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Management of Antiretroviral Therapy Case Presentations

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History of oral thrush and zoster. HIV RNA 20,000. CD4 120 ... Recurrence of zoster by 6 months. Persistent mild nausea at 6 months. Treatment Failure: ... – PowerPoint PPT presentation

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Title: Management of Antiretroviral Therapy Case Presentations


1
Management of Antiretroviral Therapy Case
Presentations
Roy M. Gulick, MD, MPH Weill Medical College of
Cornell University
2
Antiretroviral Therapy Continuing Questions
  • When to start?
  • What to start?
  • When to switch?
  • What to switch to?
  • Can you stop therapy?

3
When to Start? Case 1
  • 35 year old woman
  • Recently diagnosed
  • History of oral thrush and zoster
  • Never on treatment
  • HIV RNA 20,000
  • CD4 120
  • Do you recommend treatment?

4
When to Start? Case 2
  • 35 year old woman
  • Recently diagnosed
  • Asymptomatic
  • Never on treatment
  • HIV RNA 20,000
  • CD4 120
  • Do you recommend treatment?

5
When to Start? Case 3
  • 35 year old woman
  • Recently diagnosed
  • Asymptomatic
  • Never on treatment
  • HIV RNA 20,000
  • CD4 420
  • Do you recommend treatment?

6
Goal of Antiretroviral Therapy
  • to suppress HIV RNA (viral load level) as low as
    possible, for as long as possible
  • to preserve or enhance immune function
  • to delay clinical progression of HIV disease

7
When To Start Treatment? -- DHHS
  • treat
  • offer treatment
  • delay or treat
  • symptomatic
  • asymptomatic,
  • HIV RNA gt10-20K
  • or CD4 lt500
  • asymptomatic,
  • HIV RNA lt10-20K
  • and CD4 gt500

DHHS Guidelines, 1/28/00
8
Early vs. Late Treatment
  • DELAYED RX
  • Risk of clinical progression low in early
    disease.
  • Practical factors (adherence, toxicity outweigh
    benefits in early disease).
  • Long term effects unknown.
  • EARLY RX
  • HIV disease is progressive.
  • Rx decreases VL (and resistance) and increases
    CD4 (and immune function).
  • 3 years of virologic suppression demonstrated.

DHHS Guidelines, 1/28/00
9
What to Start? Case 1
  • 35 year old woman
  • Recently diagnosed
  • History of oral thrush and zoster
  • Never on treatment
  • HIV RNA 20,000
  • CD4 120

10
What to start?Case 1 (cont.)
  • What would you recommend?
  • Indinavir 2 nucs
  • Nelfinavir 2 nucs
  • Efavirenz 2 nucs
  • Nevirapine 2 nucs
  • Something else

11
What to Start? Case 2
  • 35 year old woman
  • Recently diagnosed
  • History of oral thrush and zoster
  • Never on treatment
  • HIV RNA 20,000
  • CD4 120
  • Concerned about her ability to adhere to therapy

12
What to start?Case 2 (continued)
  • What would you recommend?
  • Indinavir 2 nucs
  • Nelfinavir 2 nucs
  • Efavirenz 2 nucs
  • Nevirapine 2 nucs
  • Something else

13
What to Start? Case 3
  • 35 year old woman
  • Recently diagnosed
  • History of oral thrush and zoster
  • Never on treatment
  • HIV RNA 20,000
  • CD4 120
  • Recently diagnosed with pulmonary TB, taking INH,
    RIF, PZA, ETH

14
What to start?Case 3 (cont.)
  • What would you recommend?
  • Indinavir 2 nucs
  • Nelfinavir 2 nucs
  • Efavirenz 2 nucs
  • Nevirapine 2 nucs
  • Something else

15
ANTIRETROVIRAL DRUGS -- 2000
  • nucleotide RTIs
  • tenofovir (PMPA)
  • protease inhibitors
  • saquinavir
  • ritonavir
  • indinavir
  • nelfinavir
  • amprenavir
  • lopinavir
  • (ABT-378/r)
  • nucleoside RTIs
  • zidovudine (AZT, ZDV)
  • didanosine (ddI)
  • zalcitabine (ddC)
  • stavudine (d4T)
  • lamivudine (3TC)
  • abacavir (ABC)
  • NNRTIs
  • nevirapine
  • delavirdine
  • efavirenz

16
DHHS Treatment GuidelinesStrongly Recommended
  • Column A
  • efavirenz
  • indinavir
  • nelfinavir
  • ritonavir saquinavir
  • Column B
  • d4T 3TC
  • d4T ddI
  • ZDV 3TC
  • ZDV ddI

DHHS Guidelines, 1/28/00
17
Combination Rx 3-Drug Regimens
18
DHHS Treatment GuidelinesRecommended
Alternatives
  • Column A
  • abacavir
  • amprenavir
  • delavirdine
  • nelfinavir saquinavir
  • nevirapine
  • ritonavir
  • saquinavir sgc
  • Column B
  • ddI 3TC
  • AZT ddC

DHHS Guidelines, 1/28/00
19
DHHS Treatment GuidelinesOther
  • NO RECOMMENDATION INSUFFICIENT DATA
  • hydroxyurea in combination regimens
  • ritonavir indinavir
  • ritonavir nelfinavir
  • NOT RECOMMENDED SHOULD NOT BE OFFERED
  • all monotherapies
  • saquinavir HGC
  • other 2 NRTIs d4T AZT, ddC 3TC, ddC d4T,
    ddC ddI

DHHS Guidelines, 1/28/00
20
When to change?Case
  • 35 year old woman
  • Recently diagnosed
  • History of oral thrush and zoster
  • HIV RNA 20,000
  • CD4 120
  • Tolerating her current regimen (ZDV/3TC/EFV)
    reasonably well

21
When to change?Case
  • Which of the following would be the STRONGEST
    reason to change therapy?
  • HIV RNA 600 cps/ml by 6 months.
  • CD4 increase of only 10 by 6 months.
  • Recurrence of zoster by 6 months.
  • Persistent mild nausea at 6 months.

22
Treatment Failure Clinical Cohort Studies
23
When to Change Therapy?
  • lt0.5-0.75 log reduction in HIV RNA by 4 weeks or
    lt1.0 log reduction by 8 weeks
  • failure to suppress HIV RNA BLD by 4-6 months
  • repeated detection of HIV RNA after suppression
    BLD
  • any reproducible significant increase of HIV RNA
  • undetectable viremia in pts taking dual nucs
  • persistently declining CD4 cell counts
  • clinical deterioration

DHHS Guidelines, 1/28/00
24
Why Does Treatment Fail Patients?
  • adherence
  • side effects acute and longer-term
  • baseline resistance or cross-resistance
  • use of less potent antiretroviral regimens
  • sequential monotherapy
  • drug levels and drug interactions
  • tissue reservoir penetration
  • other, unknown reasons

25
What to change to?Case (f/u)
  • At 6 months, you substituted d4T for ZDV, with
    resolution of nausea.
  • At 9 months of therapy with d4T/3TC/EFV, patient
    has HIV RNA 12,000 cps/ml.

26
What to change to?Case (f/u)
  • You recommend all of the following EXCEPT
  • Review adherence and tolerability
  • Confirm HIV RNA level
  • Check CD4 count
  • Substitute 3TC with ddI
  • Order genotype

27
What to Change To?
  • very few clinical data to support specific
    strategies
  • use resistance testing
  • change at least two new drugs, and preferably at
    least three drugs
  • may be prudent to delay change in anticipation of
    new drugs
  • clinical expertise required

DHHS Guidelines, 1/28/00
28
Prospective Studies ofResistance Testing in
Salvage Rx
29
DHHS Monitoring Guidelines
  • Use of drug resistance assays
  • Recommended
  • virologic failure on HAART
  • suboptimal HIV RNA suppression after starting rx
  • Consider
  • acute HIV infection
  • Not generally recommended
  • chronic HIV infection, prior to rx
  • after discontinuation of drugs
  • HIV RNA lt1000 copies/ml

DHHS Guidelines, 1/28/00
30
Investigational Drugs 2000
  • nucleoside RTI DAPD/DXG, FTC
  • NNRTI emivirine, capravirine, calanolide A, DPC
    083 and 983
  • nucleotide RTI tenofovir
  • protease inhibitors tipranavir, BMS 232,632, Ag
    1776, PD 178390, DPC 681 and 689
  • entry inhibitors
  • fusion inhibitors T-20, T-1249
  • chemokine receptor inhibitors AMD-3100,
    TAK-799, Schering-C
  • CD4 attachment inhibitors PRO 542
  • TAT inhibitors CG 137053
  • integrase inhibitors

31
Current Approach to Salvage Rx
  • Review antiretroviral hx assess adherence and
    tolerability
  • Distinguish first, second, multiple failures
  • Perform resistance testing while on drugs
  • Identify susceptible drugs/drug classes
  • Consider PK enhancement (RTV, DLV, HU)
  • Consider novel strategies (mega-HAART STI)
  • Consider newer agents through expanded access or
    clinical trials
  • Design a regimen with gt3 active drugs (if
    possible)

32
STIs CASE
  • 43 yo man, HIV
  • Originally evaluated in 6/96 with CD4 52, HIV RNA
    325K
  • Started d4T/3TC/IDV
  • HIV RNA lt400 ever since (and in 8/00, lt50)
  • Last CD4 304 (5/00), 362 (8/00)
  • Calls Friday late afternoon from London to say
    that hes flying to Katmandu tomorrow for a two
    week trek in the Himalayas and has lost his IDV

33
QUESTION 1
  • What do you advise?
  • 1. cancel the trip and obtain meds in London
    ASAP
  • 2. take d4T and 3TC on the trip, resume 3
    drugs on return
  • 3. take d4T only on the trip, resume 3 drugs on
    return
  • 4. take nothing on the trip, resume 3 drugs on
    return
  • 5. discontinue meds, check labs on return

34
Common Reasons for Stopping Antiretrovirals
  • access
  • intercurrent illness
  • toxicities
  • surgery
  • first trimester of pregnancy
  • futility (virologic) in late-stage disease
  • non-adherence

35
Comet Study
  • Ten antiretroviral naïve patients (baseline VL
    63K, CD4 414)
  • Rx with ZDV/3TC/IDV X 28 days
  • Interrupted antiretrovirals X 28 days, VL rebound
    observed, then restarted meds
  • Viral load decline rate the same, no
    resistance-conferring mutations observed
  • With 4-12 months follow-up, VL lt200 maintained

36
Treatment Interruption (1)
  • 837 subjects took 2 nucs EFV or IDV on Dupont
    006
  • 170 had d/c gt2d for adverse event, then restarted
    later
  • for 82 with VL lt400, 70 reached lt50
  • for 88 with VL gt400, 40 reached lt50

37
Treatment Interruption (2)
  • 78 of 1246 clinic patients UAB had treatment
    interruption gt30d, then resumed for gt30d
  • prior to interruption, VL 9K, CD4 230
  • after interruption, VL 400, CD4 230 (best
    response)
  • 59 reached 90 of prior CD4
  • 77 reached within 0.3 logs of prior VL

38
CASE 1 FOLLOW-UP
  • Patient decides to proceed with the trip, and not
    to take any antiretrovirals.
  • 3 weeks later, he present with no complaints and
    asks about doing an STI.

39
QUESTION 1
  • Have you had a patient ask to do an STI?
  • Yes
  • No

40
QUESTION 2
  • Have you used an STI as part of the management of
    an HIV-infected patient (to effect
    virologic/immunologic status)?
  • 1. Yes
  • 2. No

41
Clinical Rationale for STI
  • Issues with antiretroviral regimens
  • adherence
  • toxicity
  • quality of life
  • cost
  • viral eradication not possible

42
STI The Hypothesis
  • In patients with virologic suppression on
    therapy
  • Discontinuing therapy with viral rebound will
    re-stimulate HIV specific immune responses.
  • These immune responses will be able to control
    viremia without antiretroviral therapy.

43
Clinical Settings for STI
  • Acute infection with virologic suppression on
    antiretrovirals
  • Preserve/stimulate HIV-specific cellular
    responses
  • Chronic infection with virologic suppression on
    antiretrovirals
  • stimulate HIV-specific cellular responses and/or
    provide a break from therapy
  • Virologic failure
  • promote reversion to wild type virus improve
    activity of subsequent regimen

44
STI in Acute HIV Infection
  • 8 patients with acute/recent HIV infection
    treated with antiretrovirals (VL lt50 X gt8 months)
  • All underwent STI and all experienced viral
    rebound 3 pts had VL lt5000 and remained off rx
  • Other 5 underwent second STI after resuppression
    and 2 maintained VL lt500 X 5-6 months off meds
  • HIV-specific CD4 responses maintained/augmented
    and CTL responses augmented/broadened

Rosenberg, Nature 2000
45
STI in Chronic HIV Suppression
  • SSITT study The Swiss-Spanish Intermittent
    Trial
  • 122 subjects on HAART, VL lt50 and CD4 gt300
  • STI cycles d/c X 2 wks, rx X 8 wks (4 cycles)
  • 9 of 54 (17) had VL lt5K, 3 of 54 (6) VL lt50
  • No clear changes in VL rebound levels, p24
    specific CD4 IR increased, one subject developed
    3TC and PI resistance, 2 had acute retroviral
    syndrome

Hirschel, Durban 2000
46
STI Risks
  • repopulate reservoirs
  • virologic rebound and resistance
  • CD4 decline
  • clinical
  • acute antiretroviral syndrome
  • AIDS-defining illness

47
Antiretroviral Therapy Conclusions (1)
  • The optimal time to start rx is not clear.
  • The optimal initial rx regimen is not clear.
  • There are many effective combination regimens
    available.
  • First line rx fails in 10-60 of patients.

48
Antiretroviral Therapy Conclusions (2)
  • Better salvage therapy regimens are needed.
  • Resistance testing demonstrates benefits in
    selecting antiretroviral therapy.
  • There are a number of new drugs in development,
    both in existing classes and drugs with new
    mechanisms of action.

49
Antiretroviral Therapy Conclusions (3)
  • It is too early to recommend the routine use of
    STI in any clinical setting.
  • Prospective, randomized, controlled studies are
    needed to establish the risks and benefits of
    STIs.
  • Further research is needed.

50
For more HIV-related resources, please visit
www.hivguidelines.org
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