Managing the Treatment-Experienced Patient

1
Managing the Treatment-Experienced Patient

• Eric S. Daar, MD
• Professor of Medicine, David Geffen School of
  Medicine at UCLA
• Chief, Division of HIV Medicine, Harbor-UCLA
  Medical Center
• Los Angeles, CA
• Funded by Merck Co., Inc.

2
Causes of Drug Resistance

• Resistance may be due to
• Presence of resistant virus before treatment
• Long duration of nonsuppressive therapy
• Treatment early in the ARV era
• Patient noncompliance with regimen
• Psychological, psychosocial factors
• Substance abuse
• Inadequate knowledge about dosing, adverse
  effects
• Patient intolerance to regimen
• Drug-drug or drug-food interactions
• PREVENTION is the best way to avoid resistance

3
Evaluation of Patient with Drug-Resistant HIV

• Ensure patient compliance, tolerance
• Review treatment and resistance history
• Determine level of resistant virus
• Genotypic, phenotypic susceptibility testing
• Set goals
• HIV RNA below limit of detection
• Delay CD4 decline and clinical deterioration
• Select new regimen carefully
• Ideally 2 to 3 fully active agents

4
Predicting Mutations by Drug Class
5
Time to Development of Resistance
NRTIs (3TC, FTC) NNRTIs
NRTIs (ddI, TDF, ABC, AZT, d4T), entry inhibitor
(ENF), PIs
PIs RTV
Days?Weeks
Weeks?Months
Months?Years
3TC lamivudine ABC abacavir AZT
zidovudine d4T stavudine ddI didanosine
ENF enfuvirtide FTC emtricitabine RTV
ritonavir TDF tenofovir. First-generation
NNRTIs (efavirenz, nevirapine, delavirdine).
NonRTV-boosted PI (saquinavir, indinavir,
nelfinavir, fosamprenavir, atazanavir).
RTV-boosted PI (saquinavir, fosamprenavir,
lopinavir, atazanavir, darunavir).
6
Methods of Resistance Testing
7
Resistance Testing in Clinical Practice
Adapted from Guidelines for the use of
antiretroviral agents in HIV-1-infected adults
and adolescents. Available at www.aidsinfo.nih.gov
.
8
Choosing a New Regimen

• Identify active agents
• Drug susceptibility testing
• Patients treatment history
• New agents in existing and novel classes
• Benefits shown in recent clinical trials
• Potential adverse effects, mutations,
  cross-resistance
• If several are available
• Convenience of dosing
• Adverse effects
• Drug-drug interactions
• Select 2 to 3 fully active agents
• Perform careful patient follow-up

9
New Agents for Consideration in
Treatment-Experienced Patient
10
Trials of Tipranavir RESIST 1 and 2
CPI comparator PI ENF enfuvirtide OBR
optimized background regimen r ritonavir TPV
tipranavir. Reduction in viral load of 1
log10 copies/mL from baseline. Hicks CB, et al.
Lancet 200636846675.
11
Trials of Darunavir POWER 1 and 2
CPI comparator PI DRV darunavir ENF
enfuvirtide OBR optimized background regimen
r ritonavir. Reduction in viral load of 1
log10 copies/mL from baseline. Clotet B, et al.
Lancet 2007369116978.
12
Trials of Darunavir TITAN
DRV darunavir LPV lopinavir r ritonavir.
With available data. Madruga JV, et al.
Lancet 20073704958.
13
Trials of Etravirine DUET-1 and -2
ETR etravirine optimized background regimen
NS not significant OBR optimized background
regimen alone. 1. Madruga JV, et al. Lancet
20073702938. 2. Lazzarin A, et al. Lancet
20073703948.
14
Entry and Tropism Assays

• 2 co-receptors CXCR4 and CCR5
• R5 virus in 80 of patients early in disease
• X4 or dual/mixed virus in 40 to 50 with longer
  treatment history advanced disease
• Entry assay
• Susceptibility to fusion inhibitors (eg,
  enfuvirtide)
• Tropism assay
• Susceptibility to CCR5 antagonists (eg, maraviroc)

15
Trials of Enfuvirtide TORO 1 and 2
ENF enfuvirtide optimized background regimen
OBR optimized background regimen alone. Mean
change from baseline in log10 copies/mL. 1.
Lalezari JP, et al. N Engl J Med
2003348217585. 2. Lazzarin A, et al. N Engl J
Med 2003348218695.
16
Trials of Maraviroc MOTIVATE 1 and 2
MVC maraviroc optimized background regimen
NR not reported OBR optimized background
regimen alone. Both MVC groups separately vs
placebo. Mean change from baseline in log10
copies/mL. 1. Lalezari J, et al. Available at
www.retroconference.org/2007/abstracts/30635.htm.
2. Nelson M, et al. Available at www.
retroconference.org/2007/abstracts/30636.htm.
17
Trials of RaltegravirBENCHMRK-1 and -2
RAL raltegravir optimized background regimen
OBR optimized background regimen
alone. Isentress (raltegravir) tablets
prescribing information.
18
New Drugs Theoretical Concerns

• Cross-class resistance
• New drugs in existing classes (eg, tipranavir,
  darunavir, etravirine)
• Not an issue for first-in-class agents
• New mutations
• Drugs in novel classes (eg, enfuvirtide,
  maraviroc, raltegravir)
• Possible emergence of dual/mixed or X4 virus
  (maraviroc)

19
If Virologic Suppression Is Not Possible

• Goal is to delay CD4 decline
• Treatment cessation not recommended
• 4-month interruption increased morbidity/mortality
  1
• Option continue a partially suppressive regimen
• NRTIs may have continued antiviral activity2
• Weigh against risk of further resistance
• 30 loss of susceptibility to 1 drug in 1 year3

1. Lawrence J, et al. N Engl J Med
200334983746. 2. Deeks SG, et al. J Infect
Dis 2005192153744. 3. Hatano H, et al. Clin
Infect Dis 200643132936.
20
Summary Treatment Resistance

• Causes
• Treatment-related factors
• Patient-related factors
• Evaluation
• Patient compliance
• Treatment history
• Drug susceptibility
• Management
• Set goal priority is full virologic suppression
• Consider new agents be aware of risk/benefit
• Follow-up

21
Summary Management Goals
1

• Prevention of resistance

Full virologic suppression
2
3
If no options for fully active regimen, continue
partially suppressive regimen
22
Case Example History

• 43-year-old man with HIV diagnosis in 1992
• Presented with cryptococcal meningitis
• CD4 count 18 cells/mm3
• Initial ARV treatment
• AZT 2 yr
• AZT3TC 1 yr
• AZT3TC with IDV through 1998
• Since then
• Therapy modifications (eg, NFV, SQV/r, LPV/r,
  EFV)
• Multiple reverse transcriptase and protease
  mutations
• Persistently detectable HIV RNA
• CD4 counts remaining at 50?200 cells/mm3
• Clinically stable

23
Case Example Current Status

• Treatment AZT/3TC/ABC TDF and LPV/r, past 6
  mos
• Clinically stable, only mild onychomycosis
• No hepatitis, diabetes, hypertension
• No other medications
• No adherence issues
• No drug/alcohol use
• No adverse effects
• Current testing
• CD4 count 134 cells/mm3
• HIV RNA 33,400 copies/mL

24
Case Example Resistance Testing
ATV atazanavir DLV delavirdine NFV
nelfinavir NVP nevirapine. Virus is fully
resistant to those drugs listed.
25
Case Example New Regimen

• Background regimen
• TDF and FTC along with DRV/r
• DRV instead of TPV because TPV reduces ETR levels
• Fully active drugs
• ETR, RAL, and MVC
• MVC added after negative tropism test
• Outcome
• HIV RNA undetectable by 8 wk
• Good tolerability

26
ISENTRESS (raltegravir) tablets

• Indications and Usage
• ISENTRESS in combination with other
  antiretroviral agents is indicated for the
  treatment of HIV-1 infection in
  treatment-experienced adult patients who have
  evidence of viral replication and HIV-1 strains
  resistant to multiple antiretroviral agents.
• This indication is based on analyses of plasma
  HIV-1 RNA levels up through 24 weeks in 2
  controlled studies of ISENTRESS. These studies
  were conducted in clinically advanced 3-class
  antiretroviral (NNRTI, NRTI, PI)
  treatment-experienced adults.
• The use of other active agents with ISENTRESS is
  associated with a greater likelihood of treatment
  response.
• The safety and efficacy of ISENTRESS have not
  been established in treatment-naive adult
  patients or pediatric patients.
• There are no study results demonstrating the
  effect of ISENTRESS on clinical progression of
  HIV-1 infection.

27
ISENTRESS (raltegravir) tablets

• Warnings and Precautions
• Immune Reconstitution Syndrome
• During the initial phase of treatment, patients
  responding to antiretroviral therapy may develop
  an inflammatory response to indolent or residual
  opportunistic infections, which may necessitate
  further evaluation and treatment.
• Drug Interactions
• Caution should be used when co-administering
  ISENTRESS with strong inducers of uridine
  diphosphate glucuronosyltransferase (UGT) 1A1
  (e.g., rifampin) due to reduced plasma
  concentrations of raltegravir.

28
ISENTRESS (raltegravir tablets)

• Adverse Reactions
• The most common adverse reactions (gt10) of all
  intensities, reported in subjects in either the
  ISENTRESS or the placebo treatment group,
  regardless of causality were diarrhea (16.6,
  19.5), nausea (9.9, 14.2), headache (9.7,
  11.7), and pyrexia (4.9, 10.3) respectively.
• The drug-related adverse reactions (2) of
  moderate to severe intensity reported in
  subjects in either the ISENTRESS or placebo
  treatment group were diarrhea (3.7, 4.6),
  nausea (2.2, 3.2), and headache (2.4, 1.4)
  respectively.

Intensities are defined as follows Mild
(awareness of sign or symptom, but easily
tolerated) Moderate (discomfort enough to cause
interference with usual activity) Severe
(incapacitating with inability to work or do
usual activity). Includes adverse reactions at
least possibly, probably, or very likely related
to the drug.
29
ISENTRESS (raltegravir tablets)Adverse
Reactions (cont)

• Adverse Reactions (cont)
• Creatine kinase elevations were observed in
  subjects who received ISENTRESS. Myopathy and
  rhabdomyolysis were reported however, the
  relationship of ISENTRESS to these events is not
  known. Use with caution in patients at increased
  risk of myopathy or rhabdomyolysis, such as
  patients receiving concomitant medications known
  to cause these conditions.

30
CRIXIVAN (indinavir sulfate)

• Indication
• CRIXIVAN in combination with other antiretroviral
  agents is indicated for the treatment of HIV
  infection. This indication is based on 2
  clinical trials of approximately 1 years
  duration that demonstrated
• a reduction in the risk of AIDS-defining
  illnesses or death
• a prolonged suppression of HIV RNA
• Contraindication
• CRIXIVAN is contraindicated in patients with
  clinically significant hypersensitivity to any of
  its components.
• Inhibition of CYP3A4 by CRIXIVAN can result in
  elevated plasma concentrations of the following
  drugs, potentially causing serious or
  life-threatening reactions

Drug Interactions With CRIXIVAN Contraindicated
Drugs
31
CRIXIVAN (indinavir sulfate)
Selected Warnings

• ALERT Find out about medicines that should NOT
  be taken with CRIXIVAN.
• Nephrolithiasis/urolithiasis has occurred with
  CRIXIVAN therapy. The cumulative frequency of
  nephrolithiasis is substantially higher in
  pediatric patients (29) than in adult patients
  (12.4 range across individual trials 4.7 to
  34.4). The cumulative frequency of
  nephrolithiasis events increases with increasing
  exposure to CRIXIVAN however, the risk over time
  remains relatively constant. In some cases,
  nephrolithiasis/urolithiasis has been associated
  with renal insufficiency or acute renal failure,
  pyelonephritis with or without bacteremia. If
  signs or symptoms of nephrolithiasis/urolithiasis
  occur, (including flank pain, with or without
  hematuria or microscopic hematuria), temporary
  interruption (e.g., 1-3 days) or discontinuation
  of therapy may be considered. Adequate hydration
  is recommended in all patients treated with
  CRIXIVAN.
• Acute hemolytic anemia, including cases resulting
  in death, has been reported in patients treated
  with CRIXIVAN. Once a diagnosis is apparent,
  appropriate measures for the treatment of
  hemolytic anemia should be instituted, including
  discontinuation of CRIXIVAN.

32
CRIXIVAN (indinavir sulfate)
Selected Warnings (cont)

• New onset diabetes mellitus, exacerbation of
  pre-existing diabetes mellitus and hyperglycemia
  have been reported during post-marketing
  surveillance in HIV-infected patients receiving
  protease inhibitor therapy. Some patients
  required either initiation or dose adjustments of
  insulin or oral hypoglycemic agents for treatment
  of these events. In some cases, diabetic
  ketoacidosis has occurred. In those patients who
  discontinued protease inhibitor therapy,
  hyperglycemia persisted in some cases. Because
  these events have been reported voluntarily
  during clinical practice, estimates of frequency
  cannot be made and a causal relationship between
  protease inhibitor therapy and these events has
  not been established.
• Concomitant use of CRIXIVAN with lovastatin or
  simvastatin is not recommended. Caution should be
  exercised if HIV protease inhibitors, including
  CRIXIVAN, are used concurrently with other
  HMG-CoA reductase inhibitors metabolized by the
  CYP3A4 pathway (eg, atorvastatin or
  rosuvastatin). The risk of myopathy including
  rhabdomyolysis may be increased when HIV protease
  inhibitors, including CRIXIVAN, are used in
  combination with these drugs
• Particular caution should be used when
  prescribing sildenafil, tadalafil, or vardenafil
  in patients receiving indinavir. Coadministration
  of CRIXIVAN with these medications is expected to
  substantially increase plasma concentrations of
  sildenafil, tadalafil, and vardenafil and may
  result in an increase in adverse reactions,
  including hypotension, visual changes, and
  priapism, which have been associated with
  sildenafil, tadalafil, and vardenafil.

33
CRIXIVAN (indinavir sulfate)
Selected Drug Interactions
Drugs That Should Not Be Coadministered with
CRIXIVAN
34
CRIXIVAN (indinavir sulfate)
Selected Precautions

• Indirect hyperbilirubinemia has occurred
  frequently during treatment with CRIXIVAN and has
  infrequently been associated with increases in
  serum transaminases. It is not known whether
  CRIXIVAN will exacerbate the physiologic
  hyperbilirubinemia seen in neonates.
• Reports of tubulointerstitial nephritis with
  medullary calcification and cortical atrophy have
  been observed in patients with asymptomatic
  severe leukocyturia (gt100 cells/high-power
  field).
• There have been reports of spontaneous bleeding
  in patients with hemophilia A and B treated with
  protease inhibitors.
• In patients with hepatic insufficiency due to
  cirrhosis, the dosage of CRIXIVAN should be
  lowered because of decreased metabolism of
  CRIXIVAN. Patients with renal insufficiency have
  not been studied.
• Redistribution/accumulation of body fat,
  including central obesity, dorsocervical fat
  enlargement (buffalo hump), peripheral wasting,
  facial wasting, breast enlargement, and
  cushingoid appearance, has been observed in
  patients receiving antiretroviral therapy. The
  mechanism and long-term consequences of these
  events are currently unknown. A causal
  relationship has not been established.

35
CRIXIVAN (indinavir sulfate)
Selected Precautions (cont)

• Indinavir is an inhibitor of the cytochrome P-450
  isoform CYP3A4. Coadministration of CRIXIVAN and
  drugs primarily metabolized by CYP3A4 may result
  in increased plasma concentrations of the other
  drug, which could increase or prolong its
  therapeutic and adverse effects.
• Indinavir is metabolized by CYP3A4. Drugs that
  induce CYP3A4 activity would be expected to
  increase the clearance of indinavir, resulting in
  lowered plasma concentrations of indinavir.
  Coadministration of CRIXIVAN and other drugs that
  inhibit CYP3A4 may decrease the clearance of
  indinavir and may result in increased plasma
  concentrations of indinavir.
• There are no adequate and well-controlled studies
  in pregnant patients. CRIXIVAN should be used
  during pregnancy only if the potential benefit
  justifies the potential risk to the fetus.

36
CRIXIVAN (indinavir sulfate)

• Established and Other Potentially Significant
  Drug Interactions
• Alteration in dose or regimen may be recommended
  based on drug interaction studies or predicted
  interaction
• HIV Antiviral Agents

Note ? increase? decrease
37
CRIXIVAN (indinavir sulfate)
Established and Other Potentially Significant
Drug Interactions (cont)
Note ? increase? decrease
38
CRIXIVAN (indinavir sulfate)
Established and Other Potentially Significant
Drug Interactions (cont)
Note ? increase? decrease
39
CRIXIVAN (indinavir sulfate)
Selected Adverse Reactions

• Clinical adverse experiences reported in 2 of
  patients in study ACTG 320 of unknown drug
  relationship and of severe or life-threatening
  intensity for CRIXIVAN plus zidovudine plus
  lamivudine (n571)
• Abdominal pain, 1.9 asthenia/fatigue, 2.4
  fever, 3.8 nausea, 2.8 diarrhea, 0.9
  vomiting, 1.4 acid regurgitation, 0.4
  anorexia, 0.5 anemia, 2.4 back pain, 0.9
  headache, 2.4 dizziness, 0.5 pruritus, 0.5
  rash, 1.1 cough, 1.6 difficulty
  breathing/dyspnea/shortness of breath, 1.8
  nephrolithiasis/urolithiasis (including renal
  colic, and flank pain with and without
  hematuria), 2.6 dysuria, 0.4 taste
  perversion, 0.2.

40
Before prescribing ISENTRESS (raltegravir)
tablets or CRIXIVAN (indinavir sulfate), please
read the accompanying Prescribing
Information. CRIXIVAN and ISENTRESS are
registered trademarks of Merck Co., Inc.
20804674(2)-ISN