Lessons from the 21st CROI -
Integrating Data into Antiretroviral Treatment in the Clinic
Joseph Eron MD
Professor of Medicine
University of North Carolina at Chapel Hill
Note to readers: This is meant to be provocative.
Initial Antiretroviral Therapy
What to start? - we love to talk and think about this question. CROI 2014 provided us with additional data to fuel our discussions. Here is my take on how these data to should influence our practice.
Integrase inhibitor-based three-drug therapy
First we have the ACTG 5257 study that compared raltegravir, atazanavir/r and darunavir/r each paired with TDF/FTC . I believe this is the largest randomized comparative clinical trial on initial HIV treatment that has been performed in the modern ART era. It is also the first "equivalence" trial meaning that it is very well powered to define small but potentially important differences between these three treatments. The data presented were 96 weeks results. Most readers are probably familiar with the top-line result, which was that raltegravir plus TDF/FTC was superior to each of the two boosted PI regimens when a combined endpoint of virologic failure and regimen tolerability was used. This result was in spite of the fact that in this open label trial the raltegravir was a twice-daily regimen while the PI/r arms were both all once daily. Only 1% of over 600 patients initially randomized to raltegravir discontinued for tolerability reasons and while still within the margin of equivalence the incidence of virologic failure was greater for both ATV/r compared to RAL (3.4% greater; 97.5% CI (-0.7 to 7.4) and DRV/r compared to RAL (5.6% greater; 1.3% to 9.9%). An analysis that mimicked a standard FDA "snapshot" analysis also highly favored raltegravir. The proportion of participants < 50 c/mL at 96 weeks in this analysis was 80% for RAL, 73% for DRV/r and 63% for ATV/r. Other areas in which the raltegravir plus TDF/FTC arm outperformed the PI/r arms included lipid changes  (hopefully no one was surprised) and in change in bone density where there was a smaller decrease in bone density in the raltegravir arm .
Given that this is the first presentation of a very large study and the presentation lasted less than 15 minutes there is still a substantial amount of information to come forward from this study. There are some additional observations we can make and some nuances that apply to ACTG studies that are different than what might be seen in a standard pharmaceutical-sponsored comparative trial. One important aspect of ACTG trials is that they are, for the most part, true intention-to-treat studies. By that I mean participants are encouraged to stay on study even if they switch medications, experience virologic failure or have a treatment limiting toxicity or a tolerability issue. This strategy can make the data a little harder to sort through but also can provide information that other studies cannot. For example in this study we can learn what the HIV RNA suppression rate was at 96 weeks for participants who started on a specific treatment arm no matter what happened in between. So for me an important analysis in this study was the intention to treat analysis of suppression at 96 weeks. This analysis basically demonstrated that no matter what therapy was started at baseline the likelihood that the participant's HIV RNA would be < 50 c/mL at 96 weeks was very high. At 96 weeks 94% of participants on study who were initially randomized to raltegravir were ≤ 50 c/mL compared to 89% who were initially randomized to DRV/r and 88% initially randomized to ATV/r. In other words despite some virologic failure, despite switches due to tolerability and regardless of initial treatment assignment approximately 90% of all patients were at our treatment goal at 96 weeks; a very reassuring result.
There are a few of other points, specific to this study, to discuss. With an open-label design this study is susceptible to some bias. A participant who was unhappy with her treatment assignment may have left the study or may have been more likely to have a tolerability complaint leading to switch. Overall retention on the study was very good (approx. 92% at 96 weeks) and consistent across arms. Therefore differential drop out did not seem to be a problem. Participant and investigator assessment of toxicity/tolerability can also be biased in an open-label study as preconceived notions of side effects could influence attribution of cause. A drug thought to have very good tolerability might have slightly more favorable assessments of causality in an open-label study. Many comparative studies, which include one or more boosted-PI arms that we have relied on (and cited), have been open-label including ARTEMIS , CASTLE , A5202 (EFV v. ATV/r comparison) and FLAMINGO . Therefore I don't think the open-label nature of A5257 should limit the importance of the findings.
The study also had a fairly low threshold for allowing switch in therapy for tolerability and toxicity reasons. For the PI/r arms, if a switch was thought necessary, sites were encouraged to switch between the PI arms. Many experts (including this author) believe this contributed to the "poorer" showing of ATV/r compared to the two other arms as participants on atazanavir had study provided access to DRV that did not require a specific toxicity grade level in order to switch. The participant was allowed to remain on study and the site was not penalized in any way. Therefore participants who had bilirubin elevations that may have been tolerable or ignored in clinical practice may have switched to darunavir (or raltegravir) leading to the high number of tolerability failures in the atazanavir arm (there were 47 (8%) who discontinued ATV for jaundice/hyperbilirubinemia) and an additional 25 (4%) who discontinued due to GI toxicity that was not specified). Data that will be interesting to see will be what level of bilirubin or GI toxicity led to the majority of the ATV switches. This aspect of the study does impact the "snapshot" result discussed above and also the time to tolerability switch which was a primary endpoint. On the other hand this ATV/r result may reflect "real life" where patients/providers may switch therapy more freely than they would on a clinical trial where a switch results in study discontinuation for the patient as it would in many (but not all) pharmaceutical sponsored trials.
Another point, in a clinical situation a patient may not realize she has yellowing of skin or eyes and it passes or the patient doesn't complain to her provider therefore there is no impetus to change therapy. In a clinical trial the research clinicians may be more pro-active, may have lab tests done more frequently and so a switch may be more likely, especially if, as in A5257, the patient is allowed to stay on the study even after the switch.
One more nuance that was listed on the very first slide of the presentation was that ritonavir was not provided by the study (thank you very much Abbott or is it Abbvie?). Participants randomized to one of the PI/r arms had to obtain RTV from an outside source (insurance, ADAP etc.). While this was a pain in the butt for some participants and sites I don't think it influenced the results. The main reason I say this is from experience at our site where we enrolled 80+ participants and the ritonavir had to be available to the patient prior to randomization. Once the source for the ritonavir was established (insurance, ADAP etc.) accessing ritonavir went smoothly. In addition as pointed out below not a single patient in this study developed protease inhibitor resistance. I think that is strong evidence that whenever the atazanavir or darunavir was taken it was boosted with ritonavir.
Were there advantages in receiving one of the PI/r arms as initial therapy? The quick and reasonable answer is "yes, there were resistance advantages". Out of over 1200 randomized to initial ritonavir-boosted PI therapy, none developed a primary protease inhibitor resistance mutation. This is consistent with countless other studies and is a clear advantage to a boosted PI-based regimen. I think it is important to point out though that it was not a dramatic advantage. Of participants randomized to receive raltegravir only 11 (2%) out of 603 developed a primary integrase inhibitor resistance mutation. Seven additional participants developed an M184V alone making a total of 18 that developed one or more resistance mutations. Three participants did develop M184V, K65R and an integrase mutation. Acknowledging that cross-study comparisons are risky, I should also point out when looking at the "snapshot" outcome the raltegravir 96-week result is similar to what was seen in Spring 2 in which raltegravir was compared to dolutegravir and 76% vs. 81% of RAL-treated vs. DTG-treated patients were < 50 c/mL at 96 weeks. In contrast the "snapshot" result for DRV/r in A5257 was lower than what was observed in the smaller ARTEMIS trial in which the old "TLOVR" analysis was used (73% vs. 79% ). The atazanavir/r plus TDF/FTC result in A5257 was also substantially lower than was seen in the CASTLE study at 96 weeks (63% vs. 74%) ; a result that was likely at least partially driven by a high proportion of tolerability switches away from atazanavir, as mentioned above.
There will be many additional analyses that come from A5257 that will likely influence our treatment decisions. There was a large and detailed sub-study (A5260s) that looked at several cardiovascular and metabolic outcomes. I am very curious to see the impact of the different arms on some of the important inflammatory makers like IL-6, sCD14 and sCD163. Many readers may recall that in the SPIRAL study in which patients on a suppressive protease inhibitor regimen were randomized to either continue their PI therapy or switch to raltegravir  multiple inflammatory markers including hsCRP, IL-6 and D-dimer significantly declined (improved) in the raltegravir arm . In the SPIRAL study the most common PI was lopinavir/r and very few patients were on DRV/r and of course none of the patients were treatment naïve. Results from A5257 should be very interesting.
Before I go on about how the A5257 results might be integrated into clinical practice I want to briefly discuss 96-week results from another large, randomized, comparative study of an integrase inhibitor; the SINGLE study of dolutegravir presented by Sharon Walmsley in a poster session . This study was a blinded comparison of dolutegravir combined with abacavir/3TC with the fixed dose combination of efavirenz/TDF/FTC. The 48-week results were published in the NEJM  and the 96-week results remain consistent with that publication showing that the dolutegravir arm remained superior to the efavirenz-containing arm with 80% of participants randomized to DTG suppressed to < 50 c/mL at 96 weeks in the "snapshot" analysis compared to 72% with the efavirenz FDC. The 8% difference is almost the same as what was seen at 48 weeks and is driven by differences in discontinuation due to toxicity/tolerability in this blinded study. With this longer duration of follow-up there were still no participants in the DTG arm who developed resistance mutations, either in the integrase or reverse transcriptase regions. There are now 3 large studies of DTG in ART naïve patients, two out to 96 weeks - SINGLE  and SPRING 2  and one at 48 weeks - FLAMINGO , in which no participant has developed either integrase of NRTI resistance. These studies have differing definitions of virologic failure and resistance testing is done early in virologic failure (on the first rebound specimen), which may limit the extent of resistance emergence. However, zero is still zero. Those of you who are old enough will recall that we didn't actually embrace the concept of virologic failure without resistance with boosted-PI when Abbott first presented the data from the early lopinavir-ritonavir studies. I fully agree that we need to see data from the clinic on DTG and resistance and I don't think we can say the pharmacologic/genetic barrier to resistance for DTG is the same as a boosted PI but it is likely to be close.
Therefore I think the six large comparative trials of integrase inhibitor versus other non-integrase inhibitor DHHS preferred therapies including A5257, the two studies of dolutegravir in treatment naïve patients, STARTMRK  and the two comparative studies of elvitegravir/cobicistat/TDF/FTC with EFV/TDF/FTC  and with ATV/r plus TDF/FTC  leave us with a strong data set that argue for considering an integrase inhibitor-based therapy first before considering therapy anchored by NNRTI or boosted PI. In each of the studies listed above the integrase inhibitor arm was either superior to or non-inferior but numerically greater than the comparator arm when examining proportion < 50 c/mL at the primary endpoint or at endpoints up to five years post randomization. In the integrase class we have an agent that has well-established long-term safety and efficacy data, favorable lipids and limited drug-drug interactions (raltegravir). We have a single-tablet integrase-containing regimen for which we have 3 years of data (elvitegravir/cobicistat/TDF/FTC) and a once daily integrase that does not require boosting, has demonstrated activity with either TDF/FTC or ABC/3TC, has limited drug-drug interaction and hopefully will be available in the first single tablet regimen that does not contain TDF (dolutegravir). One could make the argument that for the vast majority of patients these are all the regimens we need and given the comparative studies these integrase-containing regimens should be consider first.
One additional point comes from a very nice study also presented at CROI 2014 that examined the prevalence of transmitted drug resistance, including integrase inhibitor resistance in treatment naïve patients at 3 points in time (2000, 2003 and 2013) who were screening for treatment naïve research trials sponsored by Gilead (903, 934 and 104 and 111, the 2013 trials comparing the TAF containing QUAD with STRIBILD) . The bottom line from this study was that while the expected increase in NNRTI resistance was observed and was very consistent with other studies rising from 0.5% in 2000 to 4.2% in 2003 to 8.7% in 2013, there was only one example of a potential transmitted integrase mutation (a mixture of T66I) out of over 1600 patient samples. The fact that the group was able to test 1417 patient samples from 2013 and present those data in the first quarter of 2014 is particularly important making this study the most up to date transmitted drug resistance evaluation available. While transmitted integrase inhibitor resistance may eventually occur at a rate that exceeds recommendation for pre-treatment resistance screening  we do not appear to be anywhere near that level yet. These data may further enhance the argument for considering integrase inhibitors-based therapy first among "preferred" initial regimens.
Why do HIV clinical scientists and HIV clinicians continue to search for a "NRTI-sparing" first line antiretroviral regimen that has similar efficacy and tolerability to regimens that have a foundation of two NRTI, usually abacavir/3TC or TDF/FTC? I think one of the reasons is historical. Most of us have one or more patients that have seemingly permanent lipoatrophy related to thymidine analogue use, which makes us wary of long-term nucleoside effect. In addition, we know that TDF can have an initial impact on bone that appears greater than most alternatives and some patients will accrue renal toxicity with long-term TDF. Abacavir/3TC appeared to have potency issues at high viral load in at least one large study  though in more recent studies when paired with an integrase inhibitor this weakness was not apparent. Abacavir also has been associated with myocardial infarction in several studies, most recently in an updated analysis from the D.A.D. study presented at the 21st CROI . There are multiple other studies that have failed to show the association of abacavir with MI leaving the issue far from settled. Finally there are patients that (almost) no one would consider as candidates for either of the approved nucleoside pairs such as a patient with chronic kidney injury who is HLA B5701 + or perhaps a similar patient with chronic kidney injury who was HLA B5701 negative but who had substantial cardiovascular risk. For these and other reasons we have hunted for a NRTI-sparing regimen.
I think many of us thought that once integrase inhibitors became available the hunt was over. Combining a potent boosted-PI with raltegravir seemed like a no brainer given the PI mono-therapy was close and integrase inhibitors were potent and well tolerated. One group (led by yours truly) was so convinced that darunavir/r plus raltegravir would be successful they embarked on a single arm study because the results had to be good and a larger single arm study would be more precise in telling us how good. Unfortunately that study had an unexpectedly high number of virologic failures  and the lack of a control arm made interpretation of the results difficult and subject to legitimate questions. Small comparative studies of atazanavir combined with raltegravir were also disappointing . The two best efficacy results with NRTI-sparing regimens in treatment naïve participants were with LPV/r plus EFV in ACTG 5142 and with LPV/r plus raltegravir in the PROGRESS study . LPV/r plus EFV however had substantial side effects especially lipid elevations and when virologic failure occurred EFV resistance was common. In PROGRESS the baseline HIV RNA was quite low (just over 10,000 c/mL) limiting the generalizability of the results. In addition the 96 week suppression rates were lower than those seen in many other studies.
This array of unsuccessful or non-definitive studies left clinicians and clinical scientists uncertain about NRTI-sparing therapies and as a consequence none of the major guidelines has a NRTI-sparing regimen in its preferred, recommended or alternative regimens. The European clinical trials network (called NEAT) decided to address the question of NRTI-sparing regimens head on and designed a large, fully powered, open-label comparative study again choosing the NRTI-sparing regimen that many thought had the greatest likelihood of success (DRV/r plus raltegravir) and compared it head-to-head with DRV/r plus TDF/FTC in the NEAT 001 study. The 96-week primary results of this carefully conducted 800 patient study were presented at CROI 2014 .
At baseline the two patient groups were well balanced. Baseline characteristics were notable for the fact that approximately 88% of participants were men, only 34% had baseline HIV RNA > 100,000 c/mL, 5% had a previous AIDS diagnosis and only approximately 15% had a CD4 cell count < 200 cells/mm3. The primary endpoint included virologic failure and clinical endpoints (including death, AIDS and serious non-AIDS illnesses) but most of the endpoints were virologic failures. RAL plus DRV/r was non-inferior to DRV/r plus TDF/FTC using this primary endpoint with the estimated proportion reaching the primary endpoint at 17.4% for the RAL arm and 13.7% for the TDF/FTC arm (adjusted difference 3.7% 95% CI -1.1, 8.6%). When only the virologic endpoint was considered the adjusted difference was very similar 3.6% meeting non-inferiority but favoring the DRV/r plus TDF/FTC arm. Curiously the difference between the arms in virologic failure occurred exclusively in virologic rebounds after week 32.
Subset analyses were also presented and again raise questions about this NRTI-sparing combination. In the sub-group with baseline HIV RNA ≥ 100,000 c/mL, 36% of the RAL treated participants were estimated to reach the primary endpoint compared to 27% in the TDF/FTC for an approximate 9% difference [95% CI - 0.05 to 19.3%] not quite inferior but not non-inferior in this subgroup. For patient with CD4 < 200 cells/mm3 the difference was even greater with 39% of RAL-treated participants reaching the primary failure endpoint compared to 21.3% with TDF/FTC leading to a > 17% difference [95% CI 4.7 to 30.8] and demonstrating inferiority of the NRTI-sparing arm in this sub-group. Resistance data also favored the standard nucleoside-containing arm. Sixty-six participants on RAL met the criterion for protocol defined virologic failure compared to 52 on TDF/FTC and 36 of the samples for RAL-treated patients met criteria for genotyping (HIV RNA > 500 c/mL at or after 32 weeks) compared to only 15 on the TDF/FTC arm. No patient on the DRV/r TDF/FTC developed PI or NRTI resistance mutations while 5 on DRV/r plus RAL developed a primary InSTI resistance mutation.
The results of RAL plus DRV/r arm of NEAT 001 are not much different than those from the single arm ACTG study of Taiwo et al  mentioned above. That much smaller study had a higher proportion of subjects with HIV RNA > 100,000 c/mL at baseline and also a higher proportion with CD4 < 200 cells/mm3 and virologic failures were concentrated in that group. The fact that in both studies many of the virologic failures in the NRTI-sparing arm occurred after participants had HIV RNA levels reach < 50 c/mL raises concerns about the long term success of this regimen even in those who have achieved HIV RNA suppression. The results of NEAT 001 clearly require further analysis as the team only had the final results of the study for a short period prior to the presentation. Additional work on pharmacokinetics and adherence will certainly be completed. Regardless, I believe we are still looking for a NRTI-sparing regimen that is as robust and as tolerable as our preferred first line therapies that contain NRTI.
Another large NRTI-sparing study that was not at CROI and has not been formally presented is the randomized comparison of DRV/r plus maraviroc (150 once daily) vs. DRV/r plus TDF/FTC. Public information about this study exists on clinicaltrial.gov . The trial, called MODERN, was a double-blind, randomized trial in antiretroviral naïve participants with R5-tropic virus with a 48 week primary endpoint and over 800 patients were enrolled. "The study was terminated on October 8, 2013 following a preliminary review of the Week 48 primary efficacy data by the study's external independent Data Monitoring Committee (DMC). The DMC assessed the data as demonstrating significant differences between the treatment arms in virologic responses and failures. The DMC recommended and the Sponsor concurred that the study be terminated because of the inferior efficacy of the Maraviroc arm as compared to the comparator arm (Emtricitabine/Tenofovir)." These results hopefully will be presented in detail at the IAC meeting in Melbourne or another large conference but are another strike against a NRTI-sparing regimen that does not contain at least one reverse transcriptase inhibitor.
So where does that leave us in a treatment naïve patient who is not a good candidate for either abacavir or tenofovir? Well there is zidovudine/3TC (Joel Gallant just choked on his mojito). However it would seem we could do better than that. If the viral load is low and the CD4 is high then DRV/r (or perhaps LPV/r) plus raltegravir is likely to be OK but I would follow that patient carefully even after the HIV RNA was suppressed to < 50 c/mL. Perhaps the NEAT 001 data could be extended to DRV/r plus dolutegravir? The regimen would be all once a day and there would be less risk of differential adherence? I think these are reasonable assumptions though it seems like every time we put a NRTI-sparing "reasonable assumption" to the test that reasonable assumption falls short. Eric Daar in his summary discussed the LATTE study. This study looked at maintenance therapy in suppressed patients with the experimental integrase inhibitor "744" (which is similar to BUT NOT the same as dolutegravir) plus rilpivirine, both once daily and results were very encouraging. Could these results be extrapolated to initial therapy with dolutegravir plus rilpivirine in treatment naïve patients? One NRTI-sparing regimen that held up virologically was LPV/r plus efavirenz so maybe an RT inhibitor is a key ingredient? If I were going to study another NRTI-sparing regimen it would be DTG plus an NNRTI maybe the new NNRTI from Merck (that Eric also discussed) or rilpivirine. Those potential combinations would not be a "sure thing" and would need to be tested in a well-powered clinical trial. I am not sure that any group or pharmaceutical company would be interested in the investment.
Another alternative to the patient who is not a candidate for TDF or abacavir would be a "NRTI-lite" regimen. The GARDEL study which compared LPV/r plus 2 NRTI to LPV/r plus ONLY 3TC was presented by Pedro Cahn at EACS in the fall of 2013 . The outcomes between the two arms were highly comparable and there did not seem to be a major weakness to the "NRTI-lite" arm except for perhaps an increase in M184V emergence when virologic failure occurred. This study is likely to be published soon and we can examine the details more closely. A substantial proportion of the 2 NRTI group received ZDV plus 3TC and whether this influenced the outcome needs to be dissected. Once again we are also left with the urge to extrapolate. Maybe DRV/r plus 3TC would be just as good or even DRV/cobicistat (which may be available by the end of 2014) plus 3TC? As I pointed out a few times already - extrapolation is not without risk but I think the concept of "NRTI-lite" may one solution to the uncommon but not unheard of treatment naïve patient for whom neither TDF or abacavir are optimal. Alternatively once a patient is suppressed on a 2 NRTI containing regimen a NRTI-sparing maintenance regimen (like an once a day integrase with rilpivirine) may be an option that limits bone and renal toxicity and cardiovascular risk.
CROI: Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir with FTC/TDF: ACTG A5257 - (03/05/14)
CROI: First-Line Raltegravir (RAL) + Darunavir/Ritonavir (DRV/r) is Non-inferior to Tenofovir/Emtricitabine (TDF/FTC) + DRV/r: The NEAT 001/ANRS 143 Randomised Trial - (03/05/14)
CROI: Darunavir or Atazanavir vs Raltegravir Lipid Changes are unlinked to Ritonavir Exposure: ACTG 5257 - (03/07/14)
CROI: Bone Density Changes after Antiretroviral Initiation with Protease Inhibitors or Raltegravir - (03/10/14)
CROI: 21st Conference on Retroviruses and Opportunistic Infections: Review - Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA - (03/21/14)
CROI: GSK744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results - (03/05/14)
CROI: GSK1265744 Demonstrates Robust in Vitro Activity Against Various Clades of HIV-1 - (04/21/14)
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