Initial Antiretroviral Therapy and Early Treatment Failure: Case-based Discussion

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Initial Antiretroviral Therapy and Early
Treatment Failure Case-based Discussion
Richard H. Haubrich, MDProfessor of
MedicineUniversity of California San Diego
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Case 1

• 48-year-old Hispanic female
• Presenting symptom fatigue and cough
• Treatment naive
• History
• Diagnosed with HIV 3 years prior
• Hepatitis B- 7 years prior
• Vaginal candidiasis- 3 episodes in past year
• Medications
• Paroxetine 10 mg q day

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Case 1

• Laboratories
• HIV RNA- 23,000
• CD4 364, CD4 - 15
• Hct- 32
• AST/ ALT- 87/ 104
• Bilirubin- 1.3

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What Additional Laboratories Do You Order?

• Hepatitis B DNA
• HIV genotype or phenotype
• Serum creatinine
• Chest x-ray
• HIV tropism assay
• All except 5

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Which Resistance Test Would You Order?

• Genotype
• Phenotype
• Both
• Neither

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Prevalence of drug resistance in recently
infected ART-naïve persons
Germany9 20015 9
USA2 19992003 16
London8 20045 7
USA4 20004 10
Switzerland1 19962005 8
Los Angeles7 20035 20
Chicago7 20035 25
Europe6 20023 9
San Francisco 2004 STD3 9 PHI3 10
Burkina Faso10 4.8
USA/Australia5 20006 13
1 Yerly et al. XV International Drug Resistance
Workshop June 13-17, 2006 Sitges, Spain.
Abstract 105 2 Eshleman et al. XV International
Drug Resistance Workshop June 13-17, 2006
Sitges, Spain. Abstract 109 3 Truong et al. XV
International Drug Resistance Workshop June
13-17, 2006 Sitges, Spain. Abstract 102 4 Ross,
et al. XV International Drug Resistance Workshop
June 13-17, 2006 Sitges, Spain. Abstract 107 5
Little S, et al. XV International Drug Resistance
Workshop June 13-17, 2006 Sitges, Spain.
Abstract 97 6 Wensing et al. XV International
Drug Resistance Workshop June 13-17, 2006
Sitges, Spain. Abstract 98 7 Bennett, et al. XV
International Drug Resistance Workshop June
13-17, 2006 Sitges, Spain. Abstract 103 8
Garcia-Diaz ?, et al. 9 Oette et al. HIV 8,
Glasgow 2006, P236 10 Tebit et al. J AIDS
200643144
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U.S. Surveillance of HIV Drug Resistance at
Diagnosis

• 409 sites in 11 U.S. states, most counseling/
  testing sites
• 3130 newly diagnosed patients, naïve, 2003-6
• HIVDR prevalence 10.4

Wheeler et al, CROI, 2007.
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Additional Laboratory Test Results

• HIV genotype- no evidence of resistance
• CXR- calcified nodule
• PPD- positive at 5 mm
• HBsAg

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According to DHHS Guidelines Should the Patient
be Started on Therapy Now?

• Yes
• No

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Reasons to Start Treatment in this Patient

• CD4 count
• HIV RNA
• Clinical symptoms
• Hepatitis B
• CD4 percent
• 1 and 2
• 3 and 5

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Indications for Initiation of Therapy Chronic
Infection
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Indications for Initiation of Therapy Chronic
Infection
13
Progression to AIDS/ Death with Tx Started at CD4
gt 350
CD4 gt 17
CD4 lt 17
P 0.03
Hulgan JID 2005 192 950.
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Which is the Best NRTI Option for This Patient

• TDF FTC
• ZDV 3TC
• ABC 3TC

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What Do You Start?

• PI based regimen
• NNRTI based regimen
• All NRTI regimen
• Other

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Current Antiretroviral Medications

• PI
• Atazanavir ATV
• Fosamprenavir FPV
• Indinavir IDV
• Lopinavir LPV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• Tipranavir TPV
• Darunivir DRV
• Fusion Inhibitor
• Enfuvirtide T-20

• NRTI
• Abacavir ABC
• Didanosine DDI
• Emtricitabine FTC
• Lamivudine 3TC
• Stavudine D4T
• Zidovudine ZDV
• Zalcitabine DDC
• Tenofovir TDF
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

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Guideline revisions 2006

• Updated IAS-USA,1 WHO2 (July 2006), and HHS
  Guidelines3 (May 2006)
• What to start?
• DHHS two preferred regimens
• LPV 2NRTI
• EFV 2NRTI
• IAS-USA individualize

• Hammer S, et al. JAMA 200629682743.
• 2. www.UNAIDS.org.
• 3. www.hivatis.gov

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Are there Data that LPV or EFV is the Best First
Option?

• Yes
• No

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Does LPV Have Greater Metabolic Complications
than EFV?

• Yes
• No

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Metabolic Effects of ATV/r are Less than LPV /r
and FPV/r

• True
• False

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Slide 21
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(No Transcript)
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What about an all NRTI Regimen?

• Yes
• No way, José
• The jury is not in yet

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All NRTI Regimen- Rationale

• Triple NRTI regimens attractive, but suboptimal
  performance
• All NRTI regimen desirable for many patients
• women of childbearing potential
• psychiatric illnesses
• TB therapy with a rifampin-based regimen
• methadone
• coinfected with hepatitis B or C

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Negative Association65R with 215F/Y 2 or more
TAMs
215F/Y 2 or more TAMs
65R
N 1881 (3.2)
N 8411 (14.2)
Epidemiologic data Expected frequency 0.5
(269) Actual frequency 0.04 (24) p lt
0.001 SGS 65R and multiple TAMS rarely on same
genome
Parikh et al. JID 2006 194 651
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DART AZT 3TC TDF at week 24
65 women CD4 100 HIV-1 RNA 289,400
Percentage
Mutuluuza et al. 12th CROI 2005 22
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TIMS - Study Design
Wk 48 HIV RNA lt 50, MF 67
Quad
TDF (BID) ABC ZDV 3TC HIV RNA 5.1 CD4
153
48 wks
(n57)
Treatment naïve patients (n113)

• Stratification by
• plasma HIV RNA gt/?100,000 c/ml

Each regimen 3 pills, BID dosing
ZDV 3TC (BID) EFV HIV RNA 5.3 CD4 193
Randomize 11
Triple
48 wks
(n56)
68
Moyle et al. Antivir Ther. 20061173
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TIMS Change in Cholesterol (mmol/l)
Moyle et al. Antivir Ther. 20061173
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The Patient has Uncontrolled Depression, is NVP
an Option?

• YES
• NO

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Nevirapine Contraindications
Women
500
Women with CD4 gt 250 had a 12-fold increased risk
of symptomatic hepatic AE compared to women with
CD4 counts below 250
400
11
300
CD4 Count at Initiation of Therapy
Symptomatic Hepatic Events
250
200
0.9
100
NVP should not be initiated in adult women with
CD4 gt 250 unless the benefit outweighs the risk
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2NN Grade 3 or 4 Laboratory Toxicities
20
P lt 0.0001
15
13.6
Patients ()
10
9.1
8.3
4.5
5
0
NVP BID
NVP QD
EFV
NVP EFV
P 0.001 for 4-way comparison.
van Leth F, et al. Lancet. 20043631253
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CASE 2

• 26y old female from Addis Ababa, Ethiopia
• HIV diagnosis 2004
• No symptoms
• 2 children 6 and 1y old HIV seronegative

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Case 2

• CD4 180 cells/mm3
• HIV-1 RNA 190,000 c/ml
• Other laboratories are normal
• A resistance test is not done
• Treatment ZDV3TCEFV (600mg/d)

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Follow-up ZDV3TCEFV
No adverse effects Good adherence
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What Would You Do Now?

• Continue the regimen, counsel for adherence and
  repeat the HIV RNA
• Perform HIV genotype
• Perform HIV phenotype

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Case 2 - cont

• Adherence is discussed
• Patient adamant about 100 adherence
• Focused questions about toxicity does not reveal
  underlying mild toxicity
• Check with pharmacy reveals appropriate refills

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Case 2- cont.
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Case 2- cont.

• Genotype M7
• RT M184V, Y181C
• PR L63P

• Genotype D0
• RT Y181C
• PR L63P

• She received single dose NVP at delivery for
• prevention of MCT but she did not understand
  what it was and was unable to give an accurate
  history.

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What Percentage of Patients who Experience
Virologic Failure have Resistance?

• 25
• 50
• 75

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Probability of Drug Resistance in ARV- Naïve
Cohort Initiating HAART Therapy
Harrigan et al. J Infect Dis. 2005191339-347.
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At Early Virologic Failure to which Drugs would
You Expect Resistance Mutations?

• EFV alone
• EFV 3TC
• EFV 3TC ZDV
• None

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Does a Single NNRTI Resistance Mutation Lead to
High Level NNRTI Resistance?

• Yes
• No
• Maybe (Depends on the mutation)
• I dont care, its time for coffee

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HIV-1 RT Bound to NNRTI- and NNRTI- Associated
Drug Resistance Mutations
Active site NVP Drug resistance
mutations
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NNRTI Resistance

• NNRTI Resistance mutations common after virologic
  failure
• 50-70 for EFV 2 NRTIs
• 3TC resistance 50
• Limited prospects for sequential use of NNRTIs
• Poor results from NVP failure with 181C ? EFV
• Role of sequential NNRTIs unclear in subjects who
  fail an initial NNRTI without mutations,
  undetected minority variants may limit utility
• Future Non-cross-resistant 2nd-generation NNRTIs?

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NNRTIs Mutations You Need to Know

• Extensive cross-resistance between efavirenz,
  nevirapine, and delavirdine
• Remember K103N, Y181C
• For experts L100I, V106A, V108I, Y188L,G190S,
  P225H
• More being discovered all the time

Courtesy of P. Sax
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If There is Cross Resistance to NNRTI, Why Switch?

• No reason to switch
• Evolution of NNRTI mutations
• Evolution of NRTI mutations
• Evolution of NNRTI and NRTI mutations

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CNA3005 Slow Stepwise Appearance of Mutations in
Patient With Virologic Failure
M184V
D67N/D, K70R/K, M184V
M184V, Y215T/Y
WT
L41L/M, M184V, Y215Y
L41L, M184V, Y215Y
28 weeks of M184V only
L41L, M184V, L210L/W, Y215Y
5000 c/mL
ABC6.2, ZDV12.2-fold
400 c/mL
ABC5.9, ZDV4.1-fold
50 c/mL
Melby T, et al. 8th CROI February 4-8, 2001
Chicago, IL. Poster 448.
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TMC125-C223 Baseline Resistance - Phenotype
TMC125
efavirenz
Baseline FC
Percentage
Number of baseline NNRTI mutations
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Is there a Role for 3TC in the Next Regimen?

• YES
• No

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3TC Alone Vs Treatment Interruption E 184V

• In contrast to treatment interruption arm, 3TC
  alone resulted in
• No recovery in RC
• No increase in RT mutations
• No reversion of PR mutations
• Fewer discontinuation (due to low CD4) 43 vs 58

Castagna. XV WAC 2004WeOrB1286
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Which PI do you Choose Next?

• LPV/r
• FPV/r
• ATV/r
• SQV/r
• DRV/r

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Summary

• Trend toward earlier treatment initiation
• factors besides CD4 and HIV RNA need to be
  considered
• Initial regimen- is EFV number 1? (not for
  lipoatrophy)
• Switch early for virologic failure
• Best second NRTI combination unclear