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Antiretrovirals CROI 2015 Summary
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Joseph Eron MD
Professor of Medicine
University of North Carolina at Chapel Hill
Tenofovir alafenamide (TAF)
At this meeting the comparison of TDF/FTC/elvitegravir/cobicistat with tenofovir alafenamide (TAF)/FTC/EVG/cobi (E/C/F/TAF) in two large blinded phase 3 clinical trials were presented for activity by David Wohl and for bone/renal and metabolic outcomes by Paul Sax. The two studies included over 1700 patients and they were presented as a combined analysis. These presentations have been highlighted and discussed extensively in the last 3 weeks. There are a few points worth highlighting one more time.
First, the combined treatment response in the E/C/F/TAF arms was the highest 48 week treatment response rate in any large randomized phase III antiretroviral treatment trial presented or published to date; 92.4% of the patients treated with E/C/F/TAF had an HIV RNA < 50 c/mL at 48 weeks. Despite this response rate and the large sample size, the TAF-containing regimen was not superior to the TDF-containing regimen because the TDF arms exceeded 90% success (90.4%). The proportion with virologic failure was 4% in both groups. These results are obviously outstanding and as good as we have seen. Cross study comparisons are fraught with pitfalls though we love to talk about them. We should make sure we point out that in this study, like most recent studies, the proportion of patients with high VL is small (23%) and the proportion with low CD4 cell count (< 200 cells/mm3) is even smaller (14%). However because this is such a large study the actual numbers of patients in these groups is not small; almost 400 and 230 respectively and response rates seem consistent across these subgroups in each of these arms though the proportion < 50 c/mL at 48 weeks was numerically lower in both the TAF- (87%, 86%) and the TDF- (89%, 89%) containing arms in the high VL and low CD4 cell subgroups respectively.
As an aside I would urge the research groups to get together and present point estimates and confidences intervals with these subset results instead of the minimally informative histograms. Knowing whether the proportions with virologic failure (vs. no data) were different in these subsets would also be helpful in understanding the results. All this information could easily fit on one slide.
Second, while others would probably be best discussing the renal, bone and lipid advantages and disadvantages of E/C/F/TAF, I think the impact (or lack of impact) on bone density with the TAF-containing therapy is worth calling out. Getting dexa scans on 1700 patients was a substantial effort and the differences in loss of bone density (-1.30 vs 2.86% at the spine and -0.66 vs. -2.95%) are likely to have substantial clinical impact. Perhaps not in 25 to 45 year old men (which is the who entered this study) but certainly in older men, post menopausal women and others at risk for osteopenia and osteoporosis. I was also intrigued by the data that Anton Pozniak presented in a poster in patients with renal dysfunction (30 < eGFR < 70) who switched from suppressive therapy (65% TDF-based) to E/C/F/TAF therapy. This switch was safe with no substantial decline in renal function (measured in a subset by iohexol clearance), improvement in urinary tubular proteins (which BTW occurred in one week, which would suggest to me that these are markers of tubular function but not of tubular injury/damage) and maintenance of virus suppression. What particularly interested me was the improvement in bone density (which presumably was seen predominantly in the patients who went from TDF-containing therapy to E/C/F/TAF). I may be particularly thick but I guess I finally realized that patients on TDF-containing may be "working" to maintain bone density. We have seen lots of data (again mostly in middle aged men) showing that bone density on TDF-containing therapy remains stable over time. I think it is possible that we would not see this same stability in patients who might have trouble sustaining bone density such as post menopausal women, older men etc.
The third point concerns the emergence of resistance in the small number of patients who had resistance testing. Patients had to have 2 viral loads > 50 after suppression and the second viral load had to be > 400 c/mL or the 48 week VL was > 400. (I will totally avoid the "which resistance sample" and "what viral load" cut-off wars). This turned out to be about half of the patients who were in the virologic failure category mentioned above (16 patients or 1.8% with TAF and 19 patients or 2.2% with TDF). The number of patients with resistance was remarkably low; less than 1% in each group (7 on TAF-containing therapy and 5 on TDF). However there was no difference between the two treatments. All 7 patients on TAF-containing therapy had M184V or I and one had K65R and 5 had InSTI resistance mutations. All 5 patients on the TDF-regimen had 184V or I and two had 65R. Three had InSTI mutations. There was some hope that the very high intra-cellular levels of tenofovir-triphosphate seen with TAF would create a higher barrier to resistance that might compensate for the lower barriers of FTC and elvitegravir. While the numbers here are small there is no suggestion of an added benefit to TAF on resistance emergence in this setting. There are in vitro data suggesting that TAF has increased activity against nucleoside resistant viral variants [click] and the possibility that TAF will have added benefit over TDF in the treatment experienced patient with multiple NRTI mutations still exists though testing this hypothesis in patients is a challenge given the (fortunately) limited occurrence of these patients in clinical care.
Overall E/C/F/TAF is highly effective in treatment naïve patients with limited numbers of virologic failures and excellent tolerability. The impact on bone density is small and the initial data are suggestive that there may be less long term renal toxicity than with TDF, yet, by definition it will be a while before we know that for sure. TAF may extend the renal insufficiency "range" of a tenofovir-containing regimen down to a eGFR of 30 mL/min, although that decision will ultimately be up to the regulatory bodies (FDA, EMEA etc). Many experts are asking whether the search for a highly active "nuc-sparing" regimen can be abandoned? I am not sure - LATTE anyone?
CROI: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy - (02/26/15)
CROI: Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - (02/27/15)
CROI: Safety of Tenofovir Alafenamide in Renal Impairment - (02/27/15)
LATTE 96 week data
As most people know the LATTE study is exploring a "nuc-sparing, boosted-PI-sparing" regimen for maintenance of suppression in patient who had their plasma HIV RNA suppressed on a typical 2NRTI plus third agent regimen. The agents used as maintenance in this study are oral cabotegravir (similar but not identical to dolutegravir) and oral rilpivirine. The main goal of this study was to see if these two agents count maintain suppression as a preamble to a similar study (LATTE-2) in which the drugs are given as long active injectable agents. The oral study was done first for safety but also to show that a 2-agent, non-bPI containing regimen was robust enough to maintain suppression. Many experts, clinicians and patient advocates realized that the simplicity, tolerability, metabolic safety, limited drug-drug interactions and potential for minimal long-term complications of this the combination of a dolutegravir-like integrase inhibitor and rilpivirine might make this an attractive oral regimen IF suppression could be maintained with minimal resistance consequences.
At CROI 2015 we saw the 96-week data from this phase IIb study. The presentation included 72 weeks of follow-up in the maintenance phase, which I will focus on.
An important fact about this study is that the study is a dose ranging study for cabotegravir (10, 30 and 60 mg daily) in addition to be a test of an untested regimen. To be eligible for the maintenance phase patients treated with 2NRTI and one of the 3 doses of cabotegravir had to have an HIV RNA < 50 at 20 weeks and they began rilpivirine at week 24 they dropped the NRTI and continued on cabotegravir and rilpivirine. The comparison group was patients randomized at baseline to 2 NRTI and efavirenz who continued on this therapy. One hundred 160 patients on cabotegravir/rilpivirine entered the maintenance phase (approximately 53 at each cabotegravir dose). After 72 weeks of this maintenance therapy 86% of patients had an HIV RNA < 50 c/mL using the typical snapshot analysis. Six percent had either protocol defined virologic failure or an HIV RNA above 50 c/mL. These numbers varied somewhat by cabotegravir treatment group with 85% and 93% having virologic success in the 30 mg and 60 mg groups and a somewhat lower success rate of 79% with 10 mg cabotegravir with a larger number of virologic failures. No patient in the higher dose groups had virologic failure with resistance. Three patients in the 10 mg arm developed resistance. All three had resistance to rilpivirine and one also had a typical integrase resistance mutation (Q148R). Adverse events were uncommon and had no consistent pattern across treatment groups.
The sustained virologic suppression with this novel two-drug regimen provides the needed evidence for the LATTE-2 study with cabotegravir- and rilpivirine-LA, which is ongoing. The success of this nuc-sparing, bPI-sparing once daily therapy also provides evidence for testing a therapy, dolutegravir and rilpivirine, that is likely to be as successful, if not more successful than cabotegravir plus rilpivirine given the much greater clinical experience with dolutegravir and the pharmacologic and genetic barrier to resistance of this integrase inhibitor that has now borne out in clinical trials and in clinical practice. Clinical development of this combination is planned [click] and will initially to be studied in patients suppressed on therapy. If successful, the resulting therapy would be a small once daily combination tablet for maintenance therapy with many favorable characteristics.
CROI: Cabotegravir and Rilpivirine As 2-Drug Oral Maintenance Therapy: LATTE W96 Results - (03/05/15)
Boosted Protease Inhibitors and Fat
In a very clear presentation, Grace McComsey and her ACTG collaborators demonstrated no difference in fat gain on initial therapy in treatment naïve patients between our two most commonly used boosted PI (atazanavir and darunavir) and raltegravir each co-administered with TDF/FTC. This study was a sub-study of ACTG 5257 [click], [click] and approximately 100 individuals in each arm had dexa scanning and abdominal CT scanning at baseline and week 96 to assess changes in limb and abdominal fat. In each of the study arm median limb fat, subcutaneous abdominal fat, visceral abdominal fat, trunk fat, and lean mass increased significantly in all study arms and the increase in abdominal fat was virtually overlapping between the integrase inhibitor containing arm and either of the bPI-containing arms. There was no suggestion that visceral abdominal fat preferentially accumulated with boosted-PI therapy.
For experienced provider and sophisticated patients I am sure this is not a surprise. However, I still hear from some patients and importantly some providers who still believe that boosted-PI therapy is associated with preferential accumulation of visceral adiposity. I think we can put this concern to bed for good. That is not to say that all the fat gain that Grace and her colleagues observed is a "return to health". The inflammation associated with chronic HIV infection may impact how weight gain is distributed between lean body mass and fat when patients go on therapy. This study is likely to help answer some of these question and point us toward some patient characteristics, such as high baseline viral load, that may put them a risk for less "healthy" weight gain patterns.
CROI: Body Composition Changes after Initiation of Raltegravir or Protease Inhibitors..... - (03/16/15)
New Agents
One concern about antiretroviral therapy that I have written about in previous conference summaries is the paucity of new agents in clinical development.
Admittedly we have a large number of effective antiretroviral agents and encountering a patient who has resistance and/or intolerance to therapy that precludes the design of a fully suppressive antiretroviral regimen is an uncommon event in our clinical practices. Unfortunately these uncommon clinical situations do occur and over time more will slowly accumulate. Perhaps TAF, as mentioned above, may be helpful in some settings of resistance and we know that twice daily dolutegravir twice daily has activity against many of the resistant variants selected for by elvitegravir or raltegravir [click]. In the setting of extensive 3 or 4-class resistant virus an inhibitor in a new class working via a new mechanism would be most useful.
Attachment Inhibitor
At CROI 2015 we heard more follow-up data on the attachment inhibitor pro-drug BMS-663068 which is pro-drug that is metabolized to an active compound (BMS- 626529) that binds to the envelop gp120 and blocks attachment and virus cell entry. This drug clearly has antiretroviral activity in infected persons with an HIV RNA drop from 0.7 to 1.5 log10 drop in HIV RNA over 7 day mono-therapy period with the magnitude of the drop dependent on the dose. In the phase IIb study 4 doses of the attachment inhibitor were compared to atazanavir/r each given with raltegravir and tenofovirDF in patients with most levels of treatment experience and resistance. Results were similar to the 24-week data that have been discussed previously with good but not remarkable antiretroviral efficacy results and very good safety data over 48 weeks. Previous data suggested that some variants with high baseline IC50 in vitro may not respond well to the inhibitor and patients with baseline IC50 > 100 nM were excluded from this study and the potential for reduced response in patients with certain viral variants needs to be understood.
These data have led to the development of a phase III study, which will examine a 600 mg BID dose of the attachment inhibitor in highly treatment-experienced patients. The primary goal of the study will be to evaluate the antiretroviral effect, compared to placebo, during an 8 day functional mono-therapy period followed by treatment optimization and open label therapy for 48 weeks or longer to assess safety and long term activity. Demonstration of attachment inhibitor susceptibility is not required for study entry though this will undoubtedly be a variable used in the assessment of outcome.
CROI: Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 48 Analysis - (02/27/15)
Maturation inhibitor
Those of you who are old enough and have good memories might remember bevirimat, the "first generation" maturation inhibitor that had an oral formulation and evidence of in vivo activity [click]. This agent had a series of problems including drug formulation, limited activity and perhaps most important, relatively common HIV-1 variants with intrinsic resistance to bevirimat [click]. The development of bevirimat stopped.
At CROI 2015 we saw the first clinical data on a "second generation" maturation inhibitor that looks like it may overcome some of the problem encountered in the bevirimat development. Recall that maturation of HIV-1 requires the specific cleavage of the HIV gag poly protein by the HIV protease. There are specific cleavage sites and the order and timing of cleavage of the gag polyprotein is quite specific. So technically protease inhibitors are in fact maturation inhibitors as they prevent the formation of an intact viral capsid. Maturation inhibitors like bevirimat and the second generation compound, BMS-955176, however don't bind to the protease enzyme. They bind to the gag protein itself and prevent cleavage of gag at their specific binding site. Blocking of cleavage of one binding site is enough to disrupt overall gag cleavage and viral capsid assembly - resulting in noninfectious particles. BMS-955176 has activity in vitro against wild-type HIV and against variants that contain some of the cleavage site polymorphism that thwarted bevirimat.
BMS-955176 was tested in a classical phase Ib (or IIa) dose-ranging study in HIV-1 infected participants who were not on therapy. This agent has very good pharmacokinetics that support once daily dosing, low serum binding and tight binding to HIV gag protein. Six once daily doses of 176 were tested over a 10-day period with follow-up off therapy through day 24. Eight subjects were treated in each dose group and there were 12 placebo recipients (2 in each dose cohort). Almost all participants were white men and the median baseline HIV RNA was in the 10,000 c/mL range. The three highest doses, 40, 80 and 120 mg once daily, produced a 1.5 to 1.7 log10 (30 to 50 fold) decline in HIV RNA over the 10 day period with no substantial difference in patients that harbored virus with some of the baseline polymorphisms associated with decreased bevirimat response. There was some persistence of HIV RNA suppression after the drug was stopped consistent with the long half-life of the drug. No safety signals were apparent in this small study.
This study paves the way for a phase IIB study with longer term dosing likely with 2 or 3 of the higher doses that demonstrated the greatest antiviral effect. The potency may not be enough for this drug to be compared to an anchor agent in first line therapy but the fact that it is once daily, low milligram dosing and has activity that rivals the most potent NRTI and CCR5 antagonists suggests that this drug would have potential across the spectrum of HIV treatment and may provide a strong partner to other agents in treatment experienced patients with multi-class resistant virus.
CROI: BMS-955176: Antiviral Activity and Safety of a Second-Generation HIV-1 Maturation Inhibitor - (02/27/15)
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