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Approccio terapeutico nel paziente pre-trattato
Ivano Mezzaroma
Dipartimento di Medicina Clinica
UOC Immunologia Clinica
Università di Roma “La Sapienza”
Roma, 24 marzo 2006
Reasons for Failure of Initial HAART
Inability to take regimen (or nonadherence) is one primary reason for failure of initial therapy
Other causes have become more rare in current practice
– Inadequate potency
– Interindividual pharmacologic variability → inadequate levels in some patients)
– Drug-drug interactions now very rare causes
14%
20%
8%
58%
Toxicity
Failure
Nonadherence
Other
n = 25
n = 61
n = 44
n = 182
ICoNA Study: Reasons for Failure of Initial HAART
d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.
Reasons for Failure: Toxicity
Adverse effects are most common reason for discontinuation
Develop a plan to help patients deal with side effects
– “Minor” common side effects may be as important to the patient as major grade 3/4 events
– Nausea, vomiting, abdominal discomfort or cramping, and diarrhea are common reasons why patients stop their medications
– Most patients are asymptomatic when treatment is started
– Development of even minor symptoms can therefore be distressing
Remind patients not to “self-diagnose” by stopping one of their medications
Adherence
A major determinant of degree and duration of viral suppression
Poor adherence associated with virologic failure
Optimal suppression requires 90-95% adherence
Suboptimal adherence is common
Predictors of Inadequate Adherence
Regimen complexity and pill burden
Poor clinician-patient relationship
Active drug use or alcoholism
Unstable housing
Mental illness (especially depression)
Lack of patient education
Medication adverse effects
Fear of medication adverse effects
Predictors of Good Adherence
Emotional and practical supports
Convenience of regimen
Understanding of the importance of adherence
Belief in efficacy of medications
Feeling comfortable taking medications in front of others
Keeping clinic appointments
Severity of symptoms or illness
Improving Adherence
Establish readiness to start therapy
Provide education on medication dosing
Review potential side effects
Anticipate and treat side effects
Utilize educational aids including pictures, pillboxes, and calendars
Improving Adherence
Simplify regimens, dosing, and food requirements
Engage family, friends
Utilize team approach with nurses, pharmacists, and peer counselors
Provide accessible, trusting health care team
Claxton et al., Clin Ther .2001;23:1296–1310.
Mea
n d
ose
-tak
ing
ad
her
ence
(%
)
Studies of electronic monitoring of adherence
71
0
20
40
80
100
Overall
79
QD
69
BID
65
TID
51
QID
59
Overall
74
QD
58
BID
46
TID
40
QID
Dose-timing adherence ratesDose-taking adherence rates
P values not calculated
60
P = .008
P < .001
P = .001
Adherence is Inversely Related to the Number of Doses Per Day
Dose-taking adherence: appropriate number of doses taken during the day (optimal adherence variously defined as 70%, 80%, 90%)
Dose-timing adherence: doses taken at appropriate time intervals, within 25% of the dosing interval (e.g. BID should be taken 12 3 hours apart)
Patients Prefer QD Regimensto BID Regimens
Bass D, et al. XIV IAC, July 7-12, Barcelona, 2002, Abstract MoPe3290.
% o
f P
atie
nts
ev
er f
org
ett
ing
to
tak
e H
IV m
edic
atio
n
80
40
20
10
60
70
50
30
4 pills QD 1 morning, 1 evening
1 morning, 4 evening
68%
24%
5%0
Pat
ient
s (%
)
Changing Therapy:Considerations
Clinical status
HIV RNA level on 2 tests
CD4+ T cell count
Remaining treatment options
Potential viral resistance
Medication adherence
Patient education
Changing Therapy: Treatment Regimen Failure
Virologic failure:
– Incomplete virologic response: HIV RNA >400 copies/mL after 24 wks, >50 after 48 wks
– Virologic rebound: repeated detection of HIV RNA after viral suppression
Immunologic failure:
– CD4 increase of <25-50 cells/µL in first year of therapy
– CD4 decrease below baseline, on therapy
Clinical failure:
– occurrence of HIV-related events (after >3 months on therapy; excludes immune reconstitution syndromes)
Treatment Regimen Failure: Assessment
Review antiretroviral history
Physical exam for signs of clinical progression
Assess adherence, tolerability, pharmacokinetic issues
Resistance testing (while patient is on therapy)
Identify treatment options
Treatment Regimen Failure: Assessment
Possible causes:
– Suboptimal adherence
– Medication intolerance
– Pharmacokinetic issues
– Suboptimal drug potency
– Viral resistance
Approach depends on cause of regimen failure and remaining antiretroviral options
Treatment Regimen Failure: Assessment
Therapeutic options:
– Clarify goals: If extensive resistance, viral suppression may not be possible, but aim to reestablish maximal virologic suppression
– Remaining ARV options
– Base treatment choices on expected efficacy, tolerability, adherence, future treatment options, past medication history, and resistance testing
Virologic Failure: Changing an ARV Regimen (1)
General principles:
Prefer at least 2 fully active agents to design a new regimen
– Determined by ARV history and resistance testing
If 2 active agents are not available, consider ritonavir-boosted PI plus optimized ARV background, and/or reusing prior ARVs to provide partial activity
Consider potent ritonavir-boosted PI and a drug with a new mechanism of action (e.g., entry inhibitor) plus an optimized ARV background: may have significant activity
Virologic Failure: Changing an ARV Regimen (2)
General principles (2):
In general, 1 active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. In some patients with advanced HIV and few treatment options, this may be considered to reduce the risk of immediate clinical progression.
Consult with experts
Treatment-Experienced Patients: Goals of Therapy
Limited prior treatment:
– Maximum viral suppression
– Consider early change to prevent further resistance mutations
Extensive prior treatment:
– Preservation of immune function
– Prevention of clinical progression
– Balance benefits of partial viral suppression with risk of additional resistance mutations
Changing Therapy: Treatment Options
Limited prior treatment with low HIV RNA:
– Intensification (e.g., tenofovir)
– Pharmacokinetic (PK) enhancement
– Change to new regimen
Changing Therapy: Treatment Options
Limited prior treatment with single drug resistance:
– Change 1 drug
– PK enhancement
– Change to new regimen
Changing Therapy: Treatment Options
Limited prior treatment with >1 drug resistance:
– Change drug classes and/or add new active drugs
Changing Therapy: Treatment Options
Prior treatment with no resistance identified:
– Consider nonadherence or possibility that patient was off medications at time of resistance test
– Consider resuming same regimen or starting new regimen and repeat resistance testing early (2-4 wks)
Changing Therapy: Treatment Options
Extensive prior treatment with resistance:
– Avoid adding single active drug
– Seek expert advice
– If few or no treatment options, consider continuing same regimen. Other possible strategies:
– PK enhancement
– Therapeutic drug monitoring
– Retreatment with prior medications
– Multidrug regimens (limited by complexity, tolerability)
– New ARV drugs, e.g., enfuvirtide, investigational drugs
– Treatment interruptions not recommended
Current Guidelines for Resistance Testing
1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. March 23, 2004.2. Hirsch MS, et al. Clin Infect Dis. 2003;37:113-128. 3. Miller V, et al. AIDS. 2001;15:309-320.
DHHS[1] IAS-USA[2] EuroGuidelines [3]
Primary Infection Recommend Recommend Recommend
PEP (Source Pt) — — Recommend
Chronic (< 2 years) Consider RecommendRecommend/
Consider
Treatment Failure Recommend Recommend Recommend
Pregnancy — Recommend * Recommend *
Pediatric — — Recommend **
* Only if mother is viremic** Only if mother was viremic and on treatment at time of birth
Testing for Drug Resistance
Recommended in case of virologic failure, to determine role of resistance and maximize the number of active drugs in a new regimen
Combine with obtaining a drug history and maximizing drug adherence
Research supports use in certain settings
Perform while patient is taking ART (or within 4 weeks of regimen discontinuation)
Drug Resistance Testing: Limitations
Lack of uniform quality assurance
Relatively high cost
Insensitivity for minor viral species (<10-20%)
Interruption of Antiretroviral Therapy
Intolerable side effects
Drug interactions
First trimester pregnancy
Poor adherence
Unavailability of drugs
Many other possible causes
Interruption of Antiretroviral Therapy: Planned
Structured (supervised) treatment interruption (STI)
Insufficient data to recommend STI; research ongoing
Possible risks: decline in CD4 count, disease progression, increase in HIV transmission, development of resistance
Possible benefits: reduction in drug toxicities, preservation of future treatment options
Interruption of Antiretroviral Therapy: Planned
Several scenarios:
Patients who started ART during acute HIV infection
– Optimal duration of treatment is unknown; studies ongoing
Women who started ART during pregnancy to decrease risk of mother-to-child transmission
– If pretreatment CD4 is above currently recommended ART starting levels and patient wishes to stop therapy after delivery
Interruption of Antiretroviral Therapy: Planned
Patients with chronic infection with viral suppression and CD4 above levels recommended for starting therapy:
– Started ART with CD4 above currently recommended starting levels
– Started ART at lower CD4 but now with stable CD4 above recommended starting levels
– Small short-term prospective clinical trials suggest safety; long-term studies ongoing
– CD4 decline after treatment interruption is related to pretreatment CD4 nadir
Interruption of Antiretroviral Therapy: Planned
Patients with treatment failure, extensive ARV resistance, and few available treatment options
– Partial virologic suppression from ART has clinical benefit
– Not recommended outside clinical trial setting
Interruption of Antiretroviral Therapy
Stop all antiretroviral medications at once
– efavirenz and nevirapine have long half-lives; consider stopping these before other agents
In patients with hepatitis B who are treated with emtricitabine, lamivudine, or tenofovir, discontinuation of these may cause hepatitis exacerbation
Monitor closely
Goals of Therapy With MDR HIV
Patients with access to ≥ 2 active agents
– Complete viral suppression
Patients with access to < 2 active agents
– Reduce viral load by 1 log10 copies/mL
– Stabilize CD4+ cell counts
– Minimize drug toxicity
– Minimize mortality
– Minimize accumulation of additional mutations that could cause resistance to drugs in development
Saquinavir/Ritonavir
MaxCmin studies – Large, multinational, randomized trials comparing boosted SQV with other boosted PIs in drug-naive
and drug-experienced patients also receiving ≥ 2 NRTIs and/or NNRTIs
MaxCmin 1: IDV/RTV 800/100 mg BID vs SQV/RTV 1000/100 mg BID[1]
– Similar rate of virologic failure between treatments at Week 48 (27% vs 25%)
– Adverse events more frequent in IDV/RTV arm
– When switching from randomized treatment because of toxicity considered as failure, SQV/RTV superior (49% vs 34%, P = .009)
MaxCmin 2: LPV/RTV 400/100 mg BID vs SQV/RTV 1000/100 mg BID[2]
– Found LPV/RTV superior at Week 48
– Risk of virologic failure and treatment discontinuation greater in SQV/RTV arm
1. Dragsted UB, et al. J Infect Dis. 2003;188:635-642.
2. Youle M, et al. IAS; 2003. Abstract LB23.
< 400 copies/mL < 50 copies/mL
LPV/RTVTwice Daily
61
50
FPV/RTV Twice Daily
58
46
FPV/RTV Once Daily
50
37
010203040506070
Vir
al S
up
pre
ssio
n (
%)
Intent-to-treat, missing equals failure analysis
CONTEXT: FPV/RTV vs LPV/RTV in PI-Experienced Patients
Greater number of virologic failures in FPV/RTV arms compared with LPV/RTV arm
Once-daily arm underperformed compared with twice-daily arms
Twice-daily FPV/RTV failed to meet protocol-defined threshold for noninferiority to LPV/RTV
Elston RC, et al. IAC; 2004. Abstract MoOrB1055.
Lopinavir/Ritonavir
LPV/RTV vs NFV, plus d4T/3TC, in treatment-naive patients[1]
– 67% vs 52% of patients had viral load < 50 copies/mL at Week 48 (P < .001)
– In patients with viral load > 400 copies/mL, frequency of emergent PI-associated mutations significantly lower with boosted PI
– Supports theory that boosted PIs offer greater genetic barrier to emergent resistance than unboosted PIs
BMS 043: LPV/RTV vs ATV, plus NRTIs, in PI-experienced patients[2]
– LPV/RTV showed -0.3 log10 copies/mL greater reduction in viral load than unboosted ATV at Week 24 (P = .0032)
1. Walmsley S, et al. N Engl J Med. 2002;346:2039-2046.
2. Nieto-Cisneros L, et al. Antivir Ther. 2003;8(suppl1):S212. Abstract 117.
In Combination Therapy, Only The Active Drugs Count Early “HAART” in NRTI-experienced patients often
amounted to “serial monotherapy”
– New drugs (eg, PIs) added to a failing NRTI-based regimen
– Less sustained responses with only 1 active drug
TORO results demonstrated applicability of this principle to the use of enfuvirtide (ENF)
Several recent studies demonstrate that in triple-class-experienced patients, combining ENF + an active boosted PI improves response rate
TORO: Virologic Response to Enfuvirtide + OB Regimen
Arastéh K, et al. IAC 2004. Abstract MoOrB1058.
Pat
ien
ts W
ith
HIV
-1 R
NA
<
400
Co
pie
s/m
L (
%)
Study Week
0 16 32 48 64 80 96
34%
13%
0
10
20
30
40
50
60
70
80
90
100
26%
ITT: DC or SW = F (n = 661) (n = 334)
ENF + OBOB
TORO: Importance of Combining ENF With an Active Boosted PI
Miralles GD, et al. IDSA 2004. Abstract 921.
2%
LPV/r Naive
No LPV/r LPV/rNo LPV/r LPV/r
LPV/r Experienced
ENF +OB(n = 661)
OB(n = 334)
18% 18%
38%
55%
4%10%
24%
0
20
40
60
80
100
*P < .05
n = 158 57 171 77 93 58 239 42 Pat
ien
ts W
ith
HIV
-1 R
NA
< 4
00
Co
pie
s/m
L a
t W
eek
48 (
%)
* *
**
TORO: Impact of Number of Active Agents on Response
Henry K, et al. IAS 2002. Abstract LbOr19B.
ENF + OB
0 1-2 3-4 5
-2.0
-1.0
0
-3.0
OB
Mea
n C
han
ge
in H
IV-1
RN
A a
t W
eek
24 (
ITT
) (l
og
10 c
op
ies/
mL
)
Number of Active Antiretrovirals in OB Regimen(Genotypic Sensitivity Score)
RESIST-1: Response to TPV/r vs CPI/r
Hicks C, et al. ICAAC 2004. Abstract 1137a.
Pat
ien
ts W
ith
HIV
- 1
RN
A <
400
co
pie
s/m
L(%
)
0
100
40
60
80
0 4 8 12 16 20 24
P < .001
16.5%
34.7%
20
TPV/r (n = 311)CPI/r (n = 309)
Week
ITT: NC=F
40
20
0
60
80
0 4 8 12 16 20 24
25.1%
10.0%
P < .001
100 TPV/r (n = 311)CPI/r (n = 309)
Week
ITT: NC=F
Pat
ien
ts W
ith
HIV
- 1
RN
A <
50
cop
ies/
mL
(%)
RESIST: Impact of Enfuvirtide on Virologic Response ENF use comparable in both
arms
– 27.1% TPV/r
– 22.2% CPI/r
ENF use improved treatment response in both arms
However, TPV/r superior to CPI/r with or without ENF
Deeks S, et al. IAS 2005. Abstract WeFo0201.
No ENF ENF
13.4
21.3
CPI/r
0
20
40
60
80
100
Pat
ien
ts W
ith
HIV
-1 R
NA
< 4
00
Co
pie
s/m
L a
t W
eek
24 (
%)
30.2
53.9
TPV/r
Relationship of TPV Score to TPV Phenotype Results and Response
Valdez H, et al. Resistance Workshop 2005. Abstract 27.
-2
-1
0
-3
Med
ian
Ch
ang
e in
VL
at
Wk
24*
(lo
g10
co
pie
s/m
L)
0-1 2-3 4-5 6-7 8-9
-2.10(n = 144)
-0.89(n = 242)
-0.45(n = 260)
-0.49(n = 68)
-0.08(n = 4)
TPV Score
Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5
*24-week data from patients in RESIST-1 and -2 given TPV/r
POWER 1: Virologic Response to TMC114/r
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
0
80
60
20
40
100
Time (weeks)
Pat
ien
ts w
ith
HIV
-1 R
NA
< 5
0 co
pie
s/m
L (
%)
1 2 4 8 12 16 20 24
TMC114/r 400 QD (n = 64)TMC114/r 800 QD (n = 63)TMC114/r 400 BID (n = 63)TMC114/r 600 BID (n = 65)Comparator PIs (n = 63)
P < .001 for all dosesvs control
43%48%49%53%
18%
POWER 1: Subgroup Analyses of Response to TMC114/r 600/100 BID
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
% with HIV-1 RNA < 50 at Week 24 (ITT NC=F)
63% (n = 19)22% (n = 18)
56% (n = 34)19% (n = 36)
59% (n = 29)9% (n = 35)
46% (n = 28)16% (n = 25)
17% (n = 12)0% (n = 9)
ENF Used (Naive)
ENF Not Used
3 Primary PI Mut
TMC114 FC > 4
No Sensitive ARV in OBR
0 20 40 60 80
TMC114/r 600/100 BIDControl
53% (n = 60)18% (n = 60)Overall
100
TMC125 in Treatment-Experienced Patients Open, phase 2a study
16 HIV-infected men– Failing efavirenz or nevirapine– Resistance to efavirenz– CD4+ cell count: 389 cells/mm3
– Viral load: 10,753 copies/mL
TMC125 900 mg BID + continue NRTIs for 7 days
After 7 days, median 0.9-log decrease in viral load
Days
Med
ian
Cha
nge
in H
IV-1
RN
A
(log 1
0co
pies
/mL)
2 4 6 8
* P < .001 vs baseline
- 0.89
- 0.64
- 0.35
*
*
*
*
-0.8
-0.6
-0.4
-0.2
0
-1.4
-1.2
-1.0
Gazzard BG, et al. AIDS. 2003;17:F49-F54.
CCR5 Inhibitors in Development
1. Lalezari J, et al. ICAAC 2004. Abstract H-1137b.2. Schurmann D, et al. CROI 2004. Abstract 140LB. 3. Pozniak AL, et al. ICAAC 2003. Abstract H-443.
Me
dia
n V
L C
ha
ng
e F
rom
B
L (
log
10 c
op
ies
/mL
)
-1.6
-1.2
-0.8
-0.4
5 10 15 20 25 30
0
0
Placebo200 QD
0.4
Day
200 BID 400 QD 600 BID
Dosing
Aplaviroc (GW873140)[1]
-1.5-1.5-1.0
-0.5
0
0.5
Days
300 mg BID
Placebo 15Placebo 0725 mg QD50 mg BID100 mg QD
100 mg BID150 mg Fast150 mg Fed300 mg QD
Maraviroc (UK-427857)[3]
Dosing
Me
dia
n V
L C
ha
ng
e F
rom
B
L (
log
10 c
op
ies
/mL
)
0 5 10 15 20 25 30 35 40-2.0
0.5
0.0
-0.5
-1.0
-1.5
0 5 10 15 20 25 30Days
Vicriviroc (SCH-417690)[2]
Me
dia
n V
L C
ha
ng
e F
rom
B
L (
log
10 c
op
ies
/mL
)
10 mg BIDPlacebo
25 mg BID50 mg BID
Dosing
Treatment Strategies in Experienced Patients: Role of NRTIs Evidence for partial activity of NRTIs even with key
resistance mutations present, eg, 3TC and d4T
M184V can confer improved phenotypic susceptibility to TDF and ZDV in viruses with TAMs and K65R
TDF and D-d4FC active against virus strains with TAMs
Both can select for K65R; ZDV shows hypersusceptibility
Strategic use of NRTI combinations possible
– TDF - FTC - ZDV
– TDF - ZDV - D-d4FC1. Walmsley S, et al. CROI 2005. Abstract 580. 2. Ruiz L, et al. CROI 2005. Abstract 679.
3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART
Castagna A, et al. IAS 2005. Abstract WeFo0204.
-300
4 12 24 36 48
Mea
n C
ha
ng
e in
HIV
-1
RN
A (
log
10 c
op
ies/
mL
) Weeks
Mea
n C
ha
ng
e in
CD
4+
Cel
l C
ou
nt
(cel
ls/m
m3)
Weeks
04 12 24 36 48
P = NS-250
-200
-150
-100
-50
0
Mean CD4+ Decrease (ITT)Mean VL Increase (ITT)
P = .0015
0.5
1.0
1.5
2.0 3TC TI
In contrast to treatment interruption arm, 3TC alone resulted in:– Smaller recovery in replication capacity– No further selection of resistance mutations
3TC TI
When To Use a New Drug, and When to Wait Is there at least 1 new class available, and if so, will it be
well “protected”?
What is the expected prognosis with continued nonsuppressive therapy?
– What are the resistance consequences of continued nonsuppressive therapy?
How can I maintain the “right” mutations without allowing the “wrong” ones to emerge?
When will new drugs be available, and will they be active against the patient’s virus?
Options If New Drugs Are Not Available Multidrug salvage therapy ("mega-HAART")
– Difficult due to problems with tolerability and interactions
Dual-boosted PI therapy
– SQV (1000 mg BID) + LPV/r (400/100 mg BID): encouraging responses at Week 48 (noncomparative studies)
– Can have intolerable GI effects; ↑ risk of lipid abnormalities
– Pharmacologic interactions not always predictable
Nonsuppressive regimens
– Risk of emergence of new resistance mutations
– Potentially less response when new drugs approved in same class
Options If New Drugs Are Not Available (cont) Switch to a “holding regimen”
– Maximal negative impact on viral fitness (ie, replication capacity)
– Minimal risk of added resistance
Monotherapy with 3TC or FTC
– Over 6 months, lower virologic rebound and less CD4+ loss
– M184V linked to other mutations, reduce emergence of WT virus
Treatment interruption (TI)– No clear evidence of improved response after TI
– Risk of rapid CD4+ cell decline and increased risk of OIs
– Potentially dangerous in advanced disease (CD4+ < 200)
Continued Therapy in Patients With Virologic Failure: A Delicate Balance
Maintain mutationsDecrease fitness
Delay progression
Accumulate new mutations
Develop resistance to drugs in development
Optimizing Adherence
Optimal adherence plays a pivotal role in sustaining efficacy of ART
Influenced greatly by patient motivation and knowledge but also by convenience and tolerability of treatment regimen
– Minimizing pill count and size, frequency of dosing, and dietary requirements important in supporting higher levels of adherence
– Reducing adverse effects of therapy vital to increased adherence
Most boosted PIs administered twice daily
– ATV dosed once daily, but reduced efficacy with extensive PI resistance
Less toxic, more convenient boosted PI regimens can improve adherence, but cannot replace ongoing patient education and adherence monitoring within clinic
Pharmacology of Boosted PIs High PI concentration can inhibit drug-resistant virus and increase genetic barrier
to wild-type virus
RTV boosting improves exposure, increases activity against resistant virus, improves durability in naive patients
– However, increased exposure may increase toxicities
RTV inhibits cytochrome P450 isoenzymes such as CYP 3A4
– In addition to boosting PIs, other drugs patient may be taking can be affected by this inhibition
– Other drugs that inhibit or induce CYP 3A4 may affect PI levels
EFV commonly used NNRTI that induces CYP3A4
– Use of EFV in patients receiving boosted PIs may cause drop in PI level and loss of activity if PI
dosage not increased appropriately
Pharmacology of Boosted PIs (con’t)
Boosted PIs should not be combined until clinical trials have determined potential for drug-drug interactions
Non-HIV medications also interact with boosted PIs
– Rifampin can greatly reduce PI levels
– Boosted PIs can dangerously increase concentration of sildenafil
Must caution patients taking boosted PIs about taking any new medications and address potential interactions accordingly
Therapeutic drug monitoring (TDM) remains somewhat controversial issue in routine management of ART-treated patients
– PI drug levels correlate with efficacy and toxicities, but ability to effectively improve patient care by measuring PI levels and adjusting dosage unproven
Improves exposure
Greater activity against resistant virus
Impact on adherence
Risk of increased toxicity
Manipulating Dosage of Boosted PIs With Ritonavir: A Delicate Balance
Boosted PIs and Drug Resistance PIs may select for unique resistance patterns, but multiple mutations
are associated with cross-resistance, reduced PI susceptibility
In PI-experienced patients, use whichever PI has most remaining activity at appropriately high exposure, utilizing RTV boosting
Optimizing other drugs in ARV regimen vital to success of boosted PI in treatment-experienced patients
Patients who have failed multiple prior regimens have usually acquired widespread NRTI and NNRTI resistance
– To benefit from a new boosted PI, it is crucial to add drug from a new class, such as fusion inhibitor, ENF
– Demonstrated in TORO, RESIST, and POWER studies
Appropriate Goals and Strategies for Highly Experienced Patients
Primary ART goal for all HIV patients: complete viral suppression
Even in patients with multiple prior failures, combination of boosted PI and ENF may reduce HIV-1 RNA to undetectable levels
When complete HIV-1 RNA suppression cannot be obtained, maintaining immunologic function, preventing clinical deterioration are goals of ART
Drug selection should be based on utility against resistant virus, tolerability in patient
Patients with widespread resistance to all but 1 drug class and intact immune function, clinical status may employ “holding” strategy
– Stop ARVs, or only drug classes where resistance already widespread, and monitor CD4+ cell counts, clinical status closely
– Save remaining drug class for later when new drugs to which patient’s virus remains sensitive may become available
Summary and Implications Boosted PIs key component of regimens for drug-
experienced patients
Data suggest LPV/RTV superior to SQV/RTV in drug-experienced patients
Due to poor pharmacologic characteristics, IDV/RTV seldom used
NFV not used as boosted PI due to poor augmentation by RTV
Summary and Implications (con’t) Virologic potency of FPV/RTV appears < LPV/RTV in
experienced patients
Efficacy of ATV/RTV appears comparable to LPV/RTV in experienced patients with limited PI resistance, but inferior with widespread resistance
TPV/RTV demonstrated virologically and immunologically superior to LPV/RTV, SQV/RTV, or APV/RTV in heavily pretreated patients
TMC114/RTV improves treatment outcomes in patients with extensive drug experience relative to comparator boosted PIs
– No comparative data on TMC114/RTV vs TPV/RTV
Summary and Implications (con’t)
Adherence crucial to success of ART
Manipulation of dosages should be carefully considered with boosted PIs
– Trade-offs between convenience, toxicity, and efficacy
Boosted PIs cleared from body predominantly through hepatic metabolism
– Clinical studies of specific drug combinations required to delineate drug-drug interactions
– Should not combine boosted PIs before potential drug-drug interactions determined
Summary and Implications (con’t)
PIs show reduction in susceptibility to viruses with multiple mutations
– Use PI likely to provide most remaining activity at appropriately high exposure, with RTV
Optimizing other drugs in regimen vital to success of boosted PI
– Crucial to add drug from new class whenever possible
Goal of therapy for HIV-infected patients: complete viral suppression
– If not possible, maintain immunologic function and prevent clinical deterioration
Drug-drug interactions may result in toxicity, treatment failure, or loss of effectiveness and can significantly affect a patient's clinical outcome.
An understanding of the fundamental mechanisms of HIV drug-drug interactions may allow for the early detection or avoidance of troublesome regimens and prudent management if they develop. Although HIV drug interactions are usually thought of as detrimental, resulting in a loss of therapeutic effect or toxicity, some drug interactions such as ritonavir boosted protease inhibitor-based antiretroviral treatments are beneficial and are commonly used in clinical practice.
Drug Enzyme Inhibition Enzyme Induction
Atazanavir ++ —
Delavirdine ++ —
Efavirenz + +++
Fosamprenavir + ++
Indinavir ++ —
Lopinavir/ritonavir[1] ++++ ++
Tipranavir/ritonavir[1] ++++ +++
Nelfinavir ++ +
Nevirapine — ++
Ritonavir ++++ ++
Saquinavir[2] — —
1. Assessment also reflects the effects of ritonavir.2. Saquinavir can inhibit P450 3A4 in vitro, but this is not generally manifested clinically.
Modified from: Flexner CW. http://clinicaloptions.com/2004PK
Enzyme Inhibition and Induction
Tenofovir Interactions
25% 26% Atazanavir
34% 15% Lopinavir/ritonavir
14% 29% Saquinavir/ritonavir
ND 25% ? Atazanavir/ritonavir
Indinavir
** Abacavir
Oral contracept., Methadone
Nelfinavir, Efavirenz
ND Ribavirin
d4T-XR
ND Adefovir
Emtricitabine
* 44-60%Didanosine**Lamivudine
TenofovirCoadministered drug
Impact of Coadministration on Exposure (AUC)
* Plasma levels
Issues with Didanosine + Tenofovir + Efavirenz
1. van Lunzen J, et al. IAS 2005. Abstract TuPp0306.2. Barrios A, et al. IAS 2005. Abstract WePe12.3C16.
TEDDI trial confirms previous reports of higher rate of virologic failure in patients receiving ddI + TDF + EFV [1]
– VF: 25% after 12 weeks of TDF + ddI + EFV
EFADITE study: stably suppressed pts who switched to TDF + ddI + EFV or continued current regimen [2]
– Viral suppression maintained in most patients
– However, CD4+ ↓ on TDF + ddI + EFV
– Median change in CD4+ at Yr 1, -25 vs +46 in controls (P = .007)
– Significantly larger CD4+ declines in pts on high vs low ddI doses
Small Reductions in Renal Function With Tenofovir vs Other NRTIs
Small but statistically significant ↓ in CLCr with TDF
Clinical significance unclear
Not grounds to exclude TDF for pts at risk for renal dysfunction (dose adjust in renal insufficiency)
Other studies
GFR detects more patients with mild renal impairment than serum creatinine[2]
– 10% of TDF pts w/ Gr 3+ GFR
MACS: TDF associated with lower GFR[3]
1. Gallant J, et al. CID 2005;40:1194-8. 2. Becker S, et al. CROI 2005. Abstract 819.3. Reisler R, et al. CROI 2005. Abstract 818.
Last CLCr on treatment carried forward if treatment stopped
Days
Normal range: 80-120 mL/min
* P < .05 change from baseline for TDF vs NRTI
* * *
0
20
40
60
80
100
120
0 90 180 270 360
CL
Cr
(mL
/min
)
TDF
NRTI
Low Rate of Renal Events in Tenofovir Clinical Dataset
Risk factors for serious renal adverse events included sepsis or serious infection, history of renal disease, late-stage HIV, concomitant nephrotoxic medications, and hypertension
Nelson M, et al. CROI 2006. Abstract 781.
Serious Renal Adverse Events in EAP and Postmarketing Databases
EventEAP
N = 10343/3700 PY
Postmarketing
455,392 PY
% Cases/100,000 PY
Reporting Rate/100,000 PY
Renal failure 0.3 865 24.2
Fanconi/tubular disorder/hypophosphatemia/glycosuria < 0.1 270 22.4
Elevated serum creatinine, BUN < 0.1 189 5.1
Retrospective analysis of TDF Expanded Access Program and postmarketing data after 4 years of TDF availability
Vari Autori sostengono la necessita’ di monitorare strettamente e per periodi lunghi la funzione renale nei pazienti in terapia con tenofovir e di valutare il rischio di interazioni con altri farmaci.
Nelle linee linee-guida per la gestione delle disfunzioni renali nei pazienti con HIV tenofovir viene citato tra i farmaci potenzialmente nefrotossici (“tenofovir-related nephrotoxicity”), con raccomandazione di misurare regolarmente la funzione renale nei soggetti con filtrazione glomerulare < 90 ml/min per 1.73m2. Viene specificato che la maggior parte dei casi di tossicita’ renale sono stati osservati in pazienti in terapia con tenofovir + PI boosted con ritonavir.
EMEA ha ritenuto opportuno che GS informi (tramite Dear Doctor Letter) i Medici della necessità di uno stretto monitoraggio della funzione renale nei pazienti in terapia con tenofovir e della necessità di aggiustamenti posologici e/o della frequenza di somministrazione.
Tipranavir interazioni con ARVs (3)
NRTIs
Tenofovir
NNRTIs
– Nevirapina riduce tipranavir AUC del 15% e Cmin di <5% ma nessuna modifica della dose è necessaria
– Efavirenz non ha effetti su tipranavir/r PK quando associato con 200 mg BID di ritonavir
Nessuna modifica della dose è necessaria quando
tipranavir/r (500/200 mg BID) è co-somministrato con:
Tipranavir interazioni con ARVs (2)
Co-somministrazione di tipranavir/r (500/200 mg) con amprenavir/r, lopinavir/r o saquinavir/r ha rivelato una significativa riduzione dei livelli di Cmin dopo 4 settimane di (1182.51):
– Amprenavir: 56%
– Lopinavir: 55%
– Saquinavir: 81%
Le concentrazioni plasmatiche di TPV aumentano in presenza di amprenavir/r e lopinavir/r ma non saquinavir/r
Nessuna modifica della dose è raccomandata per queste associazioni….sono controindicate!
Open issues on antiretroviral drug interactions
Treatment of opioid dependence and coinfection with HIV and hepatitis C virus in opioid-dependent patients: The importance of drug interactions between opioids and antiretroviral agents.
McCance-Katz-E-F. Clinical Infectious Diseases 2005, 41/1 SUPPL. (S89-S95)
Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients.
Cruciani-M, Gatti-G, Vaccher-E, Di-Gennaro-G, Cinelli-R, Bassetti-M, Tirelli-U, Bassetti-D. Journal of Antimicrobial Chemotherapy 2005, 55/4 (546-549).
Natural health product-HIV drug interactions: A systematic review.
Mills-E, Montori-V, Perri-D, Phillips-E, Koren-G. International Journal of STD and AIDS 2005, 16/3 (181-186).
Antiviral hepatitis and antiretroviral drug interactions
Christian Perronne Journal of Hepatology 44 (2006) 119–125
Hormonal contraceptive use and the effectiveness of highly active antiretroviral therapy.
Chu-Jaclyn-H, Gange-Stephen-J, Anastos-Kathryn, Minkoff-Howard, Cejtin-Helen, Bacon-Melanie, Levine-Alexandra, Greenblatt-Ruth-M. American journal of epidemiology, 2005, 161-9, p.881-90.
Summary Not all drug-drug interactions can be predicted
Clinical significance cannot be excluded simply on the basis of magnitude of change in concentrations
Knowledge of drug concentrations will contribute to an understanding of the overall effects of an antiretroviral regimen
Pharmacologic characteristics of combination antiretroviral regimens need to be sufficiently understood prior to use in HIV-infected pts