Management of Antiretroviral Therapy

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Management of Antiretroviral Therapy Case
Presentations
Roy M. Gulick, MD, MPH Weill Medical College of
Cornell University
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Antiretroviral Therapy Continuing Questions

• When to start?
• What to start?
• When to switch?
• What to switch to?
• Can you stop therapy?

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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?

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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?

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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?

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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

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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
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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
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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

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What to start?Case 1 (cont.)

• What would you recommend?
• Indinavir 2 nucs
• Nelfinavir 2 nucs
• Efavirenz 2 nucs
• Nevirapine 2 nucs
• Something else

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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

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What to start?Case 2 (continued)

• What would you recommend?
• Indinavir 2 nucs
• Nelfinavir 2 nucs
• Efavirenz 2 nucs
• Nevirapine 2 nucs
• Something else

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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

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What to start?Case 3 (cont.)

• What would you recommend?
• Indinavir 2 nucs
• Nelfinavir 2 nucs
• Efavirenz 2 nucs
• Nevirapine 2 nucs
• Something else

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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

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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
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Combination Rx 3-Drug Regimens
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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
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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
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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

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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.

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Treatment Failure Clinical Cohort Studies
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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
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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

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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.

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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

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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
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Prospective Studies ofResistance Testing in
Salvage Rx
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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
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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

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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)

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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

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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

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Common Reasons for Stopping Antiretrovirals

• access
• intercurrent illness
• toxicities
• surgery
• first trimester of pregnancy
• futility (virologic) in late-stage disease
• non-adherence

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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

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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

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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

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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.

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QUESTION 1

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

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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

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Clinical Rationale for STI

• Issues with antiretroviral regimens
• adherence
• toxicity
• quality of life
• cost
• viral eradication not possible

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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.

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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

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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
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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
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STI Risks

• repopulate reservoirs
• virologic rebound and resistance
• CD4 decline
• clinical
• acute antiretroviral syndrome
• AIDS-defining illness

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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.

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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.

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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.

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