CROI REPORT: New Drugs for HIV Treatment and other random thoughts
Joseph Eron MD
Professor of Medicine
University of North Carolina at Chapel Hill
This year's CROI continued to provide interesting data on new drugs that are in development. Though many of the studies were confined to poster presentations there were multiple important studies to discuss. One area where there was more limited information was on new drugs with novel mechanisms of action that are in clinical development and this may have implications for a small minority of patients who have more limited treatment options.
New Drugs in Later Stage Clinical Development
Cynthia Brinson and colleagues (1) presented data from both the SPRING-2 and SINGLE studies of dolutegravir with 2 NRTI in treatment naïve patients providing a breakdown of 48 week efficacy results by a range of baseline demographic and clinical characteristics such as age, race, gender and baseline viral load (<100,000 v. > 100,000) and CD4 cell counts (> 350 v. < 350). As a reminder SPRING-2 was a blinded head-to-head comparison with RAL each with a choice of 2 NRTI (approximately 60% chose TDF/FTC) and SINGLE was DTG plus ABC/3TC compared to the fixed dose combination of EFV/TDF/FTC in a blinded trial. In SPRING 2 DTG was non inferior to RAL (88% vs. 85% < 50 c/mL at 48 weeks by FDA snap shot) and in SINGLE DTG plus ABC/3TC was superior to EFV/TDF/FTC (88% vs. 81%) with the difference driven predominantly by discontinuations due to AE in the EFV arm. The sub-group analyses mirrored the primary results.
In SPRING -2 all sub-group results were either very similar or slightly favoring DTG arm. With the sub-groups of high viral load (82% vs. 75%) and lower CD4 (86% vs 80%) favoring the DTG arm to the greatest degree, though confidence intervals were fairly wide and none appeared to reach statistical significance. The numbers of women and blacks were relatively low and outcomes in the two treatment arms were similar.
In SINGLE all subgroups had numerically higher success rates on the DTG plus ABC/3TC arm and point estimates were all quite similar between 5-10% higher success rates with DTG. Some of the comparison appeared to reach statistical significance on the Forrest plot that was presented. These were the sub-groups that had the larger sample sizes that had the power to more precisely distinguish difference. Again the numbers of women, black and individuals 50 years old or older were relatively small and it would be good to see combined data from the two studies looking at WITHIN arm comparison between men and women, white and non-white and younger and older patients who are treated with DTG and 2 NRTI. There was no sub-group in either study that had markedly lower responses so I suspect this type of combined analysis would show good response rates across gender, race and age.
The group also looked at AE that led to withdrawal in the two studies by the different sub-groups. As might be expected from the overall results withdrawal due to AE was substantially higher in the EFV/TDF/FTC arm compared to the other 3 arms in all 10 subgroups and there was little difference between the other 3 arms in any subgroup. Though there were no statistical analyses it seems across both studies and in at least 3 of the 4 arms a higher percentage of women compared to men withdrew due to AE. Numbers of women in the study are approximately 6 fold less than numbers of men in each arm so I suspect the estimates have fairly wide confidence intervals but this finding is consistent with at least some other studies. None of the 56 women on RAL withdrew due to an AE compared to 3/63 in SPRING 2 and 4/67 in SINGLE.
CROI: Dolutegravir Treatment Response and Safety by Key Subgroups in Treatment Naive HIV Infected Individuals - (03/16/13)
The SAILING study results were presented for the first time at the 20th CROI (2). In this study treatment experienced patients who were integrase inhibitor naïve were randomized to either raltegravir (400 mg BID) or dolutegravir (50 mg once daily). Patients had to have resistance to at least one drug in two or more ARV classes, have VL greater than 400 c/mL and have at least one fully active drug in their optimized background regimen. The OBT could contain a second agent but that drug did not need to be fully active. Notably at baseline one third of the patients were women, 50% were white, 50% had a CD4 cell count < 200 and about 50% had > 3 class resistance. Though not required it appears that the vast majority of patients receive a ritonavir-boosted protease inhibitor as part of their background therapy. At 24 weeks 79% vs. 70% of patients had HIV RNA < 50 c/mL by the snapshot analysis on the DTG vs. RAL arms respectively and this difference was statistically superior in favor of DTG treatment. The difference was driven by virologic non-response as discontinuation due to AE/death/other reasons or missing data in the snapshot window accounted for 20 patients (6%) in each arm whereas virologic non-response was 15% vs. 24%. Subset analyses showed similar results though the numeric difference (70% vs. 53%) in the baseline high viral load strata (> 50,000 c/mL) was the most striking. Though data were not presented these patients tend to actually have less resistance and perhaps have more adherence related issues but we will need the full study analysis to make that assessment.
For the first time there appeared to be emergence of resistance mutations that may be specific to DTG. Two patients had emergence of virus with a mutation at codon 263 (R263K). This mutation conveyed only a modest (< 2-fold) change in IC50 to DTG and RAL but the mutation has been selected for by DTG in vitro also conferring an increase in fold-change (3). The fact that a DTG mutation appears to have been selected for in this situation is not surprising given that these patients had previously failed ARV therapy, may not have had two fully active drugs in combination and may also be at risk for less than optimal adherence. Nine subjects on the RAL arm had InSTI-resistance emergence with the typical RAL resistance mutations.
As would be expected from the results of the SPRING 2 trial the rates and types of adverse events did not appear substantially different between the two treatment arms.
Definitive conclusions should probably wait for 48 week data which should become available around the time that DTG gets FDA approval toward the end of summer 2013. However DTG appears likely to be the optimal integrase choice in treatment experienced patients who are integrase naïve. Partnering with a boosted PI looks to result in a fairly high success rate for treatment experience patients; a group that typically has some patients with additional challenges to success over and above resistant virus.
CROI: Dolutegravir (DTG) Versus Raltegravir (RAL) in ART-Experienced, Integrase-Naive Subjects: 24-Week Interim Results From SAILING (ING111762) - (03/06/13)
Penetration into CSF
In a very challenging study that enlisted some dedicated patient volunteers, Scott Letendre, Tony Mills and colleagues studied DTG pharmacokinetics and pharmacodynamics in 12 treatment naïve volunteers who received DTG plus ABC/3TC (4). These patients had LP at baseline, 2 weeks and 16 week on treatment and remarkably all 12 patients had LP at week 2 and at or just after week 16. The bottom line is that all patients suppress HIV RNA in CSF to < 50 c/mL at or after 16 weeks and all but one had HIV RNA in CSF < 2 copies/mL (one had 5 copies/mL). DTG penetrated the CSF at levels that exceed the in vitro IC50 and the levels were similar to the unbound fraction of drug in plasma (which makes sense and suggests relatively free penetration into CSF). Change in VL in CSF did not correlate with CSF DTG concentrations but this is not surprising given that virtually all patients fully suppressed in CSF by week 16 so the change in VL ends up being a measure of baseline HIV RNA level. The variation in baseline CSF HIV RNA is fascinating (as low as 29 c/mL and as high as 400,000 c/mL) and while there is a correlation with plasma HIV RNA this correlation is by no means absolute.
CROI: Distribution and Antiviral Activity in Cerebrospinal Fluid (CSF) of the Integrase Inhibitor, Dolutegravir (DTG): ING116070 Week 16 Results - (03/06/13)
Tenofovir Alafenamide Fumarate
Tenofovir alafenamide fumarate or TAF is a much anticipated pro-drug of tenofovir. Hopefully by now everyone reading NATAP knows that there is a cascade of pro-drugs that leads to the active form of tenofovir that work inside cells - tenofovir diphosphate. Tenofovir itself is very poorly absorbed so needs to be given as a pro-drug to be orally bioavailable. Tenofovir disoproxil fumarate or TDF (Viread and the "tenofovir" component of Truvada) is the current formulation that is the DHHS-recommended preferred nucleoside analogue in combination with FTC (or 3TC) (5). TDF has been a mainstay of antiretroviral therapy for the last decade but there are concerns that have been raised related to renal dysfunction in a minority of patients with long term therapy and an initial "hit" on bone mineral density with TDF-based therapy that is larger than that seen with other ART combinations. In addition the milligram dose of TDF may limit the ability for multi-drug fixed dose combinations with certain agents such as protease inhibitors. For these reasons an alternative to TDF has been pursued. TAF may well be that alternative. TAF is at least as potent as TDF as demonstrated with short-term mono-therapy with a substantially lower milligram dose (6). In addition plasma concentrations of tenofovir are lower and TFV-DP concentrations in lymphocytes (which conveniently have high levels of the enzyme cathepsin A that converts TAF to TFV) are higher supporting the potential for greater activity with (the potential) for less toxicity at a lower milligram dose.
The fixed dose combination of elvitegravir/cobicistat/FTC/TAF -10 mg (which I will abbreviate E/C/F/TAF) has been very rapidly developed and Andy Zolopa and colleagues presented the 24 week randomized blinded comparison of E/C/F/TAF with elvitegravir/COBI/FTC/TDF in treatment naïve patients as a late-breaker at the 20th CROI (7). One hundred patients were randomized to E/C/F/TAF and 50 to the QUAD stratified by baseline viral load. Remarkably there looked to be only 6 or 7 women in the entire study and baseline viral load was about 40,000 and baseline CD4 was almost 400 c/mL. At 24 weeks 87% of patients on E/C/F/TAF and 90% of patient on the QUAD were < 50 c/mL by the FDA snapshot and a similar proportion (approximately 6 vs. 10%) had a measure VL > 50 in the 24 week window. Only one on E/C/F/TAF and two on QUAD had VL > 400 c/mL with one patient on the QUAD having a virus with resistance mutations (184V and 70E). In a PK subset plasma trough concentrations of TFV were about 7 fold lower with E/C/F/TAF and intracellular TFV-DP concentrations were about 5 fold higher with TAF. Clinical and laboratory AE did not appear different between the two arms. Curiously cholesterol levels were lower with the QUAD suggesting that the well-known "tenofovir" effect on cholesterol may well really be a tenofovir effect (or I guess a TDF effect in the gut). This is a tangent but the "tenofovir" effect on cholesterol extends to HDL - that is TDF lowers HDL while TAF appears not to lower HDL so the net effect on the total cholesterol:HDL ratio was the same in both arms.
To me the most interesting finding was the decline in bone density was significantly and substantially less in both hip and spine with E/C/F/TAF. In fact there was very little decline at all in the TAF arm though I don't know whether the change from baseline within the TAF arm was assessed for significance. Forty-eight week results will be important but this early information is encouraging.
The most puzzling finding was a significantly smaller increase in creatinine with TAF. At first you might think this is consistent with "less renal toxicity" but the renal toxicity we see with TDF doesn't typically occur in the first 4 week or 24 weeks (unless there is significant underlying renal disease) and the difference in median change in creatinine was apparent at week 4. Measures of "tubulopathy" may have favored TAF slightly but no renal AEs or proximal renal tubular dysfunction were noted in either arm. Even the clinical scientists at Gilead were scratching their heads on this one and maybe there will be a better explanation as we get more data.
Overall the data were encouraging and we look forward to the phase III studies that are starting this month.
CROI: Comparative Study of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate, Each with Elvitegravir, Cobicistat, and Emtricitabine, for HIV Treatment - (03/05/13)
Cenicriviroc is the fourth CCR-5 inhibitor to make it into later stage clinical development. Only one, maraviroc, completed clinical development and has modest use in clinical practice in the US and in Europe. Cenicriviroc is a clear once daily CCR-5 receptor antagonist with a 30+ hour half-life and activity in early phase clinical trial comparable to the other CCR-5 inhibitors. What makes cenicriviroc more interesting than the potential to be a second in class agent is the fact that this agent also inhibits binding of MCP-1 (monocyte chemoattratant protein one) to the CCR-2 receptor. CCR-2 is expressed on monocytes/macrophage and binding with its ligands, such as MCP-1, results in activation of this cell type. MCP-1 in expressed on endothelial cells, stromal cells and other inflammatory cells and the receptor ligand interaction can lead to increased inflammation in the setting of tissue injury and this interaction may be a mediator of inflammatory diseases including atherosclerosis (8). Even at this meeting an association between monocyte activation and coronary artery calcium was observed in HIV-1 infected individuals (13, 14). Monocyte/macrophage activation and resultant inflammation may be an important component of the inflammatory state in untreated and treated HIV-1 infection and an antiretroviral that may also impact ongoing inflammation has a particular attraction.
There are several caveats. The first is to demonstrate that cenicriviroc has sufficient activity as an antiretroviral to warrant further development. Joe Gathe and colleague presented the week 24 phase IIb data from a comparative trial of cenicriviroc (100 or 200 mg QD) plus TDF/FTC compared to EFV plus TDF/FTC (2;2;1 randomization) in treatment naïve patients who had R5 virus (10). Baseline HIV RNA had to be greater than 1,000 c/mL and CD4 at baseline was greater than 200 cells/mm3. The EFV and CVC were fully blinded so each patient had to take 6 pills daily because at the start of the study CVC was available in 50 mg tablets. Frankly the results were mixed. Despite a relatively low median baseline viral load of approximately 30,000 c/mL and a baseline CD4 cell count of approximately 400 cells/mm3, 76, 73 and 71% of subjects on the 100 mg CVC, 200 mg CVC and EFV arms respectively, were < 50 c/mL by the FDA snapshot analysis. Clearly these results demonstrate a comparable outcome. However, the reasons for treatment failure at week 24 varied by the third agent. Only 1 out of 28 (4%) EFV treated patients had virologic non-response where as most of the treatment failure was explained by discontinuation due to AE, discontinuation due to non AE, non virologic reasons such as lost to follow-up and withdrawal of consent. In somewhat of a contrast 12 and 13% of subjects on the 100 mg and 200 mg CVC arms had virologic non-response. Non-AE withdrawal were also high; 10 and 11% respectively. Essentially only one patient in the two CVC arms discontinued due to an AE.
The proportion of protocol defined virologic failure was more similar across arms with 12%, 16% and 11% meeting the protocol definition of virologic failure in the 100 mg CVC, 200 mg CVC and EFV arms, respectively. Protocol defined virologic failure required that a confirmatory viral load be > 400 c/mL so low level viremia > 50 c/mL but < 400 c/mL presumably would not be declared VF. Five of 13 patients with amplifiable virus on the CVC arms develop NRTI resistance mutations. One of six patients who had viral tropism assessed had emergence of a dual mixed virus. CD4 responses were quite similar. There were a greater number of grade 2 or greater clinical AE in the EFV arm and, as mentioned, a substantially greater percentage of EFV-treated patients stopped therapy due to an AE. Grade 3/4 laboratory abnormalities were quite similar between arms with the exception of a greater percentage of grade 3 and 4 CPK rises in the 200 mg CVC arm. Total cholesterol and LDL levels in the CVC arms actually fell, while they rose measurably in the EFV arm.
So one could ask the question was the first caveat met? Did CVC show enough activity/efficacy in the standard 2 NRTI plus backbone drug background format to warrant phase III study. This is a tough call. There certainly are suggestions in the data that CVC may not have had the same antiretroviral potency compared to the EFV-based regimen including perhaps some greater vulnerability in the higher viral load strata. However, several virologic failures had only low level viremia and CVC certainly appeared to be well tolerated at either dose over the early (24 week) segment of this study. CVC is neither and inducer or inhibitor of cyp3A4 and novel combinations in first line therapy could be considered and there appears to be enough signal here to warrant phase III study.
The second caveat is - Does the inhibition of the CCR-2 receptor add important clinical value? The study clearly showed dose-dependent rises in MCP-1 indicative of receptor-ligand blockage. The IC50 for the CCR-2 antagonism is roughly 20-fold higher than the IC90 for HIV-1 inhibition via CCR-5 blockage so the fold increase using the same metric (either IC50 or IC90) for both would likely lead to an even higher ratio. No clear dose dependence was seen in the anti-HIV activity was seen so dose selection will be interesting. I think this study does prove the CVC antagonizes the MCP-1:CCR-2 ligand:receptor interaction in vivo. Proving there is a clinical benefit to blocking this interaction will be a more substantial challenge but one that should clearly be pursued as the results of the phase IIb study don't really suggest that there will be dramatic advantages over maraviroc other than the once daily dosing and the potential for a clinically meaningful blockage of the MCP-1 CCR-2 interaction. Also CCR-2 blockade is not without, at least, theoretical risk as monocyte/macrophage activation may be important for the killing of certain intracellular organisms.
Dose selection and the design of future studies to establish substantial HIV activity and some clinically favorable outcome related to CCR-2 antagonism will be interesting to see.
CROI: Week 24 Primary Analysis of Cenicriviroc vs Efavirenz, in Combination with FTC/TDF, in Treatment-naïve HIV-1 Infected Adults with CCR5-tropic virus - (03/08/13)
MK-1439 is a second generation NNRTI that has pharmacokinetics that support once daily dosing and a pre-clinical profile that suggests it may have improved tolerability over efavirenz. This drug also has activity against HIV-1 variants with many of the common NNRTI-resistance mutations.
Probably the first question to ask is "do we need another NNRTI?" As usual I think the answer is "it depends". It depends on the characteristics of the drug but I think the success of rilpivirine in the fixed dose combination with TDF/FTC suggests that the right drug may get substantial use. Most people would agree that rilpivirine is a flawed drug. The clearly demonstrated decrease in activity in patients with high viral load and the strict food requirement would seem to be substantial barriers to commercial success yet the FDC of RPV/TDF/FTC appears to be used commonly in the clinic, frequently in switch situations. An NNRTI that was well tolerated without CNS effects, had little or no interaction with food and had the potential for co-formulation would likely be a useful addition to our treatment choices.
Matt Anderson and his colleagues presented the proof-of-principle study (Phase Ib/IIa) of MK-1439 (10). This is a very small study testing two doses widely bracketing the dose range (25 mg daily and 200 mg daily) with 6 subjects receiving active drug and 3 receiving placebo at each dose. MK-1439 or placebo was given for 7 days and then the HIV-1 infected subjects were given standard of care combination therapy for at least 10 days to avoid selection of NNRTI resistance during the wash-out phase of MK-1439. The study was conducted at a single site and included all men who were ART naïve or had limited ART exposure and no exposure to NNRTI.
Over the 7-day period treatment with MK-1439 resulted in a median 1.37 and 1.26 log10 decline in HIV-1 RNA with the 25 mg and 200 mg doses, respectively. Baseline HIV RNA level was not reported but it seems unlikely that these declines were censored by the lower limit of detection. These declines are in a range similar to what was seen in the Phase Ib stud7 of rilpivirine (11) though substantially less than the 7 days declines in HIV-1 RNA that were observed in the Phase Ib study of Etravirine (12). No data were available on resistance emergence as these HIV-1 infected volunteers were given combination therapy beginning on day 8 to avoid resistance selection. The pharmacokinetics of MK-1439 were consistent with once daily dosing (> 10 hour half-life) and trough concentrations achieved exceeded the protein adjusted IC95 of wild-type virus by 14 (25 mg) and 87 (200 mg) fold. There were limited adverse events. All were grade one or two and the most common side effect was headache, which is a typical finding in phase Ib/IIa studies. The longer term phase IIb study is underway. This study is examining multiple once daily doses of MK-1439 (25, 50, 100 and 200 mg) in combination with TDF/FTC in addition to a standard of care arm of EFV plus TDF/FTC. The fact that the developer of this NNRTI also recently acquired a tenofovir pro-drug to develop is worth noting. The dose selection information from the Phase IIb trial will be critical for the further development of MK-1439 and co-formulation with 2NRTI is probably also a key to commercial development.
CROI: Safety and Antiviral Activity of MK-1439, a Novel Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), In Treatment-Naïve HIV-Infected Patients - (03/05/13)
New Agents with new mechanisms - where are they?
Certainly the new antiretroviral drug pipeline is not empty. However, clinical data on new agents that work by novel mechanisms were conspicuously absent from this meeting. There was an interesting poster on the BMS-attachment inhibitor, BMS-626529, demonstrating that this molecule binds to gp120 prior to gp120 binding to CD4 - clarifying its unique mechanisms (15). We have seen that BMS-663068, the pro-drug for 529, has substantial in vivo activity in a short-term dosing study with a measureable PK-PD relationship (16). However some viruses also appear to have intrinsic resistance to BMS-626529 (15) and further clinical studies or similar compounds with broader activity are anxiously awaited. A study examining 663068 in treatment-experienced patients is ongoing (http://clinicaltrials.gov/ct2/show/NCT01384734?term=663068&rank=2).
CROI: Homology models of the attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action - (03/13/13)
We also heard that maturation inhibitor development is not dead. The team that brought us bevirimat presented information that additional compounds are being evaluated (17) though basically all we learned was that there was potential for inhibition of a broad range of viruses including those resistant to bevirimat by synthetic bevirimat derivatives but no specific molecule/formulation had been chosen for clinical development as yet (should have been a poster!)
We also heard interesting additional data from the podium (and from the audience) about a new class of integrase inhibitors that appears to work by a different mechanism primarily inhibiting an activity of the integrase enzyme that is needed to release infectious virus from the cell (i.e. at a post-integration viral assembly and release step in the life cycle) (18-19). These compounds will very likely have activity against viruses resistant to current strand transfer inhibitors like RAL, ELV and DTG. Unfortunately clinical trials seemed a ways off.
So should we be concerned? - we have plenty of single and combination drug to treat our patients. I think this will be true for 99% or more of our patients. But I think there is a risk that we will end up in a situation similar to the antibacterial world. Over the last several decades the development of new antibiotics slowed and very difficult to treat bacteria emerged (like VRE and highly resistant GNR). We were and we are limited in our ability to treat some of patients with these resistant bacteria and are limited to using a toxic detergent like colistin in some settings. I am concerned that we will have a few patients in whom our current antiretrovirals do not have sufficient activity to fully suppress replication due to high levels of drug resistance with or without additional limitations due to tolerability. Right now I have one patient, referred to me with pan-resistant virus, who is alive and successfully suppressed on dolutegravir and T-20 (Enfuvirtide). How many years can she take twice-daily injections of T-20? I have another patient with multi-class resistant virus partially sensitive to tipranavir who is suppressed on tipranavir, maraviroc and ibalizumab. What will happen to this person if ibalizumab is no longer available to him? I understand that these will be rare patients and that big (or little) pharma is going to have limited incentive to develop medications for a few hundred patients across the US and Europe. Hopefully attachment inhibitors, maturation inhibitors and non-catalytic site integrase inhibitors will continue to move forward and I can stop worrying.
1. Brinson C, Walmsley S, Arasteh K, et al. Dolutegravir treatment response and safety by key subgroups in treatment-naïve HIV+ individuals. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 554.
2. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir vs raltegravir in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762). 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 179LB
3. Quashie PK, Mesplede T, Han YS, Oliveira M, Singhroy DN, Fujiwara T, Underwood MR, Wainberg MA. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol 2012;86:2696-705.
4. Letendre S, Mills A, Tashima K, et al. Distribution and Antiviral Activity in Cerebrospinal Fluid (CSF) of the Integrase Inhibitor, Dolutegravir (DTG): ING116070 Week 16 Results. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract
5. Panel of treatment of HIV-infected pregnant women and prevention of perinatal transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/. Accessed March 6, 2013.
6. P Ruane, et al. CROI 2012; Abstract # 103
7. Zolopa A, Ortiz R, Sax P, et al. Comparative study of tenofovir alafenamide vs. tenofovir disoproxil fumarate, each with elvitegravir, cobicistat, and emtricitabine, for HIV treatment. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 99LB
8. van der Valk FM, van Wijk DF, Stroes ES. Novel anti-inflammatory strategies in atherosclerosis. Curr Opin Lipidol 2012,23:532-539
9. Gathe J, Cade J, DeJesus E, et al. Week-24 primary analysis of cenicriviroc vs. efavirenz, in combination with emtricitabine/tenofovir, in treatment-naïve HIV-1+ adult with CCR5-tropic virus. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 106LB.
10. Anderson M, Gilmartin J, Robberechts M, et al. Safety and antiviral activity of MK-1439, a novel NNRTI, in treatment-naïve HIV+ patients. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 100.
11. Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, et al. Short-term antiviral activity of TMC278--a novel NNRTI--in treatment-naive HIV-1-infected subjects. AIDS 2006,20:1721-1726
12. Sankatsing SU, Weverling GJ, Peeters M, van't Klooster G, Gruzdev B, Rakhmanova A, et al. TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen. AIDS 2003,17:2623-2627
13. Baker J, Huppler Hullsick K, Singh A, et al. Monocyte activation, but not T cell activation, predicts progression of coronary artery calcium in contemporary HIV cohort. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 66LB.
14. Fitch K, Abbara S, Burdo T, et al. Non-calcified coronary plaque and macrophage activation markers are increased in HIV+ women. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 185LB
15. Langley DR, Kimura SR, Sivaprakasam P, et. al Homology models of the attachment inhibitor BMS-626529 bound to gp120 suggest a unique mechanism of action. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract
16. Nettles RE, Schurmann D, Zhu L, Stonier M, Huang SP, Chang I, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068, an oral HIV-1 attachment inhibitor in HIV-1-infected subjects. J Infect Dis 2012,206:1002-1011
17. Urano E, Ablan S, Martin D et al. Wild Potent Antiviral Activity of 2nd Generation maturation Inhibitors Against Bevirimat-resistant Polymorphic HIV-1 Isolates. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 105.
18. Stephen Yant, L Tsai, C O'Sullivan, T Cihlar, and M Balakrishnan. Non-Catalytic Site Integrase Inhibitors Target the Integrase Domain during Virus Production and Induce a Reverse Transcription Block. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 103.
19. Desimmie B, Christ F, Thys W et al , Viral Particles Produced in Presence of LEDGIN Are Impaired for Infectivity. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta GA 2013, Abstract 104.