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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
ICoNA Study:
Reasons for Failure of Initial HAART
8%
Toxicity
Failure
Nonadherence
Other
n = 25
20%
n = 61
58%
14%
n = 44
d'Arminio Monforte A, et al. AIDS. 2000;14:499-507.
n = 182
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
Adherence is Inversely Related to the
Number of Doses Per Day
Dose-taking adherence rates
Dose-timing adherence rates
P < .001
P = .008
Mean dose-taking
adherence (%)
100
P values not calculated
P = .001
80
60
71
79
69
74
65
51
40
59
58
46
40
TID
QID
20
0
Overall QD
BID
TID
QID
Overall QD
BID
Studies of electronic monitoring of adherence

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)
Claxton et al., Clin Ther .2001;23:1296–1310.
% of Patients ever forgetting
Patients (%)
to take HIV medication
Patients Prefer QD Regimens
to BID Regimens
80
70
68%
60
50
40
30
24%
20
10
5%
0
4 pills QD
1 morning,
1 evening
1 morning,
4 evening
Bass D, et al. XIV IAC, July 7-12, Barcelona, 2002,
Abstract MoPe3290.
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
DHHS[1]
IAS-USA[2]
Primary Infection
Recommend
Recommend
Recommend
PEP (Source Pt)
—
—
Recommend
Consider
Recommend
Recommend/
Consider
Recommend
Recommend
Recommend
Recommend *
Recommend *
Chronic (< 2 years)
Treatment Failure
Pregnancy
—
Pediatric
—
—
EuroGuidelines
[3]
Recommend **
* Only if mother is viremic
** Only if mother was viremic and on treatment at time of birth
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.
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
Optimal Use of Boosted PIs
in Treatment-Experienced
Patients
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 drugnaive 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.
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
< 400 copies/mL
Viral Suppression (%)

70
60
50
40
30
20
10
0
< 50 copies/mL
61
58
50
46
50
37
FPV/RTV
Once Daily
FPV/RTV
Twice Daily
LPV/RTV
Twice Daily
Intent-to-treat, missing equals failure analysis
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-classexperienced patients, combining ENF + an active
boosted PI improves response rate
TORO: Virologic Response to
Enfuvirtide + OB Regimen
ENF + OB (n = 661)
(n = 334)
OB
Patients With HIV-1 RNA
< 400 Copies/mL (%)
100
90
ITT: DC or SW = F
80
70
60
50
34%
40
26%
30
13%
20
10
0
0
16
32
48
Study Week
Arastéh K, et al. IAC 2004. Abstract MoOrB1058.
64
80
96
Patients With HIV-1 RNA < 400
Copies/mL at Week 48 (%)
TORO: Importance of Combining ENF
With an Active Boosted PI
100
80
ENF +OB
(n = 661)
60
OB
(n = 334)
*P < .05
*
0
*
38%
40
20
55%
*
18%
18%
57
No LPV/r
171
77
LPV/r
LPV/r Experienced
Miralles GD, et al. IDSA 2004. Abstract 921.
24%
10%
4%
2%
n = 158
*
93
58
No LPV/r
239 42
LPV/r
LPV/r Naive
TORO: Impact of Number of Active
Agents on Response
Mean Change in HIV-1 RNA at
Week 24 (ITT) (log10 copies/mL)
Number of Active Antiretrovirals in OB Regimen
(Genotypic Sensitivity Score)
0
1-2
3-4
5
0
-1.0
-2.0
-3.0
Henry K, et al. IAS 2002. Abstract LbOr19B.
ENF + OB
OB
RESIST-1: Response to TPV/r vs CPI/r
100
TPV/r (n = 311)
CPI/r (n = 309)
80
ITT: NC=F
60
34.7%
40
16.5%
20
P < .001
0
0
4
8 12 16 20 24
Week
Hicks C, et al. ICAAC 2004. Abstract 1137a.
Patients With HIV- 1 RNA
< 50 copies/mL(%)
Patients With HIV- 1 RNA
< 400 copies/mL(%)
100
TPV/r (n = 311)
CPI/r (n = 309)
80
ITT: NC=F
60
40
25.1%
20
10.0%
P < .001
0
0
4
8 12 16 20 24
Week
 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
Patients With HIV-1 RNA < 400
Copies/mL at Week 24 (%)
RESIST: Impact of Enfuvirtide on
Virologic Response
100
No ENF
80
60
53.9
40
30.2
21.3
20
13.4
0
CPI/r
Deeks S, et al. IAS 2005. Abstract WeFo0201.
ENF
TPV/r
Relationship of TPV Score to TPV
Phenotype Results and Response
TPV Score
0-1
Median Change in VL at
Wk 24* (log10 copies/mL)
Median FC: 0.7-0.9
2-3
4-5
6-7
8-9
1.1-1.4
2.0-3.1
3.3-3.9
14.7-52.5
0
-0.08
-1
-0.89
-0.45
-0.49
(n = 260)
(n = 68)
(n = 4)
(n = 242)
-2
-2.10
(n = 144)
-3
Valdez H, et al. Resistance Workshop 2005. Abstract 27.
*24-week data from patients in
RESIST-1 and -2 given TPV/r
POWER 1: Virologic Response to
TMC114/r
Patients with HIV-1 RNA
< 50 copies/mL (%)
100
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)
80
P < .001 for all doses
vs control
60
40
53%
49%
48%
43%
20
18%
0
1 2
4
8
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
12
Time (weeks)
16
20
24
POWER 1: Subgroup Analyses of
Response to TMC114/r 600/100 BID
53% (n = 60)
Overall
18% (n = 60)
ENF Used (Naive)
63% (n = 19)
22% (n = 18)
56% (n = 34)
ENF Not Used
19% (n = 36)
59% (n = 29)
 3 Primary PI Mut
9% (n = 35)
46% (n = 28)
TMC114 FC > 4
16% (n = 25)
No Sensitive
ARV in OBR
17% (n = 12)
TMC114/r 600/100 BID
Control
0% (n = 9)
0
20
40
60
80
% with HIV-1 RNA < 50 at Week 24 (ITT NC=F)
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
100
TMC125 in Treatment-Experienced
Patients
 Open, phase 2a study
Days
 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
Gazzard BG, et al. AIDS. 2003;17:F49-F54.
Median Change in HIV-1 RNA
(log10 copies/ mL)
–
–
–
–
0
-0.2
2
4
6
8
*
-0.4
- 0.35
-0.6
-0.8
-1.0
-1.2
-1.4
*
- 0.64
*
- 0.89
*
* P < .001 vs baseline
0.4
Median VL Change From
BL (log10 copies/mL)
Aplaviroc (GW873140)[1]
Placebo
200 QD
200 BID
400 QD
600 BID
0
-0.4
-0.8
-1.2
-1.6
Dosing
0
5
10
15
20
25
30
Day
Median VL Change From
BL (log10 copies/mL)
Median VL Change From
BL (log10 copies/mL)
CCR5 Inhibitors in Development
Vicriviroc (SCH-417690)[2]
0.5
0.0
-0.5
-1.5
Dosing
0
5
10
Maraviroc (UK-427857)[3]
0.5
0
-0.5
Placebo 15
Placebo 07
25 mg QD
50 mg BID
100 mg QD
-1.0
-1.5
-1.5
Dosing
100 mg BID
150 mg Fast
150 mg Fed
300 mg QD
300 mg BID
-2.0
0
5
10
15
20
25
Days
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.
30
Placebo
10 mg BID
25 mg BID
50 mg BID
-1.0
35
40
15
Days
20
25
30
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-d4FC
1. 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
2.0
3TC
Weeks
TI
P = .0015
1.5
1.0
0.5
0
4
12
Mean CD4+ Decrease (ITT)
24
36
48
Mean Change in CD4+
Cell Count (cells/mm3)
Mean Change in HIV-1
RNA (log10 copies/mL)
Mean VL Increase (ITT)
0
-50
-100
-150
-200
-250
-300
4
12
3TC
24
TI
36
P = NS
Weeks
 In contrast to treatment interruption arm, 3TC alone resulted in:
– Smaller recovery in replication capacity
– No further selection of resistance mutations
Castagna A, et al. IAS 2005. Abstract WeFo0204.
48
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 mutations
Decrease 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
Manipulating Dosage of Boosted PIs With Ritonavir: A
Delicate Balance
Improves exposure
Impact on adherence
Greater activity
against resistant virus
Risk of increased
toxicity
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 drugexperienced patients
 Data suggest LPV/RTV superior to SQV/RTV in drugexperienced 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 inhibitorbased antiretroviral treatments are beneficial and are
commonly used in clinical practice.
Enzyme Inhibition and Induction
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
Tenofovir Interactions
Impact of Coadministration on Exposure (AUC)
Coadministered drug
Didanosine
Lamivudine
 Emtricitabine
 d4T-XR
 Abacavir
 Indinavir
 Lopinavir/ritonavir
 Atazanavir
 Atazanavir/ritonavir
 Saquinavir/ritonavir
 Nelfinavir, Efavirenz
 Oral contracept.,
Methadone
 Ribavirin
 Adefovir
* Plasma levels
 44-60%
*


*

 15%
 26%
 25% ?
 29%




Tenofovir
*
*


*

 34%
 25%
ND
 14%


ND
ND
Issues with Didanosine + Tenofovir +
Efavirenz
 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
1. van Lunzen J, et al. IAS 2005. Abstract TuPp0306.
2. Barrios A, et al. IAS 2005. Abstract WePe12.3C16.
Small Reductions in Renal Function
With Tenofovir vs Other NRTIs

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

120
Small but statistically significant ↓ in
CLCr with TDF
MACS: TDF associated with lower
GFR[3]
*
100
CLCr (mL/min)

*
*
Normal range: 80-120 mL/min
80
60
TDF
NRTI
40
* P < .05 change from
baseline for TDF vs NRTI
20
0
0
90
180
270
360
Days
Last CLCr on treatment carried forward
if treatment stopped
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.
Low Rate of Renal Events in
Tenofovir Clinical Dataset

Retrospective analysis of TDF Expanded Access Program and
postmarketing data after 4 years of TDF availability
Serious Renal Adverse Events in EAP and Postmarketing Databases
Event
EAP
Postmarketing
N = 10343/3700 PY
455,392 PY
%
Cases/100,000
PY
Reporting
Rate/100,000 PY
0.3
865
24.2
Fanconi/tubular
disorder/hypophosphatemia/glycosuria
< 0.1
270
22.4
Elevated serum creatinine, BUN
< 0.1
189
5.1
Renal failure

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.
 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)
Nessuna modifica della dose è necessaria quando
tipranavir/r (500/200 mg BID) è co-somministrato con:
 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
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, LevineAlexandra, 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