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

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 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

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ies

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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