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New antiretroviral drugs
1. New Antiretroviral Drugs: what we
have and how to use ?
Winai Ratanasuwan, MD, MPH
Dept. Preventive and Social Medicine
Faculty of Medicine, Siriraj Hospital
3. Potential Uses of Integrase Inhibitors in
Clinical Practice
Treatment-naive
Switch
– To simplify or reduce toxicity to a given regimen after
virologic suppression achieved
Treatment-experienced
– First failure
– After multiple failures
4. Clinical Role of Integrase
Inhibitors in Treatment-Naive
Patients
6. Potential Uses of Integrase Inhibitors:
Treatment-Naive Patients
Advantages Disadvantages
Novel mechanism of action Twice-daily dosing
Efficacy data to 144 wks Cost
Rapid HIV-1 RNA decay Some drug-drug interactions
(varies by drug)
Lack of transmitted drug
Fewer data than other agents
resistance
Low barrier to resistance
Excellent safety and tolerability
Lack of coformulation
Limited lipid effects
Limited drug interactions
7. Summary of RAL Treatment-Naive Data
Phase II (Protocol 004, N = 198): RAL comparable to EFV
in virologic efficacy at 144 wks
– HIV-1 RNA < 50 copies/mL: 78% RAL vs 76% EFV
– Fewer CNS adverse events with RAL vs EFV
– RAL had less effect on serum lipids vs EFV
Phase III (STARTMRK, N = 563): noninferior virologic
efficacy of RAL vs EFV at 96 wks
– HIV-1 RNA < 50 copies/mL: 81% RAL vs 79% EFV
– Fewer CNS adverse events with RAL vs EFV
– Lower cholesterol and triglyceride increases with RAL vs EFV
1. Gotuzzo E, et al. IAS 2009. Abstract MOPEB030.
2. Lennox J, et al. Lancet. 2009;[Epub ahead of print].
8. D:A:D: Recent and/or Cumulative PI/NNRTI
Use and Risk of MI
PI* NNRTI
1.2
1.13
1.10
1.00
0.90
IDV NFV LPV/RTV SQV NVP EFV
# PYFU: 68,469 56,529 37,136 44,657 61,855 58,946
# MI: 298 197 150 221 228 221
*Approximate test for heterogeneity: P = .02
Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.
9. RAL Drug Interactions
Fewer due to alternative metabolism: glucuronidation (UGT1A1)
TDF ↑ RAL 49%
PI interactions
– ATV
NNRTI Interactions
– ETR and EFV (RAL AUC ↓ 36%) acceptable
Rifampin
– 40% reduction in RAL AUC; RAL dose increased to 800 mg BID when administered
with rifampin[1]
– ANRS study (N = 150) of EFV vs RAL 400 mg vs RAL 800 mg for HIV/TB-
coinfected patients[2]
1. Raltegravir package insert.
2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00822315.
10. Can RAL Be Dosed Once Daily?
Study ongoing (QDMRK) to determine safety and efficacy
of RAL once daily vs twice daily
– Treatment-naive patients
– RAL 400 mg BID vs RAL 800 mg QD, both plus TDF/FTC
– Estimated enrollment: 750 patients
Primary outcome: HIV-1 RNA < 50 copies/mL at Wk 48
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00745823.
11. Treatment-Naive Patients for Whom INSTIs
May Be Considered
Currently, DHHS guidelines include INSTIs as preferred
options for treatment-naive patients
Possible patients who might be considered
– Patients unable to tolerate NNRTI (rash, CNS toxicity) or PI
(any RTV dose)
– High lipids or cardiovascular risk
– Transmitted NNRTI resistance (care must be taken to
ensure activity of other regimen components)
– Women who may become pregnant
DHHS guidelines. Available at: http://aidsinfo.nih.gov.
13. Clinical Role of Integrase
Inhibitors as Switch Strategy in
Virologically Suppressed Patients
14. Reasons to Switch Antiretrovirals in
Patients on a Suppressive Regimen
Simplification/convenience
– Reduce pill burden, dosing frequency, or avoid other specific
dosing requirements
Tolerability/toxicity
– Improve short-term tolerability, reduce risk of long-term
complications
Drug-drug interactions
Lack of adequate CD4+ response?
15. Potential Uses of Integrase Inhibitors:
Simplify or Reduce Toxicity
Advantages Disadvantages
Novel mechanism of action Must be used with adequate
support from other regimen
Potent antiretroviral activity components
Excellent safety and tolerability Low barrier to resistance
Limited lipid effects Twice-daily dosing
Limited drug interactions Cost
Some drug interactions
Fewer data than other agents
Lack of coformulation
16. Established Switch Regimens
Within-class substitutions
– NRTI substitutions (eg, change d4T to TDF)
– NNRTI substitution (eg, NVP to EFV)
– PI substitutions (eg, add boosting, remove boosting,
reduce toxicity)
Out-of-class substitution
– PI to NNRTI
Reduce the number of active agents
17. RAL Switch Regimens
RAL substituted for ENF in suppressed patients
– Many studies, including 1 randomized,[1] support this use
– Rarely, unexpected adverse effects may occur (depression)[2]
SWITCHMRK[3]
– Predefined criteria for virologic noninferiority not met
– Demonstrated lipid benefits
– When underlying resistance may be present (eg, experienced
patients, transmitted resistance), careful patient selection needed
– Lower barrier to resistance with RAL vs boosted PIs
1. De Castro N, et al. IAS 2009. Abstract MOPEB066. 2. Harris M, et al. AIDS. 2009;22:1890-1892.
3. Eron J, et al. CROI 2009. Abstract 70aLB.
18. Clinical Role of Integrase
Inhibitors in Treatment-
Experienced Patients
19. Potential Uses of Integrase Inhibitors:
First Failure
Advantages Disadvantages
Novel mechanism of action No data specific to first
failures
Expectation that activity would
be excellent What to combine (is a
boosted PI required?)
Excellent safety and tolerability
Twice-daily dosing
Limited lipid effects
Cost
Limited drug interactions
Low barrier to resistance
Lack of coformulation
20. Principles Guiding Second-Line
Integrase Inhibitor–Containing Regimens
Key strategy for success with integrase inhibitor–containing
regimens is inclusion of ≥ 2 active agents
If resistance at VF with first-line NNRTI- or PI-based regimen
involves NRTI-associated mutations, NRTIs in subsequent
regimen cannot be considered fully active
– Integrase inhibitor + 2 NRTIs may not be sufficient in these cases
In patients who discontinued first-line regimen, negative
genotypic resistance test does not necessarily indicate absence
of resistant viral population
– Particularly for M184V
Use of RAL + boosted PI merits further study in 2 NRTI +
NNRTI failure patients
21. Potential Uses of Integrase Inhibitors:
Multiple Failures
Advantages Disadvantages
Novel mechanism of action Must be used with other active
agents
Well-established data
Does a boosted PI always
Excellent safety and tolerability need to be included?
Limited lipid effects Low barrier to resistance
Limited drug interactions Cross resistance between RAL
and ELV
22. Focus on Number of Active Agents
DHHS ARV guidelines: ≥ 2, preferably 3, fully active agents
in new regimen
Highest rate of virologic suppression in patients receiving
investigational drug plus OBR containing ≥ 1 other active
agent[1-4]
Trend toward greater benefit with 3 vs 2 fully active agents[1-4]
– Not statistically significant
– Must also consider potential drug-drug interactions, adverse
events, pill burden, absence of future options
– Contribution of “partially active” agents (eg, 3TC) difficult to
calculate
No added benefit from using 4 vs 3 fully active agents
1. Cooper DA, et al. N Engl J Med. 2008;359:355-365. 2. Haubrich R, et al. CROI 2008. Abstract 790.
3. Johnson M, et al. CROI 2008. Abstract 791. 4. Gulick RM, et al. N Engl J Med. 2008;359:1429-1441.
23. BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL
by New Agents in OBR, Wk 48
Enfuvirtide Darunavir n Patients (%)
112 89
+ + 65 68
166 80
+ - 92 57
166 69
- + 92 47
- - 158 60
68 20
0 20 40 60 80 100
Cooper DA, et al. N Engl J Med. 2008;359:355-365.
24. RAL + MVC + ETR in Triple Class–
Experienced Patients
Nonrandomized cohort study
RAL + MVC + ETR (n = 28) RAL + MVC or ETR + PI (n = 28)
RAL + MVC or ETR (n = 20) RAL + PI (n = 19)
HIV-1 RNA < 50 c/mL, %
300
Mean CD4+ Cell Count
Increase (cells/mm3)
100
80
200
60
40
100
20
0
BL 4 12 24 36 48 0
Wks Regimen
Nozza S, et al. Glasgow 2008. Abstract P45. Reproduced with permission.
25. BRAVO: Efficacy of RAL Without a PI?
Retrospective cohort (chart review) 100
of RAL with or without PI
RAL + Pl (n = 332)
HIV-1 RNA < 75 copies/mL (%)
– PI cohort: 87% DRV, 36% ETR,
10% ENF (mean prior ARV: 4.1) 80 No Pl (n = 110)
– No PI cohort: 66% ETR, 17% ENF,
13% MVC (mean prior ARV: 3.8; P < .01
vs PI cohort) 60
– Most pts received NRTI TDF + FTC
GSS (similar between groups) a 40
significant predictor of Wk 12 response
(P = .04)
20
– Treatment group (PI vs non-PI) and
number of ARVs not predictive of
virologic success
0
Additional follow-up needed to evaluate Baseline Wk 4 Wk 12 Wk 24
RAL without PI n = 442 336 373 195
Skiest D, et al. IAS 2009. Abstract MOPE072. Reproduced with permission.
26. Summary: Potential Uses of Integrase
Inhibitors in Clinical Practice
Treatment naive
Switch
Treatment experienced
– First failure
– After multiple failures
28. Impact of NNRTI and NRTI
resistance on the response to the
regimen of Etravirine plus two
NRTIs in study Etravirine-C227
29. Etravirine-C227: study design
•48 weeks
• Primary analysis 24 weeks
•Active control: 1 PI + 2 NRTIs n=57
•Screening
•Etravirine 800mg bid + 2 NRTIs n=59
PI naïve
NNRTI experienced, screening viral load >1,000 copies/mL
– ≥1 NNRTI resistance-associated mutation (historical or at screening)
Active control group: investigator-selected PI
– 95% used boosted PI (61% LPV/r, 32% ATV/r)
Both control and Etravirine groups: two investigator-selected NRTIs based
on screening Virco®TYPE HIV-1 or treatment history
Etravirine arm discontinued after DSMB review
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
30. Region and country
Region All patients •Clade
Country, n (%) (n=116)
•AE
Asia and South Africa 66 (56.9)
South Africa 48 (41.4) •B
Thailand 18 (15.5)
Europe 13 (11.2)
Russia 5 (4.3)
•C
Spain 6 (5.2)
UK 2 (1.7)
Latin America 37 (31.9)
Argentina 8 (6.9)
•AE 13.8% •A1 2.6%
Brazil 27 (23.3)
•BF 2.6% •C 42.2%
Mexico 2 (1.7)
•F1 2.6% •B 36.2%
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
31. Etravirine-C227: baseline detectable
NRTI mutations •4 •5 •6 •7
•0 •1 •2 •3 A large number of NRTI
•100 •1.7 •1.8 resistance-associated
•IAS-USA NRTI resistance-associated mutations (%)
•6.8 •8.8 mutations were noted in
•90 •16.9 this first-line failure
•10.5
population
•80
•7.0
•70 •10.2 Many NRTIs were
•10.5
recycled in this study*
•60 •15.3
•38.6
– Etravirine group
•50
•28.8
– 37% recycled one,
•40
9% recycled two
•30
– control group
•20 •22.8
•20.3
– 35% recycled
•10 one, 12%
•0 recycled two
•Etravirine •Control •*Guided by resistance testing
•Group
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
32. Etravirine-C227: baseline detectable
NNRTI mutations
•0* •1 •2 •3 •4
•100 A large number of NNRTI
•5.1 •5.3
mutations* were noted in
•23.7
•Tibotec NNRTI resistance-associated
•90 •22.8
this first-line failure
population
•80
Median fold change to:
•70 •40.7 •43.9
EFV 129.8
mutations (%)
•60
NVP 88.0
•50
Etravirine 2.0
•40 •Tibotec list of NNRTI mutations
•A98G - L100I - K101E/P/Q
•30 •K103H/N/S/T
•23.7 •19.3 •V106A/M - V108I - E138G/K/Q
•20 •V179D/E/F/G/I - Y181C/I/V
•Y188C/H/L - G190A/C/E/Q/S
•10
•P225H - F227C/L - M230I/L - P236L
•6.8 •8.8
•K238N/T - Y318F
•0
•Etravirine •Control
group
•*All patients had NNRTI mutations at screening or from prior genotyping
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
33. Etravirine-C227: change in viral load
(observed)
•0 •Initial 1.3 log decline in viral load was not sustained
past 8 weeks, possibly affected by limited activity of
the BR
•Change in log viral load (mean)
•Etravirine
•Control
•−1
•−2
•−3
•0 •4 •8 •12 •16
•Weeks
•n (Etravirine)= •59 •59 •56 •46 •36 •2
• n (control)=
•57 •57 •55 •49 •33 9
•29
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
34. Etravirine arm (C227): median viral load change at week
12, by baseline Etravirine fold change and number of
TAMs + M184V
•Median change in viral load at week 12
•0
•4 •3 •Number of
•5 TAMs +
•−0.5 M184V
•−1 •2
•−1.5
•1
•−2
•0
•−2.5
•1 •10 •100
•Etravirine fold change
Use of recycled NRTIs in Etravirine group: 37% recycled one, 9%
two
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
35. C227 educational messages
While demonstrating a substantial decrease in viral load, use of Etravirine was associated with a lower
virological response versus the control PI group
– this is most likely due to high NRTI resistance and NRTI recycling
– C227 study included a large proportion of patients from resource-limited settings. Baseline NRTI
and NNRTI resistance was higher than is usual in countries where monitoring of viral load is
standard of care and virological failure is determined early
– patients were PI-naïve, therefore, the PI group was not as affected by the compromised
backbone and the pre-existing NNRTI resistance
Etravirine had a better tolerability profile than control PI treatment
– compared with the PI regimen, Etravirine was better tolerated for gastrointestinal, lipid and liver-
related events
– rash was higher in the Etravirine group, but this was generally mild and not associated
with discontinuation
In contrast to the results of C227, the results of the large Phase III DUET trials showed that Etravirine
provides substantial virological and immunological benefits in patients with NNRTI- and PI-resistant
virus
The results of the C227 study demonstrate
36. Etravirine-C227: conclusions
The level of both NRTI and NNRTI resistance was higher than what
might have been expected from a first-line failure population
– many patients recycled previously used NRTIs, which was guided
by resistance testing
Increasing numbers of TAMs and M184V were associated with
increased NNRTI resistance
The combination of high-level NRTI and NNRTI resistance adversely
impacted the Etravirine arm
– less likely to have affected the PI arm in this PI-naïve population
Consistent with treatment guidelines, patients failing a first-generation
NNRTI should immediately switch their regimen to avoid the
accumulation of resistance-associated mutations and maximise future
treatment options
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
37. DUET study design
and major inclusion criteria
•Screening •48-week treatment period •Follow-up
•6 weeks with optional 48-week extension •4 weeks
•24-week primary analysis
•Etravirine + BR*
•600 patients
target per trial
•Placebo + BR*
•*All patients received a BR
of DRV/r with optimised NRTIs and optional ENF
DUET-1 and DUET-2 differed only in geographical location; pooled analysis was pre-specified
Major inclusion criteria
– plasma VL >5,000 copies/mL and stable therapy for ≥8 weeks
– ≥1 NNRTI mutations,‡ at screening or in documented historical genotype
– ≥3 primary PI mutations at screening
Patients recruited from Thailand, Australia, Europe and the Americas
‡
From extended list of NNRTI mutations (Tambuyzer L et al. EHDRW 2007. Abstract 67)
•Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48
38. DUET trials: dosing
DRV/r dosed at 600/100mg bid
– 300mg tablets of DRV (i.e. two tablets bid)
Etravirine dosed at 200mg bid
– 100mg tablets (i.e. two tablets bid of Phase III formulation)
Etravirine matching placebo: two tablets bid
Both drugs were to be taken twice daily following a meal
– less restrictive food requirements than Phase II trials
•Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48
39. Week 96: patients with VL
<50 copies/mL (ITT-TLOVR)
•100 •Etravirine + BR
•90 •Placebo + BR
<50 copies/mL at Week 96 (%)
•80
•Patients with VL
•70 •60%
•60 •57%
•50
•39%
•40
•36%
•30
•20
•p<0.0001*
•10
•0
• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72 84 96
•Time (weeks)
57% of patients in the Etravirine + BR group achieved confirmed undetectable VL (<50 copies/mL
TLOVR) compared with 36% in the placebo group
This represents only a 3% drop from Week 48 for patients in each group
•*Logistic regression model controlling for baseline VL, ENF use and study number
•Trottier B et al. CAHR 2009. Abstract P148
41. Week 96: response (VL <50 copies/mL TLOVR)
by PSS*
•10
0 •Etravirine + BR (n=497) •Placebo + BR (n=477)
•90 •p<0.0001
<50 copies/mL at Week 96 (%)
•80 •76%
•p<0.0001
•70
•Patients with VL
•61% •59%
•60 •p<0.0001
•50 •46%
•40
•29%
•30
•20
•10 •6%
•39/84 •5/81 •117/191 •52/181 •168/222 •126/215
•0
•0 •1 •≥2
•Number of active background ARVs (PSS)
Patients in the Etravirine + BR group achieved consistently higher response rates than
patients in the placebo + BR group, irrespective of number of active background agents; the
difference was most apparent in patients with no active background agents
•*DRV considered sensitive if FC ≤10; ENF counted as sensitive if used de novo; Etravirine not
included in the PSS calculation; analysis excludes patients who discontinued except for VF
•Trottier B et al. CAHR 2009. Abstract P148
42. •Predicting response to Etravirine: weighted scores for each
individual RAM combined to produce a total weighted score
•Weight for individual
Etravirine RAMs •Total weighted score
Vingerhoets J et al. IHDRW 2008. Abstract 24