed without changing therapy and all original failure VL that were done on a real time PCR assay were re-tested with the Roche Amplicor assay and all were positive. Therefore the results were not due to the use of one of the new real-time plasma HIV RNA assays.
The explanation for these results remains elusive. This study was lacked a control group, which is a substantial criticism and it is possible that the results are a function of the patient population and not the medications though the relationship of VF with high baseline viral load would be a little harder to explain and there is a strong similarity of these results with the SPARTAN study which examined twice daily atazanavir and raltegravir in naïve patients.
Perhaps the fact that DRV/r was once daily and raltegravir was twice daily is a partial explanation but to counter that TDF/FTC is once daily and raltegravir is twice daily and this regimen seems to work fine. Perhaps there is a PK issue and those data were not yet available at the time of the presentation.
Fortunately a large, well powered study comparing DRV/r plus raltegravir vs. DRV/r plus TDF/FTC is underway in Europe which hopefully will answer the question definitively. If the results of the ACTG study influence enrollment by limiting enrollment of patients with high baseline viral load the European study may have less power to address the more pressing population. One successful 'nuc-sparing' study - PROGRESS - which combined LPV/r twice daily with raltegravir twice daily had a baseline VL just over 10,000 c/mL which is about 8 times lower that the ACTG study, so the high viral load group was not really challenged in that study to help address this question. For now it would seem that "nuc-sparing" regimens should be used cautiously, if at all.
Paradoxically they may be better in treatment experienced patients who tend to have lower viral loads. A NRTI-sparing regimen that is likely to be studied is DRV/r once daily with maraviroc 150 mg once daily. PK data on this combination were shown at CROI and once daily MVC seems reasonable. Perhaps having one medication that works at a pre-integration step (MVC) and one that works post integration (DRV/r) and that is fully once daily will be the nuc-sparing regimen we are looking for. Preliminary data from a study of DRV/r plus MVC (once daily) presented at IAC in Vienna this past summer looked promising though the numbers were small. Once again I would wait before jumping on this band wagon outside of a clinical study.
Other observations - toward curing HIV?
There remain many critical questions to be address as we size up the hurdles that need to be crossed to eradicate HIV-1. An obvious hurdle is understanding whether full rounds of HIV replication are fully suppressed in patients who have plasma HIV RNA suppressed below the limit of detection for prolonged periods of time. Several studies have shown that intensification of antiretroviral therapy does not appear to change plasma HIV RNA levels measured by single copy assays[3-6], which suggests, but does not definitively prove, that active HIV replication is not contributing to HIV RNA levels in blood in patients with plasma HIV RNA < 50 c/mL. However there have been other suggestions from these intensification studies that perhaps the antiretroviral therapy intensification is affecting ongoing HIV replication in a compartment that does directly release HIV-1 into systemic circulation at measurable levels. In the study by Buzon et al 2 LTR circle levels increased in PBMC in some patients when raltegravir was added [5] suggesting that raltegravir was inhibiting new rounds of replication. In the ACTG double-blind cross over raltegravir intensification study of Gandhi et al, there was a consistent trend in CD4 cell count increases when raltegravir was added compared to placebo; again raising the question as to whether raltegravir could be affecting HIV replication in a compartment not directly communicating with the blood. In a follow-up evaluation Gandhi et al presented further data from this blinded crossover intensification study (Gandhi et al Raltegravir Intensification of Patients on Long-Term Suppressive Antiretroviral Therapy Does Not Increase 2-LTR HIV DNA Circles in Peripheral Blood Mononuclear Cells:
Results from ACTG A5244 #51). We looked at changes in 2 LTR circles, changes in cell associated HIV DNA and changes in CD4 and CD8 activation as measured by CD4 or CD8 cells that were also positive for CD38 and DR. None of these markers changed significantly when raltegravir was added to the regimen compared to placebo whether raltegravir was added first or after the crossover from placebo to raltegravir. These analyses again do not support ongoing replication in patients who are suppressed long-term to < 50 c/mL on conventional antiretroviral therapy. However, concept of ongoing compartmentalized replication in suppressed patients remains alive. In ACTG 5244 2-LTR circles were measured only after 12 weeks of raltegravir intensification so an earlier rise in 2-LTR circles (as was seen in the Buzon study) cannot be excluded. In addition, the Spanish group showed an increase in CD4 cells when raltegravir was added as an intensification in patients suppressed on HAART with poor CD4 recovery, though this may have been a redistribution of memory CD4 cell (Massanella et al Effect of RAL Intensification in HAART-suppressed Subjects without Proper CD4 T Cell Recovery #545) and in an follow-up evaluation of intensification with raltegravir, Massanella and colleagues saw a decrease in immune activation as measured by several CD8 and CD4 activation markers that partially reversed when raltegravir was stopped (Massanella et al Dynamics of CD8 T Cell Activation during RAL Intensification and after Its Discontinuation in HAART-suppressed Subjects #281). Taken in total it is very hard to "prove a negative". That is can we ever PROVE that there is no ongoing replication in some compartment or lymph node in HIV patients that have long term plasma HIV RNA suppression on cART therapy? I don't think we can, though the evidence supporting ongoing complete rounds of replication in our suppressed patients is relatively slim at best. Perhaps we will need to intensify therapy prior to more radical attempts at HIV eradication but at this point the jury is still out.
Is IL-7 part of an eradication package?
Whether IL-7 might be a step on the path to HIV cure has not been clear to me. IL-7 is a potent and essential cytokine for thymopoiesis and T cell homeostasis and maturation. In a presentation by Sereti et al she showed that 3 weeks of treatment with IL-7 in patients with suppressed HIV RNA but CD4 100-400 increased both CD4 and CD8 cells while decreasing PD-1 expression (a marker of T cell exhaustion) (Sereti et al Recombinant Interleukin-7 (CYT107) Expands CD4 T Cells in Peripheral Blood and Gut Mucosa of Chronically HIV-Infected Immunological Non-Responder Patients). CD4 naïve and central and effector memory cells increase peaking at day 21 and decreasing some but remaining elevated at week 12. CD4 cell % and number increased in the gut mucosa. So perhaps IL-7 will be useful for patients with inadequate CD4 cell responses on therapy but this indication alone is likely to take us down the IL-2 pathway and is unlikely to be studied in very large clinical endpoint studies like ESPRIT or SILCAT. Instead perhaps the improvement in T-cell subsets, restoration of gut T-cells and decrease in T cell exhaustion can be shown to improved immunologic function and decrease inflammation and activation (especially if bacterial translocation is decreased). However, even if all these things are documented, if there is no impact on clinical endpoints it seems unlikely that IL-7 will find much of a place in HIV treatment. The authors did note that there were transient blips in HIV RNA in 8 of the 12 treated patients. Perhaps these blips are evidence of HIV release from reservoirs and T cell populations expand. Conversely proliferation of CD4 memory cells could result in an increase in the HIV latent reservoir if the numbers of resting memory CD4 cells with integrated replication competent HIV DNA increases.
CROI: Recombinant Interleukin-7 (CYT107) Expands CD4 T Cells in Peripheral Blood and Gut Mucosa of Chronically HIV-Infected Immunological Non-Responder Patients (03/13/11)
1. Lennox JL, Dejesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009.
2. Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. Aids 2008,22:1389-1397.
3. Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med 2010,7.
4. McMahon D, Jones J, Wiegand A, Gange SJ, Kearney M, Palmer S, et al. Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin Infect Dis 2010,50:912-919.
5. Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas MC, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010,16:460-465.
6. Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009,106:9403-9408.
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