Approccio terapeutico nel paziente pre-trattato

1
Approccio terapeutico nel paziente pre-trattato

• Ivano Mezzaroma
• Dipartimento di Medicina Clinica
• UOC Immunologia Clinica
• Università di Roma La Sapienza

Roma, 24 marzo 2006
2
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

3
ICoNA Study Reasons for Failure of Initial HAART
8
Toxicity
n 25
Failure
Nonadherence
20
Other
n 61
58
n 182
14
n 44
d'Arminio Monforte A, et al. AIDS.
200014499-507.
4
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

5
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

6
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

7
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

8
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

9
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

10
Adherence is Inversely Related to the Number of
Doses Per Day
Dose-timing adherence rates
Dose-taking adherence rates
P lt .001
P .008
P values not calculated
100
P .001
80
79
74
71
Mean dose-taking adherence ()
69
60
65
58
59
51
40
46
40
20
0
Overall
QD
BID
TID
QID
Overall
QD
BID
TID
QID
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 .20012312961310.
11
Patients Prefer QD Regimensto BID Regimens
68
of Patients ever forgetting to take HIV
medication
Patients ()
24
5
4 pills QD
1 morning, 1 evening
1 morning, 4 evening
Bass D, et al. XIV IAC, July 7-12, Barcelona,
2002, Abstract MoPe3290.
12
Changing TherapyConsiderations

• Clinical status
• HIV RNA level on 2 tests
• CD4 T cell count
• Remaining treatment options
• Potential viral resistance
• Medication adherence
• Patient education

13
Changing Therapy Treatment Regimen Failure

• Virologic failure
• Incomplete virologic response HIV RNA gt400
  copies/mL after 24 wks, gt50 after 48 wks
• Virologic rebound repeated detection of HIV RNA
  after viral suppression
• Immunologic failure
• CD4 increase of lt25-50 cells/µL in first year of
  therapy
• CD4 decrease below baseline, on therapy
• Clinical failure
• occurrence of HIV-related events (after gt3 months
  on therapy excludes immune reconstitution
  syndromes)

14
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

15
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

16
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

17
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

18
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

19
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

20
Changing Therapy Treatment Options

• Limited prior treatment with low HIV RNA
• Intensification (e.g., tenofovir)
• Pharmacokinetic (PK) enhancement
• Change to new regimen

21
Changing Therapy Treatment Options

• Limited prior treatment with single drug
  resistance
• Change 1 drug
• PK enhancement
• Change to new regimen

22
Changing Therapy Treatment Options

• Limited prior treatment with gt1 drug resistance
• Change drug classes and/or add new active drugs

23
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)

24
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

25
Current Guidelines for Resistance Testing
DHHS1 IAS-USA2 EuroGuidelines 3
Primary Infection Recommend Recommend Recommend
PEP (Source Pt) Recommend
Chronic (lt 2 years) Consider Recommend Recommend/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
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. 200337113-128. 3. Miller V, et al. AIDS.
200115309-320.
26
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)

27
Drug Resistance Testing Limitations

• Lack of uniform quality assurance
• Relatively high cost
• Insensitivity for minor viral species (lt10-20)

28
Interruption of Antiretroviral Therapy

• Intolerable side effects
• Drug interactions
• First trimester pregnancy
• Poor adherence
• Unavailability of drugs
• Many other possible causes

29
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

30
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

31
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

32
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

33
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

34
Optimal Use of Boosted PIs in Treatment-Experience
d Patients
35
Goals of Therapy With MDR HIV

• Patients with access to 2 active agents
• Complete viral suppression
• Patients with access to lt 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

36
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 BID1
• 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 BID2
• 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.
2003188635-642. 2. Youle M, et al. IAS 2003.
Abstract LB23.
37
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

70
61
58
60
50
50
46
50
37
40
Viral Suppression ()
30
20
10
0
LPV/RTV Twice Daily
FPV/RTV Once Daily
FPV/RTV Twice Daily
Intent-to-treat, missing equals failure analysis
Elston RC, et al. IAC 2004. Abstract MoOrB1055.
38
Lopinavir/Ritonavir

• LPV/RTV vs NFV, plus d4T/3TC, in treatment-naive
  patients1
• 67 vs 52 of patients had viral load lt 50
  copies/mL at Week 48 (P lt .001)
• In patients with viral load gt 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 patients2
• 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.
20023462039-2046. 2. Nieto-Cisneros L, et al.
Antivir Ther. 20038(suppl1)S212. Abstract 117.
39
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

40
TORO Virologic Response to Enfuvirtide OB
Regimen
Arastéh K, et al. IAC 2004. Abstract MoOrB1058.
41
TORO Importance of Combining ENF With an Active
Boosted PI
Miralles GD, et al. IDSA 2004. Abstract 921.
42
TORO Impact of Number of Active Agents on
Response
Henry K, et al. IAS 2002. Abstract LbOr19B.
43
RESIST-1 Response to TPV/r vs CPI/r
Hicks C, et al. ICAAC 2004. Abstract 1137a.
44
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.
45
Relationship of TPV Score to TPV Phenotype
Results and Response
Valdez H, et al. Resistance Workshop 2005.
Abstract 27.
46
POWER 1 Virologic Response to TMC114/r
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.

47
POWER 1 Subgroup Analyses of Response to
TMC114/r 600/100 BID
Katlama C, et al. IAS 2005. Abstract WeOaLB0102.
48
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

Gazzard BG, et al. AIDS. 200317F49-F54.
49
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.
50
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.
51
3TC Alone vs Treatment Interruption in Patients
Failing 3TC-Based HAART
Mean CD4 Decrease (ITT)
Mean VL Increase (ITT)
Weeks
2.0
3TC
TI
4
12
24
36
48
P .0015
0
1.5
-50
Mean Change in HIV-1 RNA (log10 copies/mL)
1.0
-100
Mean Change in CD4 Cell Count (cells/mm3)
-150
0.5
-200
-250
0
P NS
4
12
24
36
48
-300
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.
52
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 patients virus?

53
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

54
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 lt
  200)

55
Continued Therapy in Patients With Virologic
Failure A Delicate Balance
Accumulate new mutations Develop resistance to
drugs in development
Maintain mutations Decrease fitness Delay
progression
56
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

57
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

58
Pharmacology of Boosted PIs (cont)

• 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

59
Manipulating Dosage of Boosted PIs With
Ritonavir A Delicate Balance
Impact on adherence Risk of increased toxicity
Improves exposure Greater activity against
resistant virus
60
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

61
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 patients virus remains sensitive
  may become available

62
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

63
Summary and Implications (cont)

• Virologic potency of FPV/RTV appears lt 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

64
Summary and Implications (cont)

• 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

65
Summary and Implications (cont)

• 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

66

• 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.

67
Enzyme Inhibition and Induction
Drug Enzyme Inhibition Enzyme Induction
Atazanavir
Delavirdine
Efavirenz
Fosamprenavir
Indinavir
Lopinavir/ritonavir1
Tipranavir/ritonavir1
Nelfinavir
Nevirapine
Ritonavir
Saquinavir2
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
68
Tenofovir Interactions
Impact of Coadministration on Exposure (AUC)
Plasma levels
69
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.
70
Small Reductions in Renal Function With Tenofovir
vs Other NRTIs
120

• 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 creatinine2
• 10 of TDF pts w/ Gr 3 GFR
• MACS TDF associated with lower GFR3

100
Normal range 80-120 mL/min
80
CLCr (mL/min)
60
40
P lt .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 2005401194-8. 2.
Becker S, et al. CROI 2005. Abstract 819. 3.
Reisler R, et al. CROI 2005. Abstract 818.
71
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 Serious Renal Adverse Events in EAP and Postmarketing Databases Serious Renal Adverse Events in EAP and Postmarketing Databases Serious Renal Adverse Events in EAP and Postmarketing Databases
Event EAP N 10343/3700 PY EAP 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 lt 0.1 270 22.4
Elevated serum creatinine, BUN lt 0.1 189 5.1

• 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.
72

• 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 lt 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.

73
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 lt5 ma nessuna modifica della dose è
  necessaria
• Efavirenz non ha effetti su tipranavir/r PK
  quando associato con 200 mg BID di ritonavir

74
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!

75
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) 119125
• 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.

76
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