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New Drugs, New strategies
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Summary for IAS in Cape Town 2009
Joe Eron, MD, Univeristy of North Carolina
Back in the Game
The most important new drug presentation at IAS this year came from an old warrior in the HIV drug development game, GlaxoSmithKline. After many disappointments including an early integrase inhibitor, a CCR5 inhibitor, a promising second generation NNRTI and darunavir-like protease inhibitor, all which went belly-up in early clinical development either due to issues with activity or toxicity, GSK presented the first clinical activity of their new integrase inhibitor, S/GSK1349572 or "572", developed in a full joint venture with Shionogi [1]. This compound has multiple characteristics that may make it stand out amongst the integrase inhibitors that have reached clinical development to date. First off 572 seems to have remarkable in vivo potency. Three doses, 2, 10 and 50 mg once daily were tested over 10 days in integrase-inhibitor naïve patients who had been off therapy or were treatment naive. At the highest dose, 50 mg daily, the peak decline in viral load was 2.5 log10 copies per mL (300 fold), which is the largest decline in viral load we have seen in a short term monotherapy study with any agent in any class. Of the 10 HIV infected subject who received this dose, seven had their plasma HIV RNA fall to < 50 c/mL so the peak decline may have been even greater. The 10 mg dose reached a maximum VL decline of ~ 2.0 log10 copies/mL and even the individuals receiving the 2 mg dose had a peak decline of ~ 1.5 log10 copies/mL. In this short study the drug also seemed well tolerated and no major side effects were observed.
A second characteristic of the integrase inhibitor was very consistent and therefore predictable pharmacokinetics across the doses tested in this first in HIV-infected patients [2] and in uninfected volunteers. Concentrations increased in a predictable way with dose, the inter-subject variability in drug concentrations at a given dose was small and the concentrations were similar when the medication was given with or without food. Importantly the concentration response curve (or Emax curve) in HIV-infected patients showed encouraging pharmacodynamics. The 50 mg daily dose was on the flat part of the Emax curve meaning that this dose was likely to give the maximum response possible in patients with integrase-susceptible virus and that there was substantial security at that dose as concentrations achieved were well past the inflection point where activity decreased as concentrations fell.
Laboratory studies of resistance of this compound were also encouraging. In vitro selection of resistance to 572 was difficult[3]. In studies performed by Shionogi, high level resistance to elvitegravir occurred after 56 days in culture and high level resistance to raltegravir emerged after 84 days. Mutations seen were consistent with in vitro or in vivo resistance mutations to these integrase inhibitors. On the other hand even after 112 days in culture, clear high level resistance to 572 had not emerged (FC 1.2 to 4.1). Several mutations were seen but these mutations conferred minimal resistance to 572 and at least one of the mutations was a polymorphism. These studies suggest that 572 may have a higher barrier to resistance than either elvitegravir or raltegravir. We know raltegravir and elvitegravir are potent with approximately 2 log10 activity in short term studies [4, 5], however if there is virologic rebound in the context of combination therapy resistance will emerge in a substantial proportion of patients[6, 7]. In vitro selection studies do not always mirror what occurs in the clinic, so while promising, the selection studies with 572 should be interpreted with caution. No resistance mutations emerged in the short term monotherapy study in integrase naïve patients just presented at IAS [1] but resistance mutations were not selected for in the phase 2a studies of elvitegravir or raltegravir either [4, 5]. To date only the boosted protease inhibitor class has consistently shown a "high barrier to resistance" in longer term clinical studies and predominantly in studies conducted in previously treatment naïve patients.
Finally the issue of cross resistance between 572 and raltegravir and elvitegravir was examined. Cross resistance between viruses resistant to one of the two integrase inhibitors approved or in advanced clinical development, raltegravir and elvitegravir, is common [8] especially when resistance mutations selected in clinical studies of raltegravir are examined. In a poster presentation at IAS an array of viruses created in vitro by site directed mutagenesis with elvitegravir and raltegravir associated mutations remained susceptible to 572 [3]. These viruses included mutations from the common pathways seen in raltegravir failures in the clinic including the 155, 140-148 and 143 pathways. However, when clinical isolates were examined the story was slightly different [9]. Viruses with 155H mutation and with 143 mutations appeared to retain full susceptibility to 572. The results were mixed in viruses with the combination of mutations at the 140 and 148 codons. Many of these viruses conveyed little alteration in fold change to 572 however some showed an increase in fold change greater than 10. The relationship of fold change with specific 140-148 codon substitutions was not completely clear though some viruses with 140S and 148H appeared to have the highest fold change. These viruses were clinical isolates obtained from patients failing raltegravir and the full integrase sequence was not yet known. Mutations or polymorphisms at other sites within integrase may explain some of the variation in the level of decreased susceptibility. The question of whether 572 can rescue raltegravir failures will remain a very important one. Raltegravir resistance evolution is complex. Most viruses seen in early failure have the 155H mutation but over time the pattern evolves and in many patients, viruses with the 140-148 combination emerge. The in vitro data on cross resistance with 572 will stimulate further debate on whether patients failing raltegravir should have their raltegravir stopped as soon as failure is confirmed to avoid selection of complex resistance patterns. This strategy may make sense though advanced patients who have had a substantial CD4 gain might be put at risk of losing their CD4 increase. The success of 572 in patients with raltegravir failure may depend on pattern of mutations but will also likely depend on the strength of the partner agents (which may be very limited in some raltegravir failures) and on the barrier to further resistance with 572. In vitro selection experiments starting with raltegravir resistance viruses may be informative.
Overall the debut of 572 was impressive. Clearly the drug is very potent, has low milligram dose (desirable characteristic for co-formulation), is clearly once a day, has very predictable pharmacokinetics and pharmacodynamics, does not need boosting and in vitro assessments suggest a high barrier to resistance and the potential to have activity in patients with raltegravir resistant virus. Of course we are a long way from an approved medication or even expanded access. Tolerability and toxicity have only been assessed short term so the longer Phase IIB studies are anxiously anticipated. A pilot study to assess activity of 572 in patients with raltegravir resistant virus is also in the works. Having GSK/Shionogi back in the game with a drug in advanced clinical development is good for the field and the prospect of a 'second generation' integrase inhibitor will stimulate discussion among virologists and clinicians and hopefully will eventually benefit our patients.
Raltegravir as Initial Therapy
Recently the FDA approved raltegravir for use as initial therapy for HIV infected adults in combination with other antiretroviral medications. This approval was based on the 48 week results of STARTMRK trial, just published in the Lancet by Lennox and colleagues, which demonstrated that raltegravir plus tenofovir DF/emtricitabine was non inferior to efavirenz plus the same 2 NRTI in treatment naïve patients [10]. At 48 weeks 86.1% of the raltegravir treated patients and 81.9% of efavirenz treated patients had plasma HIV RNA levels < 50 c/mL.
At IAS we saw long term data on raltegravir as initial therapy. In a poster presentation the 144 week data from the Merck 004 study were presented [11]. This study was originally a dose finding study and 4 doses of raltegravir, 100, 200, 400, and 600 mg twice daily, were tested versus efavirenz at a dose of 600 mg daily, all in combination with TDF and lamivudine [12]. After 48 weeks when all doses had similar efficacy that compared to efavirenz all patients (N =160) on raltegravir were switched to the 400 mg twice daily dose that is now the approved dose of raltegravir. At 144 weeks, raltegravir plus TDF/3TC had sustained antiretroviral activity similar and to efavirenz with 78% vs 76% of patients having a plasma HIV RNA < 50 copies/mL. Drug related adverse events were less frequent in the raltegravir arm and over this almost 3 year study raltegravir had minimal effect on total cholesterol, LDL-C, and triglycerides and HDL rose by a mean of 6.6 mg/dL. Between 96 and 144 weeks 2 patients had viral rebound on the raltegravir arm and one patient rebounded on the efavirenz arm. Neither patient on the raltegravir arm had characteristic integrase resistance mutations.
These data are strong evidence of a sustained treatment response when raltegravir is used as initial therapy in combination with 2 NRTI. Though twice daily, raltegravir therapy is very well tolerated and has really no adverse effect on lipids. We don't yet know about long term effects on bone shape or bone density though DEXA analyses are planned for the 004 study. Resistance emergence does occur in patients who either fail to suppress or rebound on therapy but in the 004 study integrase resistance mutations occurred in less than half the patients (3 out of 8 virologic failures with genotypes). Raltegravir-based initial therapy is a very viable alternative to either efavirenz based or boosted PI-based treatment and may be the most tolerable of the three. A large trial on once daily raltegravir is ongoing and the results are anxiously awaited.
New or Novel Strategies
Several studies looked at new or alternative strategies for administering antiretroviral therapy to simplify therapy, avoid toxicity and/or increase convenience.
The ARIES study, presented by Kathleen Squires and sponsored by GSK, is a ritonavir sparing study[13]. The study consisted of two phases. During the first induction phase all subjects received abacavir/lamivudine (Epzicom) with atazanavir plus ritonavir at standard doses. Those patients who had confirmed plasma HIV RNA < 50 c/mL by week 36 then entered the randomized phase and at week 36 were randomized to either continue with the induction therapy or drop the ritonavir and increase their atazanavir to 400 mg daily. This is not really a simplification study as the pill number does not change. However, even low dose (100 mg) of ritonavir may have substantial adverse effects, which may be symptomatic (e.g. gastrointestinal) or asymptomatic (e.g. elevated triglycerides). Five hundred and fifteen subjects entered the study and 419 were randomized. Notably, over half the patients at baseline had HIV RNA levels > 100,000 c/mL. The results were pretty straightforward. At 84 weeks (48 weeks after randomization) the proportion of patients who remained on therapy and suppressed (ITT - TLOVR analysis) was similar 86% on abacavir/lamivudine and atazanavir and 81% on the arm that continued with atazanavir plus ritonavir. 3% more patients dropped out of the atazanavir/ritonavir arm for a wide variety of reasons that hinted at tolerability (patient decision, lost to follow-up, adverse event etc). There was no difference in suppression rates by baseline HIV RNA with 85% and 87% remaining suppressed and on therapy on the atazanavir arm with baseline VL < 100,000 c/mL and > 100,000 c/mL respectively. There were actually more virologic failures on the atazanavir/ritonavir arm (7 total vs. 1) though there were no new major PI mutations in any of the failures. Again, this finding may suggest tolerability and adherence issues. Important, though not surprising, was the decrease in triglycerides and total cholesterol when ritonavir was dropped from the regimen. LDL-c also seemed to decrease slightly while HDL-c remained stable and up from baseline. The proportion of patients with hyperbilirubinemia also decreased. No myocardial infarctions were observed during the study (mean age at randomization was 39 years and 85% of the participants were men). These results clearly show that dropping RTV once suppressed is feasible, tolerable and maintains HIV suppression. The strategy fits with abacavir/lamivudine (Epzicom) and not TDF/emtricitabine (Truvada) because of the effect of tenofovir on atazanavir that requires maintaining ritonavir with that NRTI combination. The ARIES study was designed and enrolled prior to the D.A.D. results that demonstrated an association of abacavir with myocardial infarction and was clearly designed to show a lipid (and therefore an implied cardiovascular) advantage to dropping ritonavir. The D.A.D. results made this study less appealing. However, now that there are studies that raise some question about the abacavir-MI association, the ARIES study strategy may be considered by clinicians especially in those patients that have difficulty tolerating even a low dose of ritonavir.
Metabolic Complications of HIV infection Update form the 5th IAS Conference in Cape Town - Pablo Tebas MD, University of Pennsylvania - (07/30/09)
Abacavir Not Associated with MIs, 2 Studies Report at IAS - (07/23/09)
Old Strategy, New Drug
Protease inhibitor monotherapy as a simplification strategy has been tested in the past with lopinavir/ritonavir and with atazanavir with ritonavir [14-17]. While generally successful there were suggestions that either boosted PI monotherapy was just not quite as good as continuing therapy with the boosted PI with nucleosides. There were greater numbers of patients with low level viremia, occasional selection of PI resistant virus and the question of whether virus remains suppressed in all compartments [18]. At IAS Arribas and colleagues presented the results of the MONET study, which tested the boosted PI simplification strategy with boosted darunavir[19]. The study design was straightforward. Subjects had to be suppressed < 50 c/mL for more than 6 months on 2 NRTI and either a boosted PI or NNRTI. They had to be naïve to darunavir and have no history of virologic failure. Two hundred fifty six patients were randomized 1:1 to continue NRTI and switch to once daily darunavir/ritonavir (800/100) or switch to once daily darunavir/ritonavir alone. Primary endpoint included virologic rebound (2 consecutive values > 50 c/mL), discontinuation of darunavir, addition of NRTI in the monotherapy arm or discontinuation of NRTI in the NRTI arm. The study population was typical; mostly men, mostly white, median age 43 and a high baseline CD4. The mean duration of previous antiretroviral therapy was remarkably long; 6.4 years and 7.4 years in the triple therapy and monotherapy arms respectively. Suppression rates were very similar. In the per protocol analysis 87.8 and 86.2% were suppressed < 50 c/mL at 48 weeks in triple therapy and monotherapy respectively and 85.3 and 84.3% in the intent to treat analysis. If patients who switched therapy but remained suppressed were included as successes then 95.1 vs. 93.5% remained suppressed < 50 c/mL at 48 weeks. All of these analyses demonstrated non-inferiority, which was defined as 95% CI of -12%. The investigators presented data on all patients at 48 weeks and almost all (97%) were suppressed < 50 though some had switched therapy and others had rebounded to > 50 c/mL but then suppressed again without changing therapy. Still there were hints of a little more viremia on the monotherapy arm. 11 vs. 7 patients met criteria for virologic rebound and 22 patients on the monotherapy arm had genotypes performed compared to 13 patients who remained on triple therapy (major PI mutations were observed in only one patient on each arm). Adverse events also didn't really improve. In fact, though likely not significant, there were numerically more clinical and laboratory adverse events in the monotherapy arm.
So where does this well-done study leave us? Is this a strategy that clinicians are likely to adopt? The arguments in favor are 1) simpler therapy in some instances though if switching from an NNRTI based regimen the pill number might actually increase, 2) preservation of the NRTI class (especially FTC or 3TC) 3) avoidance of NRTI toxicity and 4) decreased cost. The arguments against are pragmatic put perhaps compelling; 1) why mess with success? 2) boosted PI monotherapy isn't really much simpler 3) adverse events aren't really improved, at least over the observation period and 4) the gnawing concern that virologic suppression is just not quite as good. My guess is that there isn't going to be a great rush to darunavir/ritonavir monotherapy just as lopinavir/ritonavir and atazanavir monotherapy never really caught on. This may be an alternative for some patients, for example a patient suppressed on a boosted PI who was having renal dysfunction and had high cardiovascular risk such that avoiding both TDF and abacavir made sense? In general I suspect most patients and their clinicians will stick with their "nucs".
1. Lalezari J, Sloan L, DeJesus E, et al. Potent Antiviral Activity of S/GSK1349572, A Next Generation Integrase Inhibitor (INI), in INI-Naïve HIV-1-Infected Patients: ING111521 Protocol IAS. Cape Town, SA, 2009
2. Min S, Song I, Borland J, et al. Pharmacokinetic (PK) and Pharmacodynamic (PD) Relationship of S/GSK1349572, a Next Generation Integrase Inhibitor (INI), in HIV-1 Infected Patients IAS. Cape Town, SA, 2009
3. Sato A, Kobayashi M, Yoshinaga T, et al. S/GSK1349572 is a Potent Next Generation HIV Integrase Inhibitor. In: IAS. Cape Town, SA, 2009
4. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006;43:509-15
5. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 2006;43:1-5
6. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008;359:355-65
7. Grant P, Zolopa A. Integrase inhibitors: a clinical review of raltegravir and elvitegravir. J HIV Ther 2008;13:36-9
8. Goethals O, Clayton R, Van Ginderen M, et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol 2008;82:10366-74
9. Underwood M, Johns B, Sato A, Fujiwara T and Spreen W. S/GSK1349572: A Next Generation Integrase Inhibitor with Activity Against Integrase Inhibitor-Resistant Clinical Isolates from Patients Experiencing Virologic Failure while on Raltegravir Therapy. IAS. Cape Town, SA, 2009
10. Lennox JL, Dejesus E, Lazzarin A, 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
11. Gotuzzo E, Nguyen B-Y, Markowitz M, et al. Sustained Antiretroviral Efficacy of Raltegravir as part of Combination ART in Treatment-Naive HIV-1 infected patients: 144-week data. IAS. Cape Town, SA, 2009
12. Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007;46:125-33
13. Squires K, et al. Similar Efficacy and Tolerability of Atazanavir (ATV) Compared to Atazanavir/Ritonavir (ATV/r), each with Abacavir/Lamivudine (ABC/3TC) after Initial Suppression with ABC/3TC + ATV/r: 84 Week Results of the ARIES Trial. IAS. Cape Town, SA, 2009
14. Arribas JR, Delgado R, Arranz A, et al. Lopinavir-Ritonavir Monotherapy Versus Lopinavir-Ritonavir and 2 Nucleosides for Maintenance Therapy of HIV: 96-Week Analysis. J Acquir Immune Defic Syndr 2009
15. Arribas JR, Pulido F. Early virologic rebound in a pilot trial of ritonavir-boosted atanazavir as maintenance monotherapy. J Acquir Immune Defic Syndr 2007;46:118; author reply 118-9
16. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 2005;40:280-7
17. Swindells S, DiRienzo AG, Wilkin T, et al. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. Jama 2006;296:806-14
18. Vernazza P, Daneel S, Schiffer V, et al. The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. Aids 2007;21:1309-15
19. Arribas J, Horban A, Gerstoft J, et al. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA <50 copies/mL at baseline. IAS. Cape Town, SA, 2009
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