1. Multidrug Resistance New Options and Advanced Approaches to Management
Slide #1: Clinical Viewpoints: An HIV/AIDS Continuing Education Lecture Series

2. Program Presenter David Alain Wohl, MD
Associate Professor, Division of Infectious DIseases
The University of North Carolina
Chapel Hill, NC
Slide #4: Program Presenter

3. Virologic Failure, Multidrug Resistance, and General Principles of Management
Slide #12: Virologic Failure, Multidrug Resistance, and General Principles of Management

4. Antiretroviral Treatment Failure
Often associated with virologic failure, immunologic failure, and/or clinical progression
Factors associated with an increased risk of treatment failure
Baseline CD4 and HIV RNA
Incomplete medication adherence and missed clinic appointments
Drug adverse events and toxicity
Suboptimal pharmacokinetics
Suboptimal potency
Slide #13: Antiretroviral Treatment Failure
Antiretroviral treatment failure is not uncommon and it increases the risk for HIV disease progression. It is often associated with virologic failure, immunologic failure, and/or clinical progression.1
Factors associated with an increased risk of treatment failure include:1
Baseline patient factors.
Incomplete medication adherence and missed clinic appointments.
Drug adverse events and toxicity.
Suboptimal pharmacokinetics.
Suboptimal potency.
Reference
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; Available at:
Available at: Revision January 29, 2008.

5. Long-Term Risk of Developing Drug Resistance on HAART: UK CHIC Study
Time to Multi-Class Resistance
3-class resistance
2-class resistance
1-class resistance
27%
20%
19%
Patients (%)
14%
Slide: Long-Term Risk of Developing Drug Resistance on HAART: UK CHIC Study
The UK Collaborative Group on HIV Drug Resistance (UK CHIC) Study Group followed 4306 patients (1996 to 2005).1
- For 632 (15%) of the patients, at least one resistance mutation was detected after the start of HAART.
This slide shows the estimates of the percentage of patients with at least one mutation detected according to the time from the start of HAART.1
9% (95% CI, 8%-10%) by 2 years.
19% (95% CI, 17%-21%) by 4 years.
27% (95% CI, 24%-30%) by 6 years.
They also assessed the cumulative risk of having detected mutations from at least 2 of the 3 main drug classes.1
Estimates for 2, 4, and 6 years were 6% (95% CI, 5%-7%), 14% (95% CI,12%-16%), and 20% (95% CI, 18%-22%), respectively.
Estimates for accruing resistance mutations from all 3 main drug classes were 1.0% (95% CI, 0.7%-1.3%) by 2 years, 2.7% (95% CI, 2.0%-3.4%) by 4 years, and 4.1% (95% CI, 3.0%-2%) by 6 years.1
Reference
Phillips AN, Dunn D, Sabin C, et al. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS. 2005;19: 9% 6%
3.1%
2.7% 1%
Years Since Starting HAART
n=4306
Overall risk of treatment failure: 38% over 6 years.
Phillips AN, et al. AIDS. 2005;19:

6. Increased Disease Progression With Class-Wide Drug Resistance
Cumulative Survival or Remaining Free of AIDS Events
Stratified by Class-Wide Drug Resistance (CWDR)
0 CWDR
1 CWDR
Cumulative Survival
2 CWDR
Slide #15: Increased Disease Progression With Class-Wide Drug Resistance
Zaccarelli and colleagues conducted an observational, longitudinal cohort study to estimate the impact of class-wide drug resistance on HIV disease progression.1
Class-wide resistance was defined according to the International AIDS Society consensus.
Survival analysis was performed with Cox's model.
Among 623 patients enrolled and followed for a median of 19 months, 8.9%, 11.7%, 13.4%, and 27.1% had 0, 1, 2, and 3 class-wide resistance, respectively, for death; 6.1%, 9.9%, 13.4%, and 21.5%, respectively, for AIDS-related death; and 16.0%, 17.7%, 19.3%, and 35.9%, respectively, for new AIDS event/death.1
In a multivariate Cox's model, higher HIV RNA level, previous AIDS, and detection of 3 class-wide resistance (hazard ratio, 5.34; 95% CI ) were all significantly associated with increased risk of death.1
Detection of 3 class-wide resistance was also significantly associated with higher risk of AIDS-related death and new AIDS event/death.1
Reference
Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS. 2005;19:
3 CWDR
Time After Genotypic Resistance Test (months)
n=623 patients who failed HAART and underwent genotypic testing, then were followed for a median of 19 months (IQR 12-29).
Multivariate Cox's model: increased risk of death was significantly associated with higher HIV RNA, prior AIDS,
and detection of 3 CWRD (hazard ratio 5.34 [95% CI ]).
Zaccarelli M, et al. AIDS. 2005;19:

7. Assessment of Treatment Failure
Adherence
Medication intolerance
Pharmacokinetic issues
Suspected drug resistance
Slide #16: Assessment of Treatment Failure
In conducting the assessment of treatment failure, it is important to distinguish among the reasons for treatment failure.1
Assessments should address issues of adherence, medication intolerance, pharmacokinetic changes, and suspected drug resistance.1
Reference
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; Available at:
Available at: Revision January 29, 2008.

8. General Approaches to the Management of Virologic Failure
Goal is to achieve plasma HIV RNA <50 copies/mL
Identify fully active agents
Add at least two and preferably three fully active agents
Drug potency and susceptibility more important than number of drugs
Adding a single active drug is not recommended
Risk rapid development of resistance
Discontinuing or briefly interrupting therapy is not recommended
Increases risk of clinical progression
Slide #17: General Approaches to the Management of Virologic Failure
In treatment-experienced patients experiencing virologic failure, the goal is to re-establish maximal virologic suppression to an HIV RNA level of <50 copies/mL.1
To accomplish this goal, there is a need to identify fully active agents for the patient. Add at least two, and preferably three, fully active agents on the basis of drug history, resistance testing, or new mechanistic class. It is important to remember that drug potency and viral susceptibility are more important than the number of drugs prescribed. To this end, adding a single, fully active antiretroviral drug is not recommended because of the risk rapid development of resistance. Discontinuing or briefly interrupting therapy is not recommended because it increases the risk of clinical progression.1
Reference
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; Available at
Available at: Revision January 29, 2008.

9. Multidrug Resistance: Recent Clinical Trials of Interest
Slide #18: Multidrug Resistance: Recent Clinical Trials of Interest

10. Multidrug Resistance: Recent Clinical Trials of Interest
Boosted PIs
RESIST, POWER, and TITAN
Second-generation NNRTI
DUET
CCR5 antagonist
MOTIVATE
Integrase inhibitor
BENCHMRK
Slide #19: Multidrug Resistance: Recent Clinical Trials of Interest
Recent clinical trials addressing the management of patients with multidrug resistance include those evaluating new boosted PIs, a second-generation NNRTI, a CCR5 antagonist, and an integrase inhibitor.

11. RESIST Studies: Tipranavir + Ritonavir in Patients With PI Failure
Two, phase 3, multicenter, open-label trials
Patients with >3-class antiretroviral experience
>2 previous PI-based regimens for at least 3 months
>1 primary PI mutation
30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M
<3 mutations
Codons 33, 82, 84, and 90
HIV RNA >1000 copies/mL
Any CD4 cell count
Treatment arms
Control: ritonavir-boosted comparator PI regimen
Tipranavir + ritonavir
All patients received an optimized background regimen
>2 NRTIs + enfuvirtide
Slide #20: RESIST Studies: Tipranavir + Ritonavir in Patients With PI Failure
Hicks and colleagues presented a pooled analysis of RESIST 1 and 2 studies, which included class-experienced patients (>2 PI regimens).1
Eligibility criteria included >3-class antiretroviral experience, >2 previous PI-based regimens for at least 3 months, >1 primary PI mutation (ie, 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M), <3 mutations (codons 33, 82, 84, and 90), and an HIV RNA of >1000 copies/mL. There were no CD4 cell count restrictions for study entry.1
Treatment arms included a control group (ritonavir-boosted comparator PI regimen) and tipranavir + ritonavir group. All patients received an optimized background regimen that included >2 NRTIs + enfuvirtide.1
Reference
Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:
Hicks CB, et al. Lancet. 2006;368:

12. RESIST Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
Tipranavir + RTV
CPI + RTV
Change (cells/mm3)
Patients (%)
Slide #21: RESIST Studies: Combined 48-Week Analysis
Outcomes were noticeably enhanced when enfuvirtide was part of the background regimen.1
A significantly greater proportion of patients in the tipranavir + ritonavir arm had an HIV RNA <50 copies/mL compared with the comparator PI (22.8% versus 10.2%; P<0.0001). The proportions increase with first-time enfuvirtide use (28.4% versus 14.1%, respectively).1
CD4 cell increases were also significantly higher in the tipranavir + ritonavir group compared with the comparator PI group (P<0.0001).1
Reference
Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:
28.4%*
45*
22.8%*
14.1% 21
10.2%
All Patients
(n=746/737)
Enfuvirtide Use
(n=124/97)
Tipranavir + RTV
(n=740)
CPI + RTV
(n=727)
*P< versus CPI + RTV.
ITT: non-completer=failure.
Hicks CB, et al. Lancet. 2006;368:

13. POWER Studies: Darunavir + Ritonavir in Patients With 3-Class Experience
Two, phase 2b, multicenter, open-label trials
Patients with >3-class antiretroviral experience
Currently receiving a PI-containing regimen
>1 primary PI mutation (any combination, IAS-USA March 2003)
Proportion with >2 primary PI mutations limited to 30% of patients
HIV RNA >1000 copies/mL and any CD4 cell count
Treatment arms
Control: investigator chosen PI
Darunavir/r 600/100 mg bid
Other doses included 400/100 and 800/100 mg qd and 400/100 mg bid
All patients received an optimized background regimen
>2 NRTIs + enfuvirtide
Slide #22: POWER Studies: Darunavir + Ritonavir in Patients With 3-Class Experience
Clotet and colleagues presented the pooled analysis of the 48-week results from two phase 2b studies for darunavir + ritonavir in patients with 3-class failure (ie, patients with experience of at least 1 PI, 1 NNRTI and 1 NRTI and with virus that had 1 or more primary PI mutations).1
Treatment arms included a control (investigator chosen PI) and darunavir + ritonavir 600/100 mg bid. All patients received an optimized background (OB) regimen that included >2 NRTIs + enfuvirtide.1
Reference
Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369:
Clotet B, et al. Lancet. 2007;369:

14. POWER Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
Darunavir + RTV (600/100 mg bid)
Control PI
102*
58%*
Change (cells/mm3)
Patients (%)
45%*
Slide #23: POWER Studies: Combined 48-Week Analysis
Outcomes were noticeably enhanced when enfuvirtide was part of the background regimen.1
A significantly greater proportion of patients in the darunavir + ritonavir arm had an HIV RNA <50 copies/mL (45% versus 10%; P<0.0001). The proportions increase with first-time enfuvirtide use (58% versus 11%, P< respectively).1.
CD4 cell increases were also significantly higher in the darunavir + ritonavir group compared with the comparator PI group (P<0.0001).1
Reference
Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369: 19
10%
11%
All
Patients
(n=131/124)
Enfuvirtide
Use (naïve)
(n=36/35)
Darunavir + RTV
600/100 mg bid
(n=131)
Control PI
(n=124)
*P< versus control PI.
ITT: non-completer=failure.
Clotet B, et al. Lancet. 2006;369:

15. TITAN Study: Darunavir + Ritonavir Versus Lopinavir/Ritonavir Regimen
Phase 3, 96-week study
Treatment-experienced, lopinavir/ritonavir-naïve patients (n=595)
HIV RNA: 4.30 log10 copies/mL
CD4: 232 cells/mm3
PI-naïve: 31%
Susceptible to >4 PIs: 82%
Baseline susceptibility
Lopinavir fold-change >10: 10%
Darunavir fold-change >10: 2%
Randomized arms
Darunavir + ritonavir (600/100 mg bid)
Lopinavir/ritonavir (400/100 mg bid; soft-gel capsules)
Both arms received investigator-selected optimized background regimen
Slide #24: TITAN Study: Darunavir + Ritonavir Versus Lopinavir/Ritonavir Regimen
Madruga and colleagues presented the 48-week efficacy and safety data from the TITAN study.1
Non-inferiority trial.
595 mild-to-moderately treatment-experienced patients (mean baseline HIV RNA 4.3 log10 copies/mL and CD4 232 cells/μL).
Approximately 31% of patients were PI-naïve and 82% were susceptible to 4 or more PIs.
Randomized arms:1
Darunavir + ritonavir (600/100 mg bid) + optimized background regimen (OBR).
Lopinavir/ritonavir (400/100 mg bid; soft-gel capsules) + OBR.
There was an important difference between groups in baseline susceptibilities: 58 patients (10%) had a lopinavir fold-change value >10 at baseline compared with 9 patients (2%) who had a >10 fold-change value for darunavir.1
Reference
Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370:49-58.
Madruga JV, et al. Lancet. 2007;370:49-58.

16. TITAN Study: 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
71%*
60% 88 81
Patients (%)
CD4 Cell Gain (cells/mm3)
Slide #25: TITAN Study: 48-Week Analysis
At week 48, darunavir + ritonavir met the criteria for non-inferiority and superiority with regard to the primary endpoint of proportion of patients with HIV RNA <400 copies/mL (data not shown). Overall, a significantly greater proportion of patients achieved HIV RNA levels <400 copies/mL (primary outcome) compared with the lopinavir/r group (77% versus 67%; difference 10% [95% CI 2-17]; P<0.0001).1,2
Overall, a greater proportion of patients achieved HIV RNA <50 copies/mL in the darunavir + ritonavir group. This difference met the criteria for non-inferiority and superiority.1,2
There were significantly greater reductions in HIV RNA levels in the darunavir + ritonavir arm compared with the lopinavir/ritonavir arm.1,2
CD4 gains were similar between the two treatment arms.1,2
Reference
Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007;370:49-58.
Darunavir + RTV
(n=298)
Lopinavir/r
(n=297)
Darunavir + RTV
(n=298)
Lopinavir/r
(n=297)
*P=0.005 versus lopinavir/r.
ITT: non-completer=failure.
Madruga JV, et al. Lancet. 2007;370:49-58.

17. DUET Studies: Etravirine in Treatment-Experienced Patients
Two, phase 3, 96-week studies
Treatment-experienced patients with evidence of resistance to current NNRTIs
Stratified by baseline enfuvirtide use, previous darunavir use, and HIV RNA (<30K, >30K copies/mL)
Treatment arms
Etravirine 200 mg bid or placebo
All patients received optimized background therapy
Darunavir + RTV plus optimized NRTIs and optional enfuvirtide
Baseline Values
Placebo
(n=604)
Etravirine
(n=599)
Median CD4
(cells/mm3)
109 99
Mean HIV RNA
(log10 copies/mL)
4.8
OBT (%)
Enfuvirtide 47 46
0 active drugs 16 17
1 active drug 39 37
Slide #26: DUET Studies: Etravirine in Treatment-Experienced Patients
The 48-week results from the ongoing double-blind, placebo-controlled, phase 3 studies (DUET-1 [n=612; South and Central America, France, Thailand, Puerto Rico, USA] and DUET-2 [n=591; Australia, Canada, Europe, USA]) were presented for etravirine in treatment-experienced patients with evidence of resistance to currently available NNRTIs.1,2
Patients were randomized to receive either placebo or etravirine 200 mg twice-daily.1,2
Background regimens consisted of ritonavir-boosted darunavir plus at least 2 other NRTIs with or without enfuvirtide.
Baseline characteristics were similar between studies and treatment arms. Across both studies, baseline values for HIV RNA and CD4 cell counts were 4.8 log10 copies/mL and 99 to 109 cells/mm3, respectively.1,2
References
Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of etravirine (ETR; TMC125) versus placebo in 612 treatment-experienced HIV-1-infected patients. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 790.
Johnson M, Campbell T, Clotet B, et al. DUET-2: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 791.
Haubrich R, et al. 15th CROI. Boston, Abstract 790.
Johnson M, et al. 15th CROI. Boston, Abstract 791.

18. DUET Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain 98
61% 73
Patients (%)
CD4 Cell Gain (cells/mm3)
Slide #27: DUET Studies: Combined 48-Week Analysis
At week 48, 61% and 40% of patients in the etravirine and placebo arms, respectively, had HIV RNA <50 copies/mL (P<0.0001).1,2
CD4 cell gains significantly favored the etravirine arm (98 versus 73 cells/mm3; P=0.0006).1,2
References
Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of etravirine (ETR; TMC125) versus placebo in 612 treatment-experienced HIV-1-infected patients. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 790.
Johnson M, Campbell T, Clotet B, et al. DUET-2: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 791.
P<0.0001
P=0.0006
40%
Etravirine
(n=599)
Placebo
(n=604)
Etravirine
(n=599)
Placebo
(n=604)
Haubrich R, et al. 15th CROI. Boston, Abstract 790.
Johnson M, et al. 15th CROI. Boston, Abstract 791.

19. MOTIVATE Studies: Maraviroc in Treatment-Experienced Patients With R5-Only HIV
Combined analysis of two 48-week phase 2b/3 trials
Triple-class experienced (+ triple-class resistance)
R5-only virus
Stratified by baseline HIV RNA (<100K, >100K copies/mL) and enfuvirtide use in optimized background therapy (OBT)
Treatment arms
Maraviroc 150 mg once daily
Maraviroc 150 mg twice daily
Placebo
All patients received OBT (darunavir not included in OBT)
Baseline Values
Maraviroc
Placebo
(n=209)
Once Daily
(n=414)
Twice Daily
(n=426)
Median CD4
(cells/mm3)
187
196
189
Mean HIV RNA
(log10 copies/mL)
4.86
4.85
OBT (%)
<2 active
drugs 66
69.7
Enfuvirtide
43.5
40.6
42.7
Tipranavir
13.9
15.9
14.8
Slide #28: MOTIVATE Studies: Maraviroc in the Treatment-Experienced Patients With R5-Only HIV
Data were presented from the planned 48-week analysis of the double-blind, placebo-controlled, phase 2b/3 studies (MOTIVATE 1; United States and Canada] and 2; Europe, Australia, United States]) for maraviroc in treatment-experienced patients.1
Triple-class experienced patients (+ triple-class resistance) with R5-only virus.
Placebo + optimized background therapy (OBT).
Maraviroc 150 mg once-daily + OBT.
Maraviroc 150 mg twice-daily + OBT.
The OBT comprised 3 to 6 antiretroviral drugs with or without ritonavir.
Randomization also included stratification by baseline HIV RNA (<100,000 and >100,000 copies/mL) and enfuvirtide use.1
Baseline characteristics for MOTIVATE 1 and 2 were similar between studies and the three treatment arms.1
Across both studies, median baseline values for HIV RNA and mean CD4 cell counts ranged from 4.85 to 4.86 log10 copies/mL and 187 to 196 cells/mm3, respectively.
Reference
Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 791.
Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received maraviroc 150 mg;
all others received 300 mg.
Hardy D, et al. 15th CROI. Boston, Abstract 792.

20. MOTIVATE Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
124
116
Patients (%)
CD4 Cell Gain (cells/mm3)
43.2%*
45.5%* 61
Slide #29: MOTIVATE Studies: Combined 48-Week Analysis
At week 48, a significantly greater proportion of maraviroc-treated patients achieved HIV RNA <50 copies/mL compared with the OBT alone group (43.2% and 45.5% versus 16.7%; P<0.0001).1
CD4 gains were higher in the maraviroc groups compared with OBT alone.1
Reference
Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 792.
16.7%
Once-Daily
(n=414)
Twice-Daily
(n=426)
OBT Alone
(n=209)
Once-Daily
(n=414)
Twice-Daily
(n=426)
OBT Alone
(n=209)
Maraviroc
Maraviroc
All maraviroc patients received optimized background therapy.
*P< versus OBT alone.
Hardy D, et al. 15th CROI. Boston, Abstract 792.

21. BENCHMRK Studies: Raltegravir in Patients With Triple-Class Resistance
Two phase 3, 156-week studies
Treatment-experienced patients with triple-class resistance
Stratified by baseline HIV RNA, enfuvirtide and darunavir use in optimized background therapy (OBT)
Treatment arms
Raltegravir 400 mg twice-daily + OBT
Placebo + OBT
BENCHMRK 1/2
Placebo
(n=118/119)
Raltegravir
(n=232/230)
Mean CD4
(cells/mm3)
105/132
140/102
Mean HIV RNA
(log10 copies/mL)
4.5/4.7
4.6/4.7
AIDS (%)
89/91
94/91
OBT (%)
New enfuvirtide
20/20
21/19
New darunavir
25/50
27/45
Slide #30: BENCHMRK Studies: Raltegravir in Patients With Triple-Class Resistance
Cooper and Steigbigel presented the 48-week results from the triple-blind, placebo-controlled, phase 3 studies (BENCHMRK 1 [n=350; Europe, Asia and the Pacific, and Peru] and 2 [n=349; North, Central, and South America]) of the integrase inhibitor raltegravir (formerly MK-0518) in treatment-experienced patients with triple-class resistance.1,2
Patients were randomized to receive either placebo + OBT or raltegravir 400 mg twice-daily.1,2
Approximately 90% of patients had AIDS.
Baseline characteristics for BENCHMRK 1 and 2 were similar between studies and treatment arms.1,2
Across both studies, median baseline values for HIV RNA and CD4 cell counts ranged from 4.5 to 4.7 log10 copies/mL and from 105 to 140 cells/mm3, respectively.
References
Cooper DA, Gatell J, Rockstroh J, et al. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 788.
Steigbigel R, Kumar P, Eron J, et al. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 789.
Cooper D, et al. 15th CROI. Boston, Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, Abstract 789.

22. BENCHMRK Studies: 48-Week Analysis
HIV RNA <50 Copies/mL
CD4 Cell Gain
BENCHMRK-1
BENCHMRK-2
BENCHMRK-1
BENCHMRK-2
120*
65%*
98*
60%*
Patients (%)
CD4 Cell Gain (cells/mm3)
Slide #31: BENCHMRK Studies: 48-Week Analysis
At week 48, HIV RNA <50 copies/mL was achieved by 60% to 65% and 31% to 34% of patients in the raltegravir and OBT arms, respectively (P<0.001).1,2
CD4 cell gain also significantly favored the raltegravir arm (98 to 120 versus 40 to 49 cells/mm3; P<0.001).1,2
References
Cooper DA, Gatell J, Rockstroh J, et al. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 788.
Steigbigel R, Kumar P, Eron J, et al. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 789.
34% 49
31% 40
Raltegravir
Placebo
Raltegravir
Placebo
*P<0.001 versus placebo.
Cooper DA, et al. 15th CROI. Boston, Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, Abstract 789.

23. Multidrug Resistance: Advanced Approaches to Management
Slide #32: Multidrug Resistance: Advanced Approaches to Management

24. Case 1: 37-Year-Old Female With Viremia and Stable CD4 Cell Count
At time of HIV diagnosis in 1994
Cryptococcal meningitis
CD4: 32 cells/uL
Antiretroviral history
1994 to 1996: dual NRTIs
1996 to 1998: dual NRTIs + indinavir with undetectable HIV RNA
1998: viral rebound
1998 through January 2008: multiple changes in therapy
Sequential regimens included all available NRTIs except stavudine, all PIs except darunavir, and efavirenz (in 2002)
No history of using CCR5 antagonists or any entry or integrase inhibitors
Slide #33: Case 1: 37-Year-Old Female With Viremia and Stable CD4 Cell Count
This 37-year-old female had Cryptococcal meningitis and a CD4 cell count of 32 cells/uL at the time of her HIV diagnosis.
Her antiretroviral history included:
Dual NRTIs from 1994 to 1996.
Dual NRTIs + indinavir with undetectable HIV RNA between 1996 to 1998.
Experienced a viral rebound in 1998.
Since 1998, she has required multiple changes in therapy. Sequential regimens included all available NRTIs except stavudine, all PIs except darunavir, and efavirenz (in 2002).
No history of using CCR5 antagonists or any entry or integrase inhibitors.

25. Current Presentation Current presentation Regimen for past 6 months
HIV RNA: 37,000 copies/mL
CD4: 210 cells/µL (stable over last 12 months)
Regimen for past 6 months
Zidovudine/lamivudine/abacavir + tenofovir DF + tipranavir + ritonavir
States good tolerance and adherence
No diabetes mellitus, dyslipidemia, HCV or HBV infection
Not abusing drugs or alcohol
Genotype
NRTI
NNRTI PI
D67N
T69D
K70R
V118I
M184V
T215V
K219Q
K103N
I13V
L33F
F53L
I54V
L63P
A71V
G73S
I84V
L90M
Slide #34: Current Presentation
The patient presents with viremia (HIV RNA 37,000 copies/mL) with a CD4 cell count of 210 cells/µL, which has been stable over the past 12 months.
Her regimen for past 6 months was zidovudine/lamivudine/abacavir + tenofovir DF + tipranavir + ritonavir. When questioned, she states good tolerance and adherence.
Genotypic testing reveals 3-class resistance mutations.
No diabetes mellitus, dyslipidemia, HCV or HBV infection; not abusing drugs or alcohol.

26. Resistance Test DRUG SUSCEPTIBILITY ASSESSMENTGT
Slide #35: Resistance Test
The phenotypic resistance test provides further guidance on the level of susceptibility of various agents in the 3-drug classes.
Let us examine each drug class more closely.

27. Would You Use NRTIs in the Next Regimen?
DRUG
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Slide #36: Would You Use NRTIs in the Next Regimen?

28. Would You Consider NRTIs as One of the Fully Active Drugs in the Next Regimen?
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Slide #37: Would You Consider NRTIs as One of the Fully Active Drugs in the Next Regimen?

29. Would You Consider Etravirine as a Potentially Fully Active Drug in the Next Regimen?
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Slide #38: Would You Consider Etravirine as a Potential Fully Active Drug in the Next Regimen?

30. DUET Studies: Baseline Etravirine Mutations and Virologic Response
13 mutations associated with etravirine resistance
V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S
Presence of >3 etravirine resistance mutations was associated with response similar to placebo + OBR
Etravirine resistance mutations at baseline
0 or 1: 70% of patients
>3: 15%
Week 24
HIV RNA <50 Copies/mL
75%
60%
58%
Patients (%)
Slide #39: DUET Studies: Baseline Etravirine Mutations and Virologic Response
Picchio and colleagues estimated the likelihood of response to etravirine based on the presence of each etravirine resistance associated mutation at baseline.1
Data from the DUET trials showed that patients with >3 etravirine resistance-associated mutations (V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S) at baseline was associated with a diminished virologic response to etravirine. They found that the coexistence of >3 etravirine resistance-associated mutation was infrequent, even in patients with evidence of resistance to first-generation NNRTIs.1
A total of 226,491 routine clinical isolates with NNRTI resistance were examined.
Presence of >3 etravirine resistance mutations was associated with response similar to placebo + OBR.
Etravirine resistance mutations at baseline:
0 or 1: 70% of patients.
>3: 15%.
Reference
1. Picchio G, Vingerhoets J, Staes M, et al. Prevalence of etravirine (ETR; TMC125) resistance-associated mutations in a large panel of clinical isolates. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 866.
33%
(n=161) 1
(n=121) 2
(n=64)
>3
(n=60)
Number of Baseline
Etravirine Mutations
Picchio G, et al. 15th CROI. Boston, Abstract 866.

31. ADDED by Christopher Hurt, from slide provided courtesy of David Wohl.
“Weighted” contributions of each of the etravirine-associated resistance mutations. Not currently for clinical use.

32. Prevalence of Etravirine Resistance in Clinical Populations
Number of Samples
>3 Etravirine Mutations
at Baseline (%)*
DUET 1 and 21
1203 15
Thailand2
158 25
Nigeria3
214 11
Spain4
4981
9.3
Virco5
226,491
2.9
Slide #40: Prevalence of Etravirine Resistance in Clinical Populations
This slide present an overview of the prevalence of >3 etravirine resistance-associated mutations at baseline in clinical populations. The prevalence ranges from 2.9% to 25%.1-5
References
Cahn P, Haubrich R, Leider J, et al. Pooled 24-week results of DUET-1 and -2: TMC125 (etravirine; ETR) vs placebo in 1203 treatment-experienced HIV-1-infected patients. Program and abstracts of the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Illinois. Abstract H-717.
Sungkanuparph S, Manosuthi W, Kiertiburanaku S, et al. Evaluating the role of etravirine in the second-line ART after failing an initial NNRTI-based regimens in a resource-limited setting. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 865.
Taiwo B, Chaplin B, Stanton J, et al. Etravirine-resistance mutations in patients with virologic failure on nevirapine or efavirenz-based HAART. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 867.
Llibre JM, Santos J, Puig T, et al. Prevalence of mutations with impact on virological response to etravirine in routine clinical samples. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 868.
Picchio G, Vingerhoets J, Staes M, et al. Prevalence of etravirine (ETR; TMC125) resistance-associated mutations in a large panel of clinical isolates. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 866.
*V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S
1Cahn P, et al. 47th ICAAC. Chicago, Abstract H-717.
2Sungkanuparpha S, et al. 15th Boston, Abstract 865.
3Taiwo B, et al. 15th CROI. Boston, Abstract 867.
4Llibre JM, et al. 15th CROI. Boston, Abstract 868.
5Picchio G, et al. 15th CROI. Boston, Abstract 866.

33. Which Boosted PI Would You Use?
Darunavir + ritonavir
Indinavir + ritonavir
Tipranavir + ritonavir
Other
None
SUSCEPTIBILITY
ASSESSMENT
Susceptibility
DRUG
Slide #41: Which Boosted PI Would You Use?

34. Results of the Tropism Assay
Slide #42: Results of the Tropism Assay
The tropism assay revealed R5-only HIV.

35. Prevalence of Co-Receptor Tropism
Co-Receptor Usage (%) R5
R5/X4 X4
Treatment-experienced patients
Chelsea and Westminster cohort (n=141)1 78 22
<1
Demarest (n=117)2 67 28 5
MOTIVATE 1 and 2 (n=2560)3 56
41.4
2.6
TORO 1 and 2 (n=724)4 50 48 2
ACTG 5211 (n=391)5 46 4
Treatment-naïve patients
Coakley 2006 (n=1428)3 85
14.7
0.3
Homer cohort (n=979)6 82 18
Chelsea and Westminster cohort (n=402)1 81 19
Demarest (n=325)2 88 12
Slide #43: Prevalence of Co-Receptor Tropism
The prevalence of co-receptor tropism appears to vary based on the stage of disease progression. In naïve patients, approximately 80% of patients have R5-only virus, whereas in treatment-experienced patients the prevalence is lower (50% to 78%).1-6
References
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:
Demarest J, Bonny T, Vavro C, et al. HIV-1 co-receptor tropism in treatment naïve and experienced subjects. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract H-1136.
Coakley E, Benhamida J, Chappey C, et al. An evaluation of tropism profiles and other characteristics among 3988 individuals screened for the A , A (MOTIVATE 1), and A (MOTIVATE 2) studies for maraviroc. In: Program and abstracts of the 2nd International Workshop on Targeting HIV Entry; October 20-21, 2006; Boston, MA. Abstract 8.
Melby T, Despirito M, Demasi R, et al. HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis. 2006;194:
Wilkin TJ, 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:
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:
1Moyle GJ, et al. J Infect Dis. 2005;191:
2Demarest J, et al. 44th ICAAC. Washington, DC, Abstract H-1136.
3Coakley E, et a. 2nd IWTHIVE. Boston, Abstract 8.
4Melby T, et al. J Infect Dis. 2006;194:
5Wilkin T, et al. Clin Infect Dis. 2007;44:
6Brumme ZL, et al. J Infect Dis. 2005;192:

36. Case Summary Current regimen and status Phenotypic susceptibility
Zidovudine/lamivudine/abacavir + tenofovir DF + tipranavir + ritonavir
CD4: 210 cells/uL
HIV RNA: 37,000 copies/mL
Phenotypic susceptibility
NRTIs
Tenofovir DF, abacavir, stavudine
Intermediate: didanosine
PIs
Indinavir + ritonavir, darunavir + ritonavir
Intermediate: fosamprenavir + ritonavir, tipranavir + ritonavir, lopinavir/ritonavir
NNRTIs
Predicted susceptibility to etravirine
Tropism assay: “R5” only
Integrase inhibitor and enfuvirtide naïve
Slide #44: Case Summary
To summarize this case, the patient is currently receiving zidovudine/lamivudine/abacavir + tenofovir DF + tipranavir + ritonavir and presents with a CD4 of 210 cells/uL and HIV RNA of 37,000 copies/mL.
Phenotypic susceptibility among the NRTIs include tenofovir DF, abacavir, stavudine; with intermediate susceptibility to didanosine. Among the PIs, susceptibility remains to indinavir + ritonavir, darunavir + ritonavir; and intermediate susceptibility to fosamprenavir + ritonavir, tipranavir + ritonavir, and lopinavir/ritonavir. There is predicted susceptibility to etravirine.
Tropism assay reveals “R5” only virus and the patient is both integrase inhibitor and enfuvirtide naïve.

37. What Would You Recommend Be Included in the Next Regimen?
PI plus ritonavir + NRTIs
PI plus ritonavir + 1 new drug* + NRTIs
PI plus ritonavir + 2 new drugs* + NRTIs
PI plus ritonavir + 3 new drugs* + NRTIs
PI plus ritonavir + 4 new drugs* + NRTIs
Something else
Slide #45: What Would You Recommend Be Included in the Next Regimen?
PI plus ritonavir + NRTIs.
PI plus ritonavir + 1 new drug* + NRTIs.
PI plus ritonavir + 2 new drugs* + NRTIs.
PI plus ritonavir + 3 new drugs* + NRTIs.
PI plus ritonavir + 4 new drugs* + NRTIs.
Something else.
*New drugs for this patient would include enfuvirtide, etravirine, maraviroc, or raltegravir.

38. MOTIVATE 1 and 2: Combined 24-Week Analysis
HIV RNA <50 Copies/mL
OBT alone
Maraviroc qd
Maraviroc bid
61%
58%
55%
52%
53%
44%*
45%*
43%
Patients (%)
29%
Slide #46: MOTIVATE 1 and 2: Combined 24-Week Analysis
Gulick and colleagues showed that from the pooled 24-week analysis of the MOTIVATE trials, a substantial percentage of patients with R5-only virus achieved HIV RNA <50 copies/mL even with 0 active agents in their background regimen. This percentage increased from 43% to up to 61% as the number of active agents in the background regimen increased from 1 to 3.1
Reference
Gulick RM, van der Ryst E, Lampiris H, et al. Efficacy and safety of once-daily (QD) compared with twice-daily (BID) maraviroc plus optimized background therapy (OBT) in treatment-experienced patients infected with CCR5-tropic-HIV-1: 24-week combined analysis of the MOTIVATE 1 and 2 studies. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WePeB116LB.
23%
18%
19% 9% 3%
All Patients
(n=118/232/235)
None
(n=35/51/56) 1
(n=44/130/134) 2
(n=59/88/104)
>3
(n=64/132/121)
Number of Active Agents (OSS) in OBT
*P< versus placebo.
All maraviroc patients received OBT.
OSS=overall susceptibility score based on phenotypic and genotypic susceptibility at baseline.
Gulick RM, et al. 4th IAS Conference. Sydney, Abstract WePEB116LB.

39. BENCHMRK Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
HIV RNA <50 Copies/mL
OBT
Raltegravir
OBT
Raltegravir
75%
70%
67%
59%
52%
Patients (%)
Patients (%)
48%
45%
43%
Slide #47: BENCHMRK Studies: Combined 48-Week Analysis
The proportion of patients with HIV RNA <50 copies/mL tended to remain greater in the raltegravir + OBT arm when stratified by the number of active drugs in the OBT, assessed by the genotypic or phenotypic sensitivity scores. The greatest percentage of patients with HIV RNA <50 copies/mL were those with 3 or more active agents in the OBT.1,2
References
Cooper DA, Gatell J, Rockstroh J, et al. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 788.
Steigbigel R, Kumar P, Eron J, et al. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 789.
37%
13% 8% 3%
(n=65/112) 1
(n=92/166)
>2
(n=68/158)
(n=12/33) 1
(n=54/71)
>2
(n=153/313)
Genotypic Sensitivity Score
Phenotypic Sensitivity Score
(upper cut-off)
Cooper DA, et al. 15th CROI. Boston, Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, Abstract 789.

40. Discussion
If you do not feel there is a need to include more than two of the new drugs,* what information would guide the decision as to which one(s) to use?
Slide #48: Discussion
If you do not feel there is a need to include more than two of the new drugs (ie, enfuvirtide, etravirine, maraviroc, or raltegravir), what information would guide the decision as to which one(s) to use?
*New drugs for this patient would include enfuvirtide, etravirine, maraviroc, or raltegravir.

41. Case 2: 48-Year-Old Male With Advanced AIDS
At time of HIV diagnosis in 1990
CD4: 118 cells/mm3
Pneumocystis pneumonia, CMV retinitis, thrush
Antiretroviral history (never achieved HIV RNA <500 copies/mL)
1990 to 1993: NRTI monotherapy (zidovudine, didanosine, stavudine)
1993 to 1995: zidovudine/lamivudine
1995 to 1996: Saquinavir + ritonavir
1996: zidovudine/lamivudine + ritonavir
1996 to 1999: zidovudine/lamivudine + abacavir + amprenavir
1999 to 2001: stavudine + lamivudine + efavirenz
2001 to 2003: off treatment
2003 to 2007: tenofovir DF + lamivudine + efavirenz + lopinavir/ritonavir
2007 to present: zidovudine/lamivudine + tenofovir DF + darunavir + ritonavir + enfuvirtide
Slide #49: Case 2: 48-Year-Old Male With Advanced AIDS
This 48-year-old male had a CD4 cell count of 118 cells/mm3 and Pneumocystis pneumonia, CMV retinitis, and thrush at the time of HIV diagnosis.
The patient has not achieved an HIV RNA <500 copies/mL with treatment. His antiretroviral history includes:
NRTI monotherapy (zidovudine, didanosine, stavudine) from 1990 to 1993.
Zidovudine/lamivudine from 1993 to 1995.
Saquinavir + ritonavir from 1995 to 1996.
In 1996 he received before being switched to zidovudine/lamivudine + abacavir + amprenavir, which he received up to 1999.
Stavudine + lamivudine + efavirenz from 1999 to 2001.
He was off treatment from 2001 to 2003, after which he received tenofovir DF + lamivudine + efavirenz + lopinavir/ritonavir until 2007.
He is currently receiving zidovudine/lamivudine + tenofovir DF + darunavir + ritonavir + enfuvirtide.

42. Current Presentation Current presentation Current regimen
HIV RNA: 975,000 copies/mL
CD4: 9 cells/mm3
Current regimen
Zidovudine/lamivudine + tenofovir DF + darunavir + ritonavir + enfuvirtide
Injection site reactions and moderate diarrhea
Comorbid conditions
Lipodystrophy, wasting, hyperlipidemia
Other medications
Trimethoprim-sulfamethoxazole, fluconazole, azithromycin, valganciclovir, atorvastatin
Genotype
NRTI
NNRTI PI
M41L
T69AKG
V75S
V118I
M184V
L210W
T215Y
K219E
K103N
V108V/I
Y181C
L10V
K20R
V32I
L33F
E34Q
M36I
K43T
M46I
F53L
I54L
L63P
A71V
G73G/C
T74P V77I
I84V
L90M
Slide #50: Current Presentation
The patient presents with an HIV RNA of 975,000 copies/mL and a CD4 of 9 cells/mm3 and is experiencing injection site reactions and moderate diarrhea from his current regimen (zidovudine/lamivudine + tenofovir DF + darunavir + ritonavir + enfuvirtide).
Comorbid conditions include lipodystrophy, wasting, and hyperlipidemia, and he is receiving trimethoprim-sulfamethoxazole, fluconazole, azithromycin, valganciclovir, and atorvastatin in addition to his HAART regimen.
Genotypic testing reveals 3-class resistance mutations.

43. Resistance Test DRUG SUSCEPTIBILITY ASSESSMENTGT
Slide #51: Resistance Test
The phenotypic resistance test provides further guidance indicating resistance across all agents.
Let us examine each drug class more closely.

44. Which NRTIs Might Be of Benefit?
DRUG
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Slide #52: Which NRTIs Might Be of Benefit?

45. NRTI Resistance: Everything One Needs To Know*
Selected by
Effects on other NRTIs
M184V
Lamivudine,
Emtricitabine
Loss of susceptibility to lamivudine, emtricitabine
Decreased susceptibility to abacavir, didanosine (clinically insignificant)
Delayed TAMs and increased susceptibility to zidovudine,
stavudine, tenofovir DF
TAMs
Zidovudine, stavudine
Decreased susceptibility to all NRTIs based on number of TAMs
Greatest loss of susceptibility with 41/210/215 pathway
Q151M T69ins
Zidovudine/didanosine,
didanosine/stavudine
Resistance to all NRTIs
T69ins: tenofovir DF resistance
K65R
Tenofovir DF, abacavir,
didanosine
Variable decreased susceptibility to tenofovir DF, abacavir,
didanosine (and lamivudine, emtricitabine)
Increased susceptibility to zidovudine
L74V
Abacavir, didanosine
Decreased susceptibility to abacavir, didanosine
Increased susceptibility to zidovudine, tenofovir DF
44, 118
Increased NRTI resistance with 41/210/215 pathway
Slide #53: NRTI Resistance: Everything One Needs to Know (according to Joel Gallant, MD)
This slide summarizes the key issues related to NRTI resistance.
*According to Joel Gallant, MD

46. Continuing NRTIs in the Presence of Resistance Has Virologic Benefit
Selective single-class interruption in the presence of resistance
Nonrandomized studies in adults with multidrug-resistant HIV1,2
Viral rebound during NRTI interruption precedes genotypic switch1
PI interruption led to little change in HIV RNA levels or genotype2
Enfuvirtide resistance waned rapidly following enfuvirtide interruption (background regimen continued)2
Change in HIV RNA
Interrupt NRTI (n=6)
(continue PI)1
Change (log10 copies/mL)
Slide #54: Continuing NRTIs in the Presence of Resistance Has Virologic Benefit
The use of partial treatment interruption is controversial. Data from Deeks and colleagues showed that HIV-infected patients with multidrug-resistant HIV could maintain immunologic and virologic benefit with simplified regimens.1
48-week nonrandomized study.
Patients with multidrug resistance who interrupted either PI (n=18) or NRTI therapy (n=6).
Interruption of PI treatment (ie, maintaining NRTI therapy):1
Associated with stable HIV RNA levels (mean change: log10 copies/mL per week).
Patients who had interrupted NRTI therapy (ie, maintained PI therapy):1
Experienced immediate increases in HIV RNA levels.
Most patients had a loss of the M184V mutation.
The same investigators found that enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals.2
These and other data indicate that NRTIs can maintain antiviral activity in the setting of drug-resistance mutations, whereas PIs can select for drug-resistance mutations that do not have as much of an impact on viral fitness.1,2
Treatment strategies in this patient population should be aimed at maintaining the therapeutic benefit of treatment while minimizing drug exposure.
References
Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192:
Deeks SG, Lu J, Hoh R, et al. Interruption of enfuvirtide in HIV-1 infected adults with incomplete viral suppression on an enfuvirtide-based regimen. J Infect Dis. 2007;195:
Interrupt enfuvirtide (n=16)2
Interrupt PI (n=18)
(continue NRTI)1
Week of Interruption
1Deeks SG, et al. J Infect Dis. 2005;192;
2Deeks SG, et al. J Infect Dis. 2007;195:

47. Is There a Role for NNRTIs?
DRUG
SUSCEPTIBILITY
Susceptibility
ASSESSMENT
Slide #55: Is There a Role for NNRTIs?

48. DUET Studies: Baseline Etravirine Mutations and Virologic Response
13 mutations associated with etravirine resistance
V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S
Presence of >3 etravirine resistance mutations was associated with response similar to placebo + OBR
Etravirine resistance mutations at baseline
0 or 1: 70% of patients
>3: 15%
Week 24
HIV RNA <50 Copies/mL
75%
60%
58%
Patients (%)
Slide #56: DUET Studies: Baseline Etravirine Mutations and Virologic Response
Picchio and colleagues estimated the likelihood of response to etravirine based on the presence of each etravirine resistance associated mutation at baseline.1
Data from the DUET trials showed that patients with >3 etravirine resistance-associated mutations (V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, G190A/S) at baseline was associated with a diminished virologic response to etravirine. They found that the coexistence of >3 etravirine resistance-associated mutation was infrequent, even in patients with evidence of resistance to first-generation NNRTIs.1
A total of 226,491 routine clinical isolates with NNRTI resistance were examined.
Presence of >3 etravirine resistance mutations was associated with response similar to placebo + OBR.
Etravirine resistance mutations at baseline:
0 or 1: 70% of patients.
>3: 15%.
Reference
1. Picchio G, Vingerhoets J, Staes M, et al. Prevalence of etravirine (ETR; TMC125) resistance-associated mutations in a large panel of clinical isolates. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 866.
33%
(n=161) 1
(n=121) 2
(n=64)
>3
(n=60)
Number of Baseline
Etravirine Mutations
Picchio G, et al. 15th CROI. Boston, Abstract 866.

49. Which PIs Are Options? DRUG SUSCEPTIBILITY ASSESSMENT
Slide #57: Which PIs Are Options?

50. Discussion Other options Do you include PIs if all are resistant?
Enfuvirtide
Maraviroc
Raltegravir
Do you include PIs if all are resistant?
What is the likelihood of this patient being enfuvirtide resistant?
Slide #58: Discussion
What other options would you consider?
Enfuvirtide.
Maraviroc.
Raltegravir.
Do you include PIs if all are resistant?
What is the likelihood of this patient being enfuvirtide resistant?

51. TORO 1 and 2: Enfuvirtide Susceptibility
Biological Cutoff
ENF Naïve
Slide #59: TORO 1 and 2: Enfuvirtide Susceptibility
Melby and colleagues showed the shift in IC50 between patients naïve or experienced to enfuvirtide.1
Reference
Melby T, Sista P, DeMasi R, et al. Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2. AIDS Res Hum Retroviruses. 2006;22:
ENF Failure
Normalized IC50 (mg/mL)
Melby T, et al. AIDS Res Hum Retroviruses. 2006;22:

52. HIV RNA Patterns in 25 Subjects on Enfuvirtide Salvage Therapy
Enfuvirtide resistance can emerge rapidly
Dependent on quality of the optimized background regimen
HIV RNA Values 6 5 4
HIV RNA (log10 copies/mL)
Slide #60: HIV RNA Patterns in 25 Subjects on Enfuvirtide Salvage Therapy
These data were provided through a personal communication with Dr. Deeks, and show that enfuvirtide resistance can emerge rapidly, depending on the quality of the optimized background regimen. 3 2 1 8 16 24 32 40
Week of Enfuvirtide Therapy
SCOPE cohort.
Personal communication. Deeks SG, 2005.

53. Clinical Case 2 Enfuvirtide resistance testing was performed
Fold-change value was several hundred, at the upper limit of detection and well above susceptible range
What is the likelihood this patient has no detectable CXCR4-utilizing virus?
Slide #61: Clinical Case 2
An enfuvirtide resistance test revealed that the fold-change value was several hundred, at the upper limit of detection and well above susceptible range.
What is the likelihood this patient has no detectable CXCR4-utilizing virus?

54. Prevalence of Co-Receptor Tropism
Co-Receptor Usage (%) R5
R5/X4 X4
Treatment-experienced patients
Chelsea and Westminster cohort (n=141)1 78 22
<1
Demarest (n=117)2 67 28 5
MOTIVATE 1 and 2 (n=2560)3 56
41.4
2.6
TORO 1 and 2 (n=724)4 50 48 2
ACTG 5211 (n=391)5 46 4
Treatment-naïve patients
Coakley 2006 (n=1428)3 85
14.7
0.3
Homer cohort (n=979)6 82 18
Chelsea and Westminster cohort (n=402)1 81 19
Demarest (n=325)2 88 12
Slide #62: Prevalence of Co-Receptor Tropism
The prevalence of co-receptor tropism appears to vary based on the stage of disease progression. In naïve patients, approximately 80% of patients have R5-only virus, whereas in treatment-experienced patients the prevalence is lower (50% to 78%).1-6
References
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:
Demarest J, Bonny T, Vavro C, et al. HIV-1 co-receptor tropism in treatment naïve and experienced subjects. In: Program and abstracts of the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy; October 30-November 2, 2004; Washington, DC. Abstract H-1136.
Coakley E, Benhamida J, Chappey C, et al. An evaluation of tropism profiles and other characteristics among 3988 individuals screened for the A , A (MOTIVATE 1), and A (MOTIVATE 2) studies for maraviroc. In: Program and abstracts of the 2nd International Workshop on Targeting HIV Entry; October 20-21, 2006; Boston, MA. Abstract 8.
Melby T, Despirito M, Demasi R, et al. HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response. J Infect Dis. 2006;194:
Wilkin TJ, 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:
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:
1Moyle GJ, et al. J Infect Dis. 2005;191:
2Demarest J, et al. 44th ICAAC. Washington, DC, Abstract H-1136.
3Coakley E, et a. 2nd IWTHIVE. Boston, Abstract 8.
4Melby T, et al. J Infect Dis. 2006;194:
5Wilkin T, et al. Clin Infect Dis. 2007;44:
6Brumme ZL, et al. J Infect Dis. 2005;192:

55. Prevalence of D/M or X4 HIV by Treatment Status and CD4 Count
Prevalence of D/M or X4 Tropism
Treatment-naïve patients
Treatment-experienced patients
P<0.001
Patients (%)
P=0.04
Slide #63: Prevalence of D/M or X4 HIV by Treatment Status and CD4 Cell Count
Hunt and colleagues assessed viral coreceptor usage in treatment-naive and experienced HIV-infected participants with detectable viremia from 2 clinic-based cohorts. Of 182 treatment-experienced patients, 75 (41%) harbored D/M or X4-tropic viruses, compared with 178 (18%) of the 976 treatment-naive participants (P<0.001). This difference remained significant after adjustment for CD4 cell count, as shown on this slide.
Reference
1. Hunt PW, Harrigan PR, Huang W, et al. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia. J Infect Dis. 2006;194:
P<0.001
P=0.02
<134
135 to 257
258 to 365
>365
CD4 Cell Count (cells/mm3)
Hunt P, et al. J Infect Dis. 2006;194:

56. Results of the Tropism Assay
Slide #64: Results of the Tropism Assay
The tropism assay revealed the patient has dual/mixed (D/M) virus.

57. Discussion
Is there a benefit to using maraviroc in a patient with D/M virus?
Slide #65: Discussion
Is there a benefit to using maraviroc in a patient with D/M virus?

58. Study 1029: Maraviroc in Treatment-Experienced Patients With D/M or X4 Virus (Week 48 Results)
HIV RNA <50 Copies/mL
CD4 Cell Gain
Difference from
placebo + OBT (97.5% CI)
+15
(-18, +47)
+28
(-5, +61) 78
Patients (%)
CD4 Cell Gain (cells/mm3) 65
Slide #66: Study 1029: Maraviroc in Treatment-Experienced Patients With D/M or X4 Virus (Week 48 Results)
Goodrich and colleagues presented the 48-week results of the use maraviroc in a phase 2b study in 167 treatment-experienced patients with dual/mixed (R5/X4) virus.1
HIV RNA: 36,380 copies/mL.
Patients were randomized to receive either maraviroc (150 mg qd or bid) + optimized background regimen (OBR) or an OBR alone. The OBR included 3 to 6 antiretroviral agents.1
At week 48, there were similar virologic outcomes in all groups, however there were numerically greater CD4 cell increases with maraviroc.1
Maraviroc was well tolerated and there were no cases of hepatotoxicity, lymphoma, or adenocarcinoma.1
Reference
Goodrich JM, Saag M, van der Ryst E, et al. 48-week safety and efficacy of maraviroc, a novel CCR5 antagonist, in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced patients infected with dual/mixed-tropic HIV-1. Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, California. Abstract LB-2. 51
27%
22%
18%
Once-Daily
(n=57)
Twice-Daily
(n=52)
OBT Alone
(n=54)
Once-Daily
(n=57)
Twice-Daily
(n=52)
OBT Alone
(n=54)
Maraviroc
Maraviroc
All maraviroc patients received optimized background therapy.
Goodrich JM, et al. 45th IDSA. San Diego, Abstract LB-2.

59. Discussion
If raltegravir were the only fully active drug in the regimen, what are the chances of integrase resistance?
Slide #67: Discussion
If raltegravir were the only fully active drug in the regimen, what are the chances of integrase resistance?

60. BENCHMRK Studies: Combined 48-Week Analysis
HIV RNA <50 Copies/mL
HIV RNA <50 Copies/mL
OBT
Raltegravir
OBT
Raltegravir
75%
70%
67%
59%
52%
Patients (%)
Patients (%)
48%
45%
43%
Slide #68: BENCHMRK Studies: Combined 48-Week Analysis
The proportion of patients with HIV RNA <50 copies/mL tended to remain greater in the raltegravir + OBT arm when stratified by the number of active drugs in the OBT, assessed by the genotypic or phenotypic sensitivity scores. The greatest percentage of patients with HIV RNA <50 copies/mL were those with 3 or more active agents in the OBT.1,2
References
Cooper DA, Gatell J, Rockstroh J, et al. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 788.
Steigbigel R, Kumar P, Eron J, et al. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 789.
37%
13% 8% 3%
(n=65/112) 1
(n=92/166)
>2
(n=68/158)
(n=12/33) 1
(n=54/71)
>2
(n=153/313)
Genotypic Sensitivity Score
Phenotypic Sensitivity Score
(upper cut-off)
Cooper D,A et al. 15th CROI. Boston, Abstract 788.
Steigbigel R, et al. 15th CROI. Boston, Abstract 789.

61. Discussion
Even with a PSS=0 (upper cutoff), >50% of subjects on raltegravir had HIV RNA <50 copies/mL at week 48
However, do not use raltegravir as monotherapy when other agents are available
Slide #69: Discussion
Even with a PSS=0 (upper cutoff), >50% of subjects on raltegravir had HIV RNA <50 copies/mL at week 48.
However, do not use raltegravir as monotherapy when other agents are available.

62. Considerations for Choosing a Non- Suppressive “Holding Regimen”
Never use an NNRTI
NNRTI mutations have no beneficial impact on viral fitness
Accumulation of additional mutations may result in cross-resistance to second-generation NNRTIs
Always use lamivudine or emtricitabine
Simple and well-tolerated drugs
M184V decreases viral fitness
Persistent viral load reduction in presence of M184V
Increased activity of zidovudine, stavudine, tenofovir DF
Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations
If possible, continue therapy until availability of at least 2 new active drugs
Slide #70: Consideration for Choosing a Non-Suppressive “Holding Regimen
Never use an NNRTI.
NNRTI mutations have no beneficial impact on viral fitness.
Accumulation of additional mutations may result in cross-resistance to second-generation NNRTIs.
Always use lamivudine or emtricitabine.
Simple and well-tolerated drugs.
M184V decreases viral fitness.
Persistent viral load reduction in presence of M184V.
Increased activity of zidovudine, stavudine, tenofovir DF.
Choose PIs and/or NRTIs based on resistance and tolerability/toxicity considerations.
If possible, continue therapy until availability of at least 2 new active drugs.

63. Principles for Using New Drugs
Have a clear understanding of treatment goals
Virologic suppression is possible in most patients
Immunologic preservation
Prevention of HIV disease progression
Quality of life, minimize side effects and toxicities
Incorporate as much information as possible
Use input from patient on dosing, side effects
Treatment history
Resistance testing: past and present
Use new agents wisely
Include 2, and preferably 3, fully active agents when possible
Preferably at least one from a new class
Slide #71: Principles for Using New Drugs
Have a clear understanding of treatment goals.
Virologic suppression is possible in most patients.
Immunologic preservation.
Prevention of HIV disease progression.
Quality of life, minimize side effects and toxicities.
Incorporate as much information as possible.
Use input from patient on dosing, side effects.
Treatment history.
Resistance testing: past and present.
Use new agents wisely.
Include 2, and preferably 3, fully active agents when possible.
Preferably at least one from a new class.

64. Evaluation Form
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A post-activity brief online survey will be ed to you in 4 to 8 weeks to assess how your participation in this educational activity has affected your practice of medicine.
Slide #72: Evaluation Form

65. Slides Available on CCHIV
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Slide #65: Evaluation Form