1. New Kids on the Block Novel Agents and Treatment Strategies
Joseph J. Eron Jr. MD Professor of Medicine
University of North Carolina
At Chapel Hill
I like to thank the organizers for the opportunity to give this talk, though not for the title. I am grateful for the opportunities I have already had to study these new drugs, work with colleague on study design and interpreting the results and see the benefit of some of these agents in my patients in the clinic

2. 282 patient randomized
Study halted
only 27 subjects reached 24 weeks
19 PCB subject died
1 AZT treated patient died

3. Why We Need New Antiretroviral Agents
Treatment Naïve Individuals
We need well tolerated, highly active and convenient antiretroviral therapy for ALL individuals who need treatment
Women of child-bearing potential
Individuals with TB and other complex medical illnesses
Transmitted Resistance
Risk of Minority Variants

4. Why We Need New Antiretroviral Agents
Treatment Experienced Individuals
Expand treatment choices
Avoid complex regimens and toxic agents
Full suppression of HIV replication in patients with resistant HIV-1
Developed World – multi-drug resistant variants
5-10% of patients in care have > 3 class resistance
Greater success in patients with less extensive resistance?
Developing World – highly NRTI-resistant variants
Currently limited treatment choices

5. Resistance in the Developing World
Sungkanuparph et al Clin Infect Dis 2007;44:447-52
Similar data from DART (AIDS 2006), rural Malawi (Lancet 2006) and others

6. New ART Agents in Advanced Clinical Development
Phase
RTI
Entry In
Integrase In
Maturatn In 3
Etravirine
(TMC125)*
Maraviroc*
Raltegravir
(MK-0518)* 2B
Rilpivirine
(TMC 278)
BILR 355
Vicriviroc
TNX-355
Elvitegravir
(GS-9137) 2A
Apricitabine
Amdoxovir
Fosalvudine
Elvucitabine
UK-453,061
INCB009471
mAb004
PRO 140
Bevirimat
(PA 457)
WESS203
TUAB106
INCB once daily tested at 200 mg over 14 days 1.8 log decline at day 16
PRO 140 (Saag et al) – 3 single dose infusions
Apricitabine 21 days of functional monotherapy compared to 3TC in experienced patients with M184V, 0.7 to 0.9 log10 declines
UK-453,061 multiple doses 7 days monotherapy 1.7 log 10 decline
WEPEB114LB
WESS201
WESS202
*Expanded access program available

7. New ART Agents in Advanced Clinical Development
Phase
RTI
Entry In
Integrase In
Maturatn In 3
Etravirine
(TMC125)*
Maraviroc*
Raltegravir
(MK-0518)* 2B
Rilpivirine
(TMC 278)
BILR 355
Vicriviroc
TNX-355
Elvitegravir
(GS-9137) 2A
Apricitabine
Amdoxovir
Elvucitabine
mAb004
PRO 542
Bevirimat
(PA 457)
*Expanded access program available

8. New Agents from New Classes
Integrase Inhibitors
Raltegravir
Elvitegravir

9. HIV Integrase Mechanism
Strand
transfer

10. BENCHMRK-1 and -2: Raltegravir in Treatment-Experienced Pts
Randomized, double-blind, placebo-controlled, parallel phase III studies
Raltegravir 400 mg twice daily + OBR
BENCHMRK-1 (n = 232)
BENCHMRK-2 (n = 230)
Placebo + OBR
BENCHMRK-1 (n = 118)
BENCHMRK-2 (n = 119)
HIV infected;
triple-class resistant;
VL > 1000 copies/mL
BENCHMRK-1 (N = 350)
(Europe, Asia/Pacific, Peru)
BENCHMRK-2 (N = 349)
(North, South America)
Primary endpoints: Week 16
Planned duration: Week 48
BENCHMARK, Blocking Integrase in Treatment Experienced Patients With a Novel Compound against HIV: MeRcK, MK-0518; OBR, optimized background regimen; Pts, patients, VL, viral load.
The results of BENCHMRK-1 and -2, two parallel phase III studies of the integrase inhibitor raltegravir, were presented at the 2007 Conference on Retroviruses and Opportunistic Infections.[1,2] These studies were performed in the Europe, Australia, and the Pacific Rim (BENCHMRK-1) and in North, Central, and South America (BENCHMRK-2). Inclusion criteria included genotypic or phenotypic resistance to ≥ 1 drug from PI, NRTI, and NNRTI classes and an HIV-1 RNA > 1000 copies/mL. Patients were randomized on a 2-to-1 basis to receive raltegravir 400 mg BID or placebo, both with an OBR. The primary endpoint was the proportion of patients with an HIV-1 RNA < 400 copies/mL at 16 weeks.
Baseline characteristics were similar across arms with the exception of a greater racial distribution in the BENCHMRK-2 trial. Mean baseline CD4+ cell count across the arms ranged from cells/mm³ and mean baseline viral load ranged from 32,000-48,000 copies/mL. Patients had a median treatment duration of 11-12 prior years of antiretroviral therapy and 12 prior agents.
Approximately 60% of patients in each treatment arm had a genotype sensitivity score of 0 or 1 for the OBR. It should be noted that in the baseline resistance assessment of the drugs in the OBR, patients were considered resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry. In the case that enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was assigned to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive. This approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR.
References
1. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB.
2. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB.
Cooper D, et al. CROI Abstract 105aLB. Steigbigel R, et al. CROI Abstract 105bLB.

11. Percent of Patients with Virologic Response <50 c/mL (NC=F)
Cooper and Steigbigel CROI 2007 LB 105 a+b
Percent of Patients with Virologic Response <50 c/mL (NC=F)
BENCHMRK-1
BENCHMRK-2
61%
62%
33%
36% .
* + OBT p<0.001 at Week 16 for both parameters

12. BENCHMRK Combined Efficacy* < 400 copies/mL at Week 16
Cooper and Steigbigel CROI 2007 LB 105 a+b
BENCHMRK Combined Efficacy* < 400 copies/mL at Week 16
* Virological failures carried forward
Patients who received RAL DRV/r and T-20 98% (43/44) < 400 c at 16 wks

13. Raltegravir vs Efavirenz In Treatment Naïve Patients (plus TDF/3TC)
100 80 60
Pts With VL < 50 c/mL (%) * 40 * 20
*P < .001 for MK-0518 at each dose vs EFV 2 4 8 12 16 24
Week
MK mg 39
MK mg 40
MK mg 41
MK mg 40
Efavirenz 38 37
Markowitz M et al TUAB104
Murray et al TUAB103
Markowitz M, et al IAC Abstract THLB0214.

14. Integrase Inhibitor Elvitegravir (GS-9137) in Experienced Patients
Randomized, active-control, phase II dose-finding study – each arm with RTV
PI experienced patients with at least 1 PI resistance mutation (median = 11)
OBT = NRTI +/- T20 (new in approx 20%)
CPI, comparator PI; DAVG24, timed-average difference at Week 24; DRV, darunavir; DSMB, data and safety monitoring board; ENF, enfuvirtide; OBR, optimized background regimen; RTV, ritonavir; TPV, tipranavir; VL, viral load.
Elvitegravir, formerly GS‑9137, is an integrase inhibitor currently in phase IIb development. In a phase I study, elvitegravir/ritonavir 50/100 mg monotherapy was shown to achieve an elvitegravir half‑life of approximately 12 hours and a viral load reduction of more than 1.5 log10 copies/mL in all 6 patients. These studies also indicated that elvitegravir benefits from pharmacologic boosting with ritonavir 100 mg, which allows the drug to be administered once daily at a substantially lower dose.[1]
At the 2007 Conference of Retroviruses and Opportunistic Infections, phase II data were presented.[2] This was a randomized, active-control, dose-ranging study (blinded to elvitegravir dose) comparing 3 elvitegravir/ritonavir doses (20/100 mg, 50/100 mg, and 125/100 mg QD) vs a control arm in which patients received the best available PI (49% included darunavir; 27% included tipranavir). All patients received an OBR of NRTIs, with or without enfuvirtide. It should be noted that darunavir and tipranavir were initially not allowed in the OBR for the elvitegravir arm based on lack of information about drug-drug interactions between these agents and elvitegravir. Eligible patients had a baseline viral load ≥ 1000 copies/mL, any CD4+ cell count, and ≥ 1 protease resistance mutation. In practice, patients had a median of 11 PI mutations from the International AIDS Society-USA list, suggesting considerable PI experience, and nearly 50% of the patients had genotypic susceptibility scores of 0 for the NRTIs in their OBRs. A range of 17% to 26% of patients (depending on the arm) were using enfuvirtide for the first time.
The primary endpoint was the time‑weighted average change from baseline at Week 24.
Certain events that occurred during the course of this study may make analysis of these data challenging.
A Data and Safety Monitoring Board analysis at Week 8 recommended to discontinue the 20-mg arm for apparent limited efficacy. Those patients received the 125-mg dose in an open-label fashion starting at Week 16. The data from these patients were censored from the analysis.
After Week 16, use of darunavir and tipranavir were permitted to be added to the OBR for the elvitegravir arm after data indicated that no significant interactions were likely. At Week 16, 4 patients had added either of these PIs; by Week 24, a total of 15% had done so. In the comparator PI arm, by contrast, (as noted above) 49% had included darunavir and 27% had included tipranavir.
References
1. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43:1-5.
2. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 143LB.
Zolopa A, et al. CROI Abstract 143LB.
*CPI included 49% darunavir, 27% tipranavir

15. Elvitegravir 125 mg/RTV 100 mg: Influence of Activity of OBT*
*Data from GS mg patients after addition of a PI were excluded

16. Integrase Inhibitor Resistance1 3 2
35/38
32/41
26/28
Raltegravir: two major pathways (N155 or Q148):Q148H/G140S most common.
Most have multiple mutations
In Phase II study majority of failures had GSS =0
Elvitegravir: Multiple different mutations/combinations including N155 and Q148.
Median number of mutation/variant =4
1Hazuda DRW 2007; Grinsztejn et al. Lancet 2007; 369: , 2Steigbigel CROI 2007 LB 105b, 3McColl et al DRW 2007

17. IC50 ratio of mutants vs. WT HIV-1 in infectivity assay
Mutations can confer cross resistance to structurally diverse integrase inhibitors
399 / 838 / 2194X
502X
IC50 ratio of mutants vs. WT HIV-1 in infectivity assay
Wei et al CROI 2007, Hazuda etal DRW 2007

18. Integrase Inhibitors Raltegravir Elvitegravir
Extremely potent, rapid suppression; very well tolerated short term
High risk of resistance in treatment failure
Twice daily dosing with modest drug interactions
Greater number of malignancies vs. PCB in pooled analyses
No direct evidence for relationship to raltegravir
Elvitegravir
Phase III study challenging
Cross resistance likely with raltegravir
Once daily but requires RTV co-administration.
A high likelihood of success is dependent on additional active agents

19. New Agents from New Classes
CCR5 Inhibitors
Maraviroc
Vicriviroc

20. Dual tropic and X4 Viruses
R5 Viruses
Utilize the CCR5 co-receptor
Nonsyncytium inducing (NSI) phenotype
Transmitted variants
Prevalent in early disease
Dual tropic and X4 Viruses
Utilize the CXCR4 co-receptor
Syncytium inducing (SI) phenotype
Emerge in later disease in up to 50% of patients
Associated with accelerated CD4 T-cell decline and disease progression
CD4
This section of the presentation aims to illustrate the key steps involved in the entry of HIV-1 into CD4 positive cells.
This slide shows an artists impression of the outer surface of a CD4 positive cell. The CD4 molecules are shown here in purple and the chemokine receptors CXCR4 and CCR5 are shown in green and orange, respectively.
Note: these molecules are depicted here in a way that makes it easy to illustrate their role in the entry process; their actual structure in the cell membrane is somewhat different.
CXCR4
CCR5
T-cell surface
Berger EA, et al. Nature. 1998;391:240.

21. Prevalence of Coreceptor Tropism
Study Authors
Population
Sample (n)
R5 Only
Dual/ Mixed
X4 Only
Demarest et al[1]
Naive
325
88%
12% 0%
HOMER[2]
979
82%
18%
0.1%
Moyle et al[3]
402
81%
19% NA
Experienced
117
67%
28%
5.0%
125
78%
22%
Melby et al[4]
724
50%
48%
2.0%
Wilkin et al[5]
391
49%
47%
4.0%
Nelson, Lalezari et al[6,7]
1076
56%
44%
Virologic responses to CCR5 antagonists have been most apparent in patients without detectable D/M or X4 virus. Therefore, it is important to define those patients most likely to be without detectable D/M or X4 virus. Although there are numerous methods for assessing coreceptor tropism, most of the experience in clinical trials has been with the Trofile assay, which was commercially developed. Several studies have used this assay to define the prevalence of coreceptor usage in various patient populations.
This slide summarizes data from 8 cohorts, 3 of treatment-naive patients and 5 of treatment-experienced patients. Dual/mixed or X4 virus appears to be less prevalent among those who have yet to receive treatment. Nevertheless, even in the naive setting, 12% to 19% of individuals had detectable D/M or X4 virus.[1-3]
In those with more treatment experience, approximately 20% to 50% of subjects had detectable D/M or X4 virus. Based on this information, we might conclude that there will be more eligible (ie, with no detectable D/M or X4 virus) patients among less treatment-experienced subjects who are often in the earlier stages of disease. Regardless of stage of disease, however, it will be necessary to assess patients for viral tropism prior to the use of a CCR5 inhibitor in order to detect the presence or absence of D/M or X4 virus and thus assess susceptibilty of the virus in any given patient.[1,3-7]
References
1. Demarest J, Bonny T, Vavro C, et al. HIV-1 coreceptor tropism in treatment naive and experienced subjects. Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2,2004; Washington, DC. Abstract H-1136.
2. Brumme ZL, Goodrich J, Mayer HB, et al. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. J Infect Dis. 2005;192:
3. Moyle GJ, Wildfire A, Mandalia S, et al. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis. 2005;191:
4. Melby T, Despirito M, Demasi R, Greenberg M, Heilek-Snyder G, Graham N. HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis. 2006;194:
5. Wilkin T, Su Z, Kuritzkes DR, et al. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis. 2007;44:
6. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104bLB.
7. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104aLB.
Demarest J, et al. ICAAC Abstract H Brumme ZL, et al. J Infect Dis. 2005;192: Moyle GJ, et al. J Infect Dis. 2005;191: Melby T, et al. J Infect Dis. 2006;194: Wilkin T, et al. Clin Infect Dis. 2007;44: Nelson M, et al. CROI Abstract 104aLB. 7. Lalezari J, et al. CROI Abstract 104bLB.

22. Maraviroc: MOTIVATE 1 and 2: Trial Design Patients with 3 class resistance or experience
Randomization 1:2:2 MOTIVATE 1 N = 601 MOTIVATE 2 N = 475
OBT* + maraviroc (150 mg† BID)
OBT* + maraviroc (150 mg† QD)
OBT* + placebo
Planned interim analysis
24w
6 weeks
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥ 100,000 copies/mL
48w
R5 HIV-1 infection by Tropism Assay
No DRVr in OBT
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)
† Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC

23. MOTIVATE 1 and 2: 24 Week VL < 50 copies/mL (ITT, NC = F)
Placebo + OBR (n = 209)
MVC QD + OBR (n = 414)
MVC BID + OBR (n = 426)
100
100
MOTIVATE 1
MOTIVATE 2 90 90 80 80 70 70 60 60
P < .0001*
P < .0001* 50 50
Patients (%)
Patients (%)
48.5%
45.6% 40
42.2% 40
40.8%
P = .0006*
P = .0005* 30
BID, twice daily; ITT, intent to treat; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; NC = F, noncompleter equals failure; OBR, optimized background regimen; QD, once daily; VL, viral load.
Likewise in both studies, each maraviroc arm showed approximately 40% to 50% of the treated patients reaching < 50 copies/mL vs 20% to 25% in the placebo arms.[1,2] The BID dose performed slightly better than the QD arm but both were significantly better than placebo.
CD4+ cell count increase that accompanied these virologic results was approximately 110 cells/mm³ in the 2 maraviroc treatment arms in both studies vs 50 cells/mm³ in the placebo arm (P < vs placebo in a last-observation-carried-forward analysis; data not shown).
References
1. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104bLB.
2. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 104aLB. 30
24.6% 20 20
20.9% 10 10 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
Time (Weeks)
Time (Weeks)
*P values vs placebo at Week 24.
Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.

24. MOTIVATE 1 and 2: Percentage of Patients with HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT*
Includes all patients who received at least one dose of study medication
Placebo + OBT
MVC QD + OBT
100
MVC BID + OBT 90 80 70 61 58 60 55 53 52
Patients (%) 50 43 43 40 29 30 19 20 18 9 10 3 N= 35 51 56 44
130
134 59 88
104 64
132
121 1 2
≥ 3
Number of active drugs in OBT*
* Based on overall susceptibility score LOCF
MOTIVATE 1 & 2-Week 24

25. Maraviroc Treatment Naïve MERIT Study: Phase 3 Trial Design
Randomization 1:1
Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*
Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*
Screening (6 weeks)
48 wk
96 wk
Primary analysis
Patient eligibility criteria:
R5 HIV-1 infection
No evidence of resistance to EFV, ZDV, or 3TC
MVC QD arm discontinued at end of Phase 2b (week 16)
Due to evidence of decreased activity compared to EFV)
Saag et al IAS WESS 104

26. Vircriviroc ACTG 5211 Phase II Study : 24 Week Data
Mean Change in HIV RNA (log10 copies/mL)
Mean Change in CD4
(cells/mm3) –9 84
142
–1.91
–2.25
–1.75
–0.34
Treatment experienced patients N=118
R5 virus
8 patients have developed malignancies
6 VCV 2 PCB (one post crossover)
Gulick et al IAS 2007 TUAB 102
Gulick et al WAC 2006 THLB 0217

27. CCR5 Inhibitor Virologic Failure
Two mechanisms
Emergence of pre-existing X4 or dual tropic variants (2/3 of patients)
“Cross resistant” by definition
No immunologic consequences observed so far
HIV remains R5 but uses receptor with compound bound
Difficult to detect without phenotype
Cross resistance may or may not occur

28. CCR5 Inhibitors Maraviroc Vicriviroc Well tolerated
P450 metabolized but neither inhibitor or inducer
Twice daily dosing but different doses depending on co- administered drugs
No virologic activity against dual/mixed viruses
40-50% of TEP have dual/mixed virus
Dual mixed variants may not be detected with current assay
Vicriviroc
Once daily dosing but optimal dose not selected
Association with malignancy needs further study
Treatment naïve study was stopped for decreased efficacy

29. New Agents from Existing Classes
NNRTI Inhibitors
Etravirine
Rilpivirine

30. Etravirine Phase III DUET-1 and -2 study design
Screening
6 weeks
600 patients target per trial
48-week treatment period with optional 48-week extension
Follow up
4 weeks
24-week primary analysis
ETR + BR*
Placebo + BR*
*BR = DRV/r with optimised NRTIs and optional enfuvirtide
Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks
≥1 NNRTI RAM, at screening or in documented historical genotype
≥3 primary PI mutations at screening
Patients recruited from: DUET-1: Thailand, France, North and South America DUET-2: Australia, Europe, North America
BR = background regimen; DRV/r = darunavir/ritonavir; RAM = resistance-associated mutation
Madruga et al and Lazzarin et al Lancet 2007

31. Patients with viral load <50 copies/mL at Week 24 (primary endpoint; TLOVR)
ETR + BR
Placebo + BR 20
100 80 60 40
DUET-1
62%
44%
p=0.0003 20
100 80 60 40
Time (weeks) 4 8 12 16 24
DUET-2
p=0.0050
56%
Responders (%) + 95% CI
39% 4 8 12 16 20 24
Time (weeks)
CI = confidence interval; intent-to-treat (ITT) population; TLOVR = time to loss of virological response imputation algorithm
Madruga et al and Lazzarin et al Lancet 2007

32. Response according to number of active background ARVs
Placebo + BR
ETR + BR
DUET-1
DUET-2 20 40 60 80
100 7%
35%
70%
73%
44%
82%
62%
80% 1 2 3
Patients with viral load <50 copies/mL at Week 24 (%)
47% 9%
59% 1
24%
Number of active background ARVs (PSS)
68% 2
61%
66% 3
65% 20 40 60 80
100
Patients with viral load <50 copies/mL at Week 24 (%)
Darunavir and enfuvirtide are counted as active if FC<10 or used de novo, respectively; PSS = phenotypic sensitivity score
Madruga et al and Lazzarin et al Lancet 2007

33. No mutation (reference)*
The number of baseline ETR RAMs correlated with the virological response to ETR
ETR RAMs: V90I, A98G,
L100I, K101E/P, V106I, V179D/F
Y181C/I/V, G190A/S
Proportion of patients with confirmed viral load <50 HIV-1 RNA copies/mL
This graph demonstrates that the number of baseline TMC125 RAMs correlates with the virological response at Week 24.
The first bar is the reference response (in the subgroup of patients without detectable NNRTI mutations). The red bars show the virological response in the subgroups of patients with 0–5 TMC125 RAMs.
the virological response in the subgroup with 0 TMC125 RAMs is slightly above the reference response (note that these patients can have other NNRTI mutations, but none that are included in the list of 13 TMC125 RAMs).
the virological response in the subgroups with 1 or 2 TMC125 RAMs is lower than the reference response, but above the 25% threshold.
the virological response in the subgroups with 3, 4 or 5 TMC125 RAMs is below the 25% threshold.
the overall response in the TMC125 and placebo groups is shown. The overall response in the placebo group is lower than in the subgroups of patients with 0, 1, 2 or 3 TMC125 RAMs.
therefore, a decreased response to TMC125 is only seen in the presence of 3 or more TMC125 RAMs.
Importantly, 86.4% of the patients have 0, 1 or 2 TMC125 RAMs, and only 13.6% have 3 or more TMC125 RAMs.
No mutation (reference)* 1 2 3 4 5
Overall TMC125 group
Overall placebo group
Number of ETR RAMs (13)
Patients (n) 52
161
121 64 32 19 9
406
414
Patients† (%) 40 30 16 8 5 2
86%
*no detectable baseline NNRTI RAMs from the list of 44; †n=406 (100%)

34. Virologic responders (%, 95% CI)
TTCA
Rilpivirine (TMC 278) in Treatment Naive Patients <50 Copies/mL Through 48 Weeks (TLOVR)(NC=F)
TMC278 25mg qd (n=93)
TMC278 75mg qd (n=95)
TMC mg qd (n=91)
EFV 600mg qd (n=89)
Each plus 2 NRTI 75% ZDV/3TC, 25% TDF/FTC
100 80 60 40 20
81%
81%
80%
77%
Virologic responders (%, 95% CI) 2 4 8 12 16 20 24 32 40 48
Time (Weeks)
TLOVR, time to loss of virologic response; NC=F, non-completer=failure; CI, confidence interval
Pozniak A, et al. Oral presentation presented at 14th CROI, 2007

35. Next Generation NNRTI Etravirine (TMC-125) Rilpivirine (TMC-278)
Twice daily dosing
Elimination half-life: hours
Rash, typically mild, most common AE, no CNS effects
ETR RAMs may not be reported on all genotypes
Limited added effect when > 3 active agents?
Rilpivirine (TMC-278)
Once-daily dosing; low mg dose – optimal for FDC
Lipid neutral, perhaps less CNS effects (unblinded)
RT, reverse transcriptase. 35

36. Impact of New Agents on ARV Treatment New strategies for success?
Treatment naïve patients
Rilpivirine, raltegravir or maraviroc with 2 NRTI
May improve tolerability and expand target populations
Novel combinations that spare nucleosides or ritonavir can be explored
Limited data on 4 class and potentially now even 5 class resistance. After this current “cadre” of new agents maraviroc, raltegravir and etravirine and the similar compounds vircriviroc, elvitregravir and rilpivirine landscape for novel agents may be bear for several years.

37. Impact of New Agents on ARV Treatment New strategies for success?
Highly treatment experienced patients
Where available resistance testing guides choice
Avoid regimens with only one fully active agent
Greatest certainty of activity is with agents with no likelihood of pre-existing resistance (integrase inhibitors, T-20)
Variants with decreased response may be present for ETR, new PI and CCR5 inhibitors
If more than 2 “fully” active agents are available; how many are enough?
Combinations of these new agents need to be explored
Treatment experienced patients in developing world
New agents allow alternatives to recycled nucleosides
Limited data on 4 class and potentially now even 5 class resistance. After this current “cadre” of new agents maraviroc, raltegravir and etravirine and the similar compounds vircriviroc, elvitregravir and rilpivirine landscape for novel agents may be bear for several years.

38. Treatment Goals and Challenges New strategies for success?
All patients
Zero tolerance for virologic failure
High bar for safety even in treatment experienced patients

39. Acknowledgements
Data, Slides and/or Discussion were generously provided by:
Andrew Cheng (Gilead)
Matthias Egger
Trip Gulick
Daria Hazuda, Bach-Yen Nguyen (Merck)
Edward King (Clinical Care Options)
David Margolis
Prema Menezes
Sonia Napravnik
Andrew Phillips
Randy Tressler (Pfizer)
Charlie van der Horst
Brain Woodfall and colleagues (TiboTec)