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Summary from ICAAC/IDSA for Treatment Naïve patients
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New Data, More Options, Some Questions
Joseph J. Eron Jr. MD
Professor of Medicine
University of North Carolina at Chapel Hill
At this conference we saw several studies that addressed therapy for the treatment naïve patient. The 96 week data from the CASTLE study (comparing atazanavir/ritonavir to lopinavir/ritonavir) and from the ARTEMIS study (comparing once daily darunavir/ritonavir to lopinavir/ritonavir) were presented. We also saw the first presentation of the 48 week Phase III data comparing raltegravir to efavirenz in treatment naïve patients each combined with tenofovir/emtricitabine. Almost immediately following the conference DHHS guidelines for treatment naïve individuals were updated listing once daily darunavir/ritonavir as a preferred first line protease inhibitor and moving abacavir/lamivudine to alternative status.
STARTMRK: A randomized blinded comparison of raltegravir to efavirenz each in combination with fixed dose combination tenofovir/emtricitabine in treatment naïve patients.
Jeff Lennox presented the results of this study on behalf of his collaborators and Merck. Treatment naïve patients were randomized, one to one, to receive raltegravir 400 mg twice daily (or matching placebo) or efavirenz at the standard 600 mg once daily (or placebo) each combined with fixed dose combination tenofovir/emtricitabine. All patients had to have VL > 5,000 c/ml and were screened for pre-existing NNRTI and NRTI resistance. The primary outcome was at 48 weeks (though the study is on going) and like most studies now in treatment naïve patients this was a "non-inferiority" study essentially designed to show that raltegravir was at least as good as efavirenz with a non-inferiority margin of 12%. The analysis was non-completer = failure at 48 weeks (not TLOVR). The investigators also had a pre-planned analysis at 8 weeks comparing CNS adverse events between the two arms. Approximately 280 patients were randomized to each arm and follow-up was excellent with only 8.5% and 12.4% of patients discontinuing in the RAL arm and EFV arm respectively. This 4% difference was driven predominantly by more discontinuations on the EFV arm due to adverse events.
The study population was (disappointingly) mostly male (> 80%) though more than half were non-white. Baseline viral load was just over 100,000 and baseline CD4 count was just over 200 cells/mm3, which is pretty typical for treatment naïve studies started in the last 2-3 years. Less than 10% of patient had hepatitis B or C and about 20% had non-subtype B virus.
At 48 weeks 86% of the patients on the RAL arm had HIV RNA levels < 50 c/mL compared to 82% on the EFV arm. The result clearly met the goal of non-inferiority (with a p value of < 0.001). Given the sample size, the difference between the two arms was not significant, though the confidence interval around the difference was not presented. Given that the sample size was somewhat smaller than several other recent large naïve trials (KLEAN, ARTEMIS, CASTLE) it will be helpful to learn this confidence interval. Regardless, these results are remarkable for two reasons. One, this may be the highest proportion below 50 copies at 48 weeks we have seen in a well powered phase III trial and two, this is one of the few head-to-head well powered trials with efavirenz in which non-inferiority was clearly established. Lennox and colleagues went on to show that the time to confirmed virologic suppression was statistically significantly shorter in the RAL arm. This finding was similar to what Marty Markowitz demonstrated in the Phase II trial, confirming the observation[1]. We have been intrigued by this observation of rapid suppression with raltegravir though, as in the Phase II trial the proportion of patients who suppress is ultimately very similar between the two arms. CD4 cell count increases were greater in the RAL arm (189 vs. 163 cells/mm3) but this small difference, though significant, is not likely to be clinically very important. On the other hand moderate and severe drug related adverse events were half as likely on the RAL arm (16% vs. 31.9%) and CNS adverse events were significantly less common at 8 weeks on RAL (10.3%) than on the EFV arm (17.7%). Serious adverse events were very similar between the 2 arms (approximately 10% in each) though notably there was only one malignancy in the RAL arm while there were 9 recorded in the EFV. This fact is worth pointing out as there was a non-significant numerical difference in malignancies in the BENCHMRK trials, with more malignancies on the RAL arms, which raised some concerns. The fact the numerical difference goes in the opposite direction in this trial probably lays the concern about raltegravir and malignancies to rest.
Two other important issues are the comparative impact of these therapies on lipid changes and the emergence of resistance in virologic failures. Raltegravir in this study was truly close to "lipid neutral". Small rises in total cholesterol, HDL cholesterol and calculated LDL cholesterol were seen and TG fell by a similarly small amount. Increases in all these parameters were significantly greater in the EFV arm when compared to the RAL arm with the difference in total cholesterol (23 mg/dL) and triglycerides (40 mg/dL) being the most pronounced. However HDL also rose to a significantly greater extent in subjects on the EFV arm so the important total cholesterol to HDL ratio declined slightly (a good thing) in each arm and the difference was not significant.
Resistance emergence was also described in detail and was uncommon in both arms. A very stringent definition of virologic failure was used for this analysis. Any participant who had a VL > 50 at the time of study discontinuation, at week 24 or on two consecutive occasion greater than 1 week apart after an initial response was consider a virologic failure for the resistance analysis. Twenty-seven subjects on the RAL arm and 39 on the EFV arm met one of these definitions but it is likely that some of these individuals may have still been on the way down with a viral load > 50 c at week 24. Not surprisingly, given the stringent definition, only a minority of these individuals had a viral load > 400 c/mL and their samples were subject to a resistance test; 12 in the RAL arm and 8 in the EFV arm. Four of the 12 on the RAL arm had integrase inhibitor mutations associated with RAL resistance and 3 of the 8 on the EFV arm had known EFV resistance mutations. So resistance emergence to the study drug on each arm seemed quite comparable and uncommon.
Overall, given the potency of raltegravir and the phase II study results these phase III data are not too surprising, though the proportion < 50 c/mL at 48 weeks is notably high and appears to be the result, not only of potency, but also of sustained tolerability. The blinded nature of the study allows rigorous assessment of tolerability and toxicity. However the convenience of the fixed dose combination efavirenz/tenofovir/emtricitabine single pill regimen was not put to the test in this study or any other large study to date. The activity, tolerability, lipid profile and pregnancy category of raltegravir will make it an attractive non-ritonavir containing alternative to efavirenz based initial therapy but it is unlikely to supplant the convenience of one pill once daily regimen. Nonetheless based on these results raltegravir is likely to be added to the crowded first-line menu and these results may also give clinicians confidence in raltegravir to replace the anchor agent of a successful first line therapy regimen if that agent is causing trouble with tolerability or toxicity.
Ninety six week data for two once daily boosted PI.
Two studies that recently published 48 week data presented 96 week data at the ICAAC/IDSA conference. In CASTLE, atazanavir/r once daily combined with tenofovir/emtricitabine was compared to the capsular form of lopinavir/ritonavir twice daily with the same NRTI in almost 900 treatment naïve patients. Forty-eight week results published in the Lancet this summer demonstrated that atazanavir/r was non-inferior to lopinavir/r in this setting[2]. Atazanavir/r had more favorable effects on total cholesterol and triglycerides and like other boosted PI emergence of primary PI resistance occurred rarely. The 96 week data further solidified these results. In the intent to treat analysis at 96 weeks 74% of patients on the atazanavir/r arm had plasma HIV RNA levels < 50 c/mL compared to 68% on LPV/r. This difference was statistically significant (p < 0.05 - though probably not much less). However in an on-treatment analysis similar proportions of patients were less than 50 copies/mL at 96 weeks (89% in the ATV/r arm and 88% in the LPV/r arm) and virologic failures were uncommon in both arms. The difference between arms at 96 weeks was driven predominantly by discontinuations in the LPV/r arm. ATV/r also had significantly less effect on total cholesterol and TG though the difference in effect on calculated LDL was modest and HDL went up to a greater extent on LPV/r. As was demonstrated in the published 48 week data, treatment responses to ATV/r were maintained at low CD4 cell counts while the effectiveness of the LPV/r based regimen dropped off again mainly due to tolerability. Atazanavir/r also maintained its activity in participants who had baseline VL > 100,000. GI tolerability was better with atazanavir/r though as expected substantially more patients had high bilirubin levels and/or became clinically jaundiced on boosted atazanavir. Resistance emergence remained uncommon as only one patient on the ATV/r arm had primary PI mutations AND failed to suppress long term. No patient on LPV/r had emergence of major PI mutations. NRTI mutations appeared to emerge at approximately the same low rate in both treatment arms.
These results confirm the longevity of the response to atazanavir/r with TDF and FTC and provide longer term tolerability data. The small but significant difference in treatment response at 96 weeks that was not seen at 48 weeks was not driven by virologic failures on LPV/r but by treatment discontinuations (in fact 4% on LPV/r vs. 1% on ATV/r just withdrew consent). To me, a treatment discontinuation, for convenience, tolerability or a non-life threatening toxicity, does not have the same clinical importance as a virologic failure because in the clinical setting such a patient would have a more convenient or tolerable alternative prescribed and would likely remain suppressed on therapy; whereas a virologic failure may result in FTC/3TC resistance or, more rarely, additional drug resistance. However these longer term results and the results by CD4 strata confirm the tolerability of atazanavir/r without compromising on antiretroviral or immunologic activity or engendering a greater risk of resistance. Sweeping conclusions need to be tempered somewhat by the fact that individuals on the LPV/r arm received the capsular form through 48 weeks and the vast majority continued on the capsule form throughout the study. However the durability, tolerability, lipid effects and minimal resistance risk of the 3 pill once daily regimen of atazanavir, ritonavir and fixed dose tenofovir/emtricitabine supports the use of this regimen in first line therapy.
The ARTEMIS study comparing DRV/r (800/100 mg once daily) with LPV/r (800/200 mg divided twice daily or given once daily) each combined with TDF/FTC also recently had 48 week data published and presented 96 week data at ICAAC/IDSA. In this almost 700 patient study DVR/r was non-inferior to LPV/r at 48 weeks when comparing proportion of subjects with VL < 50c/mL and in the higher viral load strata (> 100,000 c/mL) DRV/r had a significantly greater virologic response[3]. At 96 weeks the proportion < 50 c/mL in the ITT-TLOVR analysis was 79% vs. 71% in the DRV/r and LPV/r arms respectively and this difference in the overall study population was statistically significant (P = 0.012). Significantly better responses were seen with DRV/r in the > 100,000 c/mL strata and in subjects with baseline CD4 cell counts < 200 cells/mm3. In this study there was a significantly lower virologic failure rate in the DRV/r arm (12% vs. 17%), though some of the difference was also driven by discontinuation due to adverse events. Gastrointestinal AE (predominantly diarrhea) occurred more commonly on the LPV/r arm. Resistance emergence was minimal on both arms with no participants in either arm developing primary PI mutations when those patients with virologic failure at > 1,000 c/mL were examined by genotype analysis. Further analysis of lower level virologic failures is ongoing. Similar to the CASTLE study the differences in lipids were in triglycerides and total cholesterol. Differences in calculated LDL were minimal and HDL rose slightly but significantly more on the LPV/r arm. Notably the proportion of participants who had grade 2-4 AST and ALT elevations were very similar between the 2 treatment arms reinforcing the clinical impression that with the exception of tipranavir/r the frequency of elevated transaminases is very similar between ritonavir-boosted PI.
These results confirm and extend the week 48 results and suggest that over the longer term DRV/r may provide both better virologic responses and better tolerability than LPV/r when both are combined with TDF/FTC in the overall study population and in particular in those with lower CD4 cell counts or higher viral loads. Once again the LPV/r formulation was the capsular formulation at the start of the study though by the end of the study the majority of patients were on the tablet formulation. Participants were also allowed to take LPV/r once daily or twice daily. The majority opted for twice daily therapy. Even in this subgroup DRV/r outperformed LPV/r in a post-hoc analysis. With the recent FDA approval of DRV/r at 800 mg/100mg once daily for treatment naïve patients clinicians now have another relatively simple (4 pills once daily) regimen when this boosted PI is combined with TDF/FTC.
Summary
Therapy options for treatment naïve patients continue to expand. The data presented at ICAAC/IDSA for raltegravir, atazanavir/r and darunavir/r provide strong evidence for using any of these three "anchor" agents with TDF/FTC in first line therapy. The key question and the "art" of medicine is "How to choose, among an array of active, well tolerated therapies with modest or minimal resistance risk?" The question can be broken down further by asking, "Does any data presented trump a one pill once a day regimen?" Raltegravir is the first anchor agent to take on efavirenz head-to-head and provide a decisive results showing clear non-inferiority in a study not crippled by a very low response rate[4]. The fact that the proportion of subjects with VL < 50 c/mL was numerically greater on the raltegravir arm adds a further measure of confidence in this treatment. Raltegravir remains twice a day however (though a once a day study in treatment naïve patients has started) and many clinician may also be influenced by the marked success of raltegravir in the treatment experienced patient. Atazanavir/r and darunavir/r now both have strong (and durable data) albeit against LPV/r and not against efavirenz. The need to use ritonavir may influence some clinicians negatively though the lack of resistance emergence may be particularly important in patients who face adherence challenges. Similar to raltegravir some clinicians may be influenced by the success of darunavir in treatment experienced patients and there are no data comparing ATV/r with DRV/r. A planned large ACTG study which will compare all three; RAL, DRV/r and ATV/r each combined with TDF/FTC, may provide further information though the results are not likely to be available for years. Ultimately the appropriate first line therapy is an individual's choice guided by her or his clinician who hopefully is informed by the most up to date data and guidelines and is influenced by patient characteristics. Based on the ARTEMIS data and recent FDA approval the DHHS now lists DRV/r once daily as a first line therapy similar to the IAS-USA guidelines published this summer[5]. The inclusion of raltegravir into the preferred list for treatment naïve patients is likely not too far in the future.
From Jules: what about stdies comparing Atriple to DRV and ATV, is this being strategically avoided?
ICAAC/IDSA Presentations:
Lennox et al Safety and Efficacy of Raltegravir-Based Versus Efavirenz-Based Combination Therapy in Treatment-Naïve HIV-1 Infected Patients STARTMRK Protocol 021 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, poster abstract H-896a, Washington, 2008.
Molina et al Atazanavir/Ritonavir vs Lopinavir/Ritonavir in Antiretroviral-Naïve HIV-1-Infected Patients: CASTLE 96 Week Efficacy and Safety 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, poster abstract H-1250b, Washington, 2008.
Mills et al Efficacy and safety of darunavir/ritonavir 800/100mg once-daily versus lopinavir/ritonavir in treatment-naïve, HIV-1-infected patients at 96 weeks: ARTEMIS (TMC114-C211) 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, poster abstract H-1250a, Washington, 2008.
Additional References
1. Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H. 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 2007,46:125-133.
2. Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008,372:646-655.
3. Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, Fourie J, De Meyer S, De Pauw M, Lefebvre E, Vangeneugden T, Spinosa-Guzman S. 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.
4. Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, Delfraissy JF, Jemsek J, Rivero A, Rozenbaum W, Schrader S, Sension M, Vibhagool A, Thiry A, Giordano M. Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV. J Acquir Immune Defic Syndr 2004,36:1011-1019.
5. Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, Fischl MA, Gatell JM, Hirsch MS, Jacobsen DM, Montaner JS, Richman DD, Yeni PG, Volberding PA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. Jama 2008,300:555-570.
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