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Transcript of New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD,...
Winai Ratanasuwan, MD, MPH
Dept. Preventive and Social Medicine
Faculty of Medicine, Siriraj Hospital
New Antiretroviral Drugs: what we have and how to use ?
The Current Role of Integrase Inhibitors in Clinical Practice
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
Clinical Role of Integrase Inhibitors in Treatment-Naive
Patients
DHHS 2009: Recommended Regimens for Treatment-Naive PatientsDHHS Guidelines “Preferred”
Regimens, Decemember 2009[1]
NNRTI-based regimen EFV*
+ TDF/FTCPI-based regimen ATV/RTV QD
DRV/RTV QDRAL
1. DHHS guidelines. Available at: http://aidsinfo.nih.gov. .
Potential Uses of Integrase Inhibitors: Treatment-Naive Patients
Advantages
Novel mechanism of action
Efficacy data to 144 wks
Rapid HIV-1 RNA decay
Lack of transmitted drug resistance
Excellent safety and tolerability
Limited lipid effects
Limited drug interactions
Disadvantages
Twice-daily dosing
Cost
Some drug-drug interactions (varies by drug)
Fewer data than other agents
Low barrier to resistance
Lack of coformulation
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 EFV1. Gotuzzo E, et al. IAS 2009. Abstract MOPEB030. 2. Lennox J, et al. Lancet. 2009;[Epub ahead of print].
D:A:D: Recent and/or Cumulative PI/NNRTI Use and Risk of MI
Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.
*Approximate test for heterogeneity: P = .02
# PYFU: 68,469 56,529 37,136 44,657
61,855 58,946
# MI:
298
197
150
221 228 221
IDV NFV LPV/RTV SQV NVP EFV
PI* NNRTI1.2
1.13
1.00
1.10
0.90
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.
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.
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.
Other First-line Considerations
Standard regimens
–
NNRTI + NRTIs
–
Boosted PI + NRTIs
Novel class-sparing regimens
–
ATV + RAL
–
LPV/RTV + RAL
–
DRV/RTV + RAL
–
MVC + RAL?
–
RIL + RAL?
Clinical Role of Integrase Inhibitors as Switch Strategy in
Virologically Suppressed Patients
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?
Potential Uses of Integrase Inhibitors: Simplify or Reduce Toxicity
Disadvantages
Must be used with adequate support from other regimen components
Low barrier to resistance
Twice-daily dosing
Cost
Some drug interactions
Fewer data than other agents
Lack of coformulation
Advantages
Novel mechanism of action
Potent antiretroviral activity
Excellent safety and tolerability
Limited lipid effects
Limited drug interactions
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
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.
Clinical Role of Integrase Inhibitors in Treatment-
Experienced Patients
Potential Uses of Integrase Inhibitors: First Failure
Disadvantages
No data specific to first failures
What to combine (is a boosted PI required?)
Twice-daily dosing
Cost
Low barrier to resistance
Lack of coformulation
Advantages
Novel mechanism of action
Expectation that activity would be excellent
Excellent safety and tolerability
Limited lipid effects
Limited drug interactions
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
Potential Uses of Integrase Inhibitors: Multiple Failures
Advantages
Novel mechanism of action
Well-established data
Excellent safety and tolerability
Limited lipid effects
Limited drug interactions
Disadvantages
Must be used with other active agents
Does a boosted PI always need to be included?
Low barrier to resistance
Cross resistance between RAL and ELV
Focus on Number of Active Agents
DHHS ARV guidelines: ≥ 2, preferably 3, fully active agents in new regimenHighest 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 agents1. 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.
BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL by New Agents in OBR, Wk 48
0
65
166
68
112
158
20 40 60 80 100
+
+
-
n Patients (%)
92
Enfuvirtide
166- 92
Darunavir
+
-
-
+
Cooper DA, et al. N Engl J Med. 2008;359:355-365.
8968
4769
60
5780
20
RAL + MVC + ETR in Triple Class– Experienced Patients
Nonrandomized cohort study
0
100
200
300
Mea
n C
D4+
Cel
l Cou
nt
Incr
ease
(cel
ls/m
m3 )
Nozza S, et al. Glasgow 2008. Abstract P45. Reproduced with permission.
RAL + MVC + ETR (n = 28)RAL + MVC or ETR (n = 20)
RAL + MVC or ETR + PI (n = 28)RAL + PI (n = 19)
020406080
100
BL 4 12 24 36 48Wks
HIV
-1 R
NA
< 5
0 c/
mL,
%
Regimen
BRAVO: Efficacy of RAL Without a PI?Retrospective cohort (chart review) of RAL with or without PI
–
PI cohort: 87% DRV, 36% ETR, 10% ENF (mean prior ARV: 4.1)
–
No PI cohort: 66% ETR, 17% ENF, 13% MVC (mean prior ARV: 3.8; P < .01 vs PI cohort)
–
Most pts received NRTI TDF + FTC
GSS (similar between groups) a significant predictor of Wk 12 response (P = .04)
–
Treatment group (PI vs non-PI) and number of ARVs not predictive of virologic success
Additional follow-up needed to evaluate RAL without PI n = 442 336 373 195
HIV
-1 R
NA
< 7
5 co
pies
/mL
(%)
Baseline Wk 4 Wk 12 Wk 240
20
40
60
80RAL + Pl (n = 332)No Pl (n = 110)
Skiest D, et al. IAS 2009. Abstract MOPE072. Reproduced with permission.
100
Summary: Potential Uses of Integrase Inhibitors in Clinical Practice
Treatment naive
Switch
Treatment experienced
–
First failure
–
After multiple failures
Etravirine possible use
Impact of NNRTI and NRTI resistance on the response to the regimen of Etravirine plus two NRTIs in study Etravirine-C227
Etravirine-C227: study design
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
•Screening•Active control: 1 PI + 2 NRTIs n=57
•Etravirine 800mg bid + 2 NRTIs n=59
•48 weeks• Primary analysis 24 weeks
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Region and country
RegionCountry, n (%)
All patients(n=116)
Asia and South AfricaSouth AfricaThailand
66 (56.9)48 (41.4)18 (15.5)
EuropeRussiaSpainUK
13 (11.2)5 (4.3)6 (5.2)2 (1.7)
Latin AmericaArgentinaBrazilMexico
37 (31.9)8 (6.9)
27 (23.3)2 (1.7)
•AE 13.8% •A1 2.6%•BF 2.6% •C 42.2%•F1 2.6% •B 36.2%
•Clade
•B
•AE
•C
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine-C227: baseline detectable NRTI mutations A large number of NRTI
resistance-associated mutations were noted in this first-line failure population
Many NRTIs were recycled in this study*
–
Etravirine group
–
37% recycled one, 9% recycled two
–
control group
–
35% recycled one, 12% recycled two
•IAS-
USA
NR
TI re
sist
ance
-ass
ocia
ted
mut
atio
ns (%
)
•90
•80
•70
•60
•50
•40
•30
•20
•10
•0•Etravirine •Control
•100•0 •1 •2 •3 •4 •5 •6 •7
•Group
•16.9
•10.2
•15.3
•20.3
•28.8
•8.8
•10.5
•22.8
•38.6
•10.5
•6.8•1.7
•7.0
•1.8
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
•*Guided by resistance testing
Etravirine-C227: baseline detectable NNRTI mutations
Median fold change to:
EFV
129.8
NVP
88.0
Etravirine
2.0•Tibotec list of NNRTI mutations
•A98G -
L100I -
K101E/P/Q •K103H/N/S/T
•V106A/M -
V108I -
E138G/K/Q •V179D/E/F/G/I -
Y181C/I/V•Y188C/H/L -
G190A/C/E/Q/S•P225H -
F227C/L -
M230I/L -
P236L •K238N/T -
Y318F
•*All patients had NNRTI mutations at screening or from prior genotyping
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
•Tib
otec
NN
RTI
resi
stan
ce-a
ssoc
iate
dm
utat
ions
(%)
•100
•90
•80
•70
•60
•50
•40
•30
•20
•10
•0
•23.7
•40.7
•23.7
•19.3
•43.9
•22.8
•Etravirine •Control group
•0* •1 •2 •3 •4
•8.8•6.8
•5.3•5.1 A large number of NNRTI mutations* were noted in this first-line failure population
Etravirine-C227: change in viral load (observed)
•Etravirine•Control
•0
•−1
•−2
•−3
•Cha
nge
in lo
g vi
ral l
oad
(mea
n)
•Weeks
•0
•4 •8 •12 •16
•59 •56 •46 •36 •2 9
•59•n (Etravirine)=•57 •55 •49 •33 •29•57• n (control)=
•Initial 1.3 log decline in viral load was not sustained past 8 weeks, possibly affected by limited activity of the BR
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
Etravirine arm (C227): median viral load change at week 12, by baseline Etravirine fold change and number of TAMs + M184V
Use of recycled NRTIs in Etravirine group: 37% recycled one, 9% two
•Number of TAMs + M184V
•−2.5
•−2
•−1.5
•−1
•−0.5
•0
•1 •10 •100•Etravirine fold change
•Med
ian
chan
ge in
vira
l loa
d at
wee
k 12
•0
•2
•4 •3•5
•1
Woodfall B, et al. HIV8, 2006. Abstract PL5.6
C227 educational messagesWhile 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
–
the
need
to
switch
patients
who
experience
virological
failure,
to
minimise
the
accumulation
of
Etravirine-C227: conclusionsThe level of both NRTI and NNRTI resistance was higher than whatmight 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
•Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48
•24-week primary analysis
DUET study design and major inclusion criteria
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
•Screening
•6 weeks
•600 patients target per trial
•48-week treatment period with optional 48-week extension
•*All patients received a BR
of DRV/r with optimised NRTIs and optional ENF
•Etravirine + BR*
•Placebo + BR*
•Follow-up
•4 weeks
‡From extended list of NNRTI mutations (Tambuyzer L et al. EHDRW 2007. Abstract 67)
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
Week 96: patients with VL <50 copies/mL (ITT-TLOVR)
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
•36%
•57%
•p<0.0001*
•60%
•39%
•100
• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72
84 96•Time (weeks)
•Pat
ient
s w
ith V
L <5
0 co
pies
/mL
at W
eek
96 (%
) •90
•80
•70
•60
•50
•40
•30
•20
•10
•0
•Etravirine + BR •Placebo + BR•Etravirine + BR •Placebo + BR
Week 96: change in CD4 cell count from baseline (ITT; imputed)
•*Analysis of covariance model;
•Trottier B et al. CAHR 2009. Abstract P148
•+86
•+128•+98
•+73
•Cha
nge
in C
D4
cell
coun
t (m
ean
±SE
), (c
ells
/mm
3 )
•250
•p<0.0001*
• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72
84 96
•Time (weeks)
•225•200•175•150•125•100•75•50•25
•0•–25
•Etravirine + BR •Placebo + BR
Week 96: response (VL <50 copies/mL TLOVR) by PSS*
•*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
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
•Pat
ient
s w
ith V
L <5
0 co
pies
/mL
at W
eek
96 (%
)•Placebo + BR (n=477)•Etravirine + BR (n=497)
•Number of active background ARVs (PSS)•0 •1 •≥2
•46%
•6%
•61%
•29%
•76%
•59%
•39/84 •5/81 •117/191 •52/181 •168/222 •126/215
•p<0.0001
•p<0.0001
•p<0.0001
•10
0
•90
•80
•70
•60
•50
•40
•30
•20
•10
•0
•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