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

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Management of Antiretroviral Therapy – Case Presentations

Roy M. Gulick, MD, MPH

Weill Medical College of Cornell University

antiretroviral therapy continuing questions
Antiretroviral Therapy: Continuing Questions
  • When to start?
  • What to start?
  • When to switch?
  • What to switch to?
  • Can you stop therapy?
when to start case 1
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?
when to start case 2
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?
when to start case 3
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?
goal of antiretroviral therapy
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
when to start treatment dhhs
symptomatic

asymptomatic,

HIV RNA >10-20K

or CD4 <500

asymptomatic,

HIV RNA <10-20K

and CD4 >500

treat

offer treatment

delay or treat

When To Start Treatment? -- DHHS

DHHS Guidelines, 1/28/00

early vs late treatment
EARLY RX:

HIV disease is progressive.

Rx decreases VL (and resistance) and increases CD4 (and immune function).

3+ years of virologic suppression demonstrated.

DELAYED RX:

Risk of clinical progression low in early disease.

Practical factors (adherence, toxicity outweigh benefits in early disease).

Long term effects unknown.

Early vs. Late Treatment

DHHS Guidelines, 1/28/00

what to start case 1
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
what to start case 1 cont
What to start?Case 1 (cont.)
  • What would you recommend?
    • Indinavir + 2 nucs
    • Nelfinavir + 2 nucs
    • Efavirenz + 2 nucs
    • Nevirapine + 2 nucs
    • Something else
what to start case 2
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
what to start case 2 continued
What to start?Case 2 (continued)
  • What would you recommend?
    • Indinavir + 2 nucs
    • Nelfinavir + 2 nucs
    • Efavirenz + 2 nucs
    • Nevirapine + 2 nucs
    • Something else
what to start case 3
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
what to start case 3 cont
What to start?Case 3 (cont.)
  • What would you recommend?
    • Indinavir + 2 nucs
    • Nelfinavir + 2 nucs
    • Efavirenz + 2 nucs
    • Nevirapine + 2 nucs
    • Something else
antiretroviral drugs 2000
nucleoside RTIs

zidovudine (AZT, ZDV)

didanosine (ddI)

zalcitabine (ddC)

stavudine (d4T)

lamivudine (3TC)

abacavir (ABC)

NNRTIs

nevirapine

delavirdine

efavirenz

nucleotide RTIs

*tenofovir (PMPA)

protease inhibitors

saquinavir

ritonavir

indinavir

nelfinavir

amprenavir

lopinavir

(ABT-378/r)

ANTIRETROVIRAL DRUGS -- 2000
dhhs treatment guidelines strongly recommended
Column A

efavirenz

indinavir

nelfinavir

ritonavir + saquinavir

Column B

d4T + 3TC

d4T + ddI

ZDV + 3TC

ZDV + ddI

DHHS Treatment Guidelines:Strongly Recommended

DHHS Guidelines, 1/28/00

combination rx 3 drug regimens
Study

Regimen

Results (48 wk f/u)

Dupont 006

(N=450)

NEJM1999

ZDV/3TC/EFV,

EFV/IDV,

ZDV/3TC/IDV

EFV regimen superior (?due to excess drop out with IDV)

Glaxo 3005 + 3014

ICAAC 1999 + 2000

ZDV/3TC/ABC,

ZDV/3TC/IDV

comparable VL response (?concern of baseline VL >100K)

Atlantic

(N=298)

Durban 2000

d4T/ddI/NVP,

d4T/ddI/IDV,

d4T/ddI/3TC

comparable VL responses

Combination Rx: 3-Drug Regimens
dhhs treatment guidelines recommended alternatives
Column A

abacavir

amprenavir

delavirdine

nelfinavir + saquinavir

nevirapine

ritonavir

saquinavir sgc

Column B

ddI + 3TC

AZT + ddC

DHHS Treatment Guidelines:Recommended Alternatives

DHHS Guidelines, 1/28/00

dhhs treatment guidelines other
DHHS Treatment Guidelines:Other

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

when to change case
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
when to change case1
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.
treatment failure clinical cohort studies
Clinical

Cohort

N

Failure rate

(% above LD, time)

Amsterdam

271

40% , 48 wks

Cleveland

310

53%, 1 yr

Hopkins

273

63%, 1 yr

Swiss

1517 exp

1157 naïve

38%, 2 yrs

20%, 2 yrs

UCSF

337

50%, 48 wks

Treatment Failure: Clinical Cohort Studies
when to change therapy
When to Change Therapy?
  • <0.5-0.75 log reduction in HIV RNA by 4 weeks or <1.0 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

why does treatment fail patients
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
what to change to case f u
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.
what to change to case f u1
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
what to change to
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

prospective studies of resistance testing in salvage rx
Study

Intervention

Results

VIRADAPT

(N=108)

Lancet 1999

genotype vs. none;

6 month f/u

genotype group had superior VL response

GART

(N=153)

AIDS 2000

genotype (with expert opinion) vs. none; 12 wk f/u

genotype group had superior VL response

VIRA 3001

(N=118)

Durban 2000

phenotype vs. none; 16 wk f/u

phenotype group had superior VL response

Prospective Studies ofResistance Testing in Salvage Rx
dhhs monitoring guidelines
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 <1000 copies/ml

DHHS Guidelines, 1/28/00

investigational drugs 2000
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:
current approach to salvage rx
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 >3 active drugs (if possible)
sti s case
STI’s: CASE
  • 43 yo man, HIV+
    • Originally evaluated in 6/96 with CD4 52, HIV RNA 325K
    • Started d4T/3TC/IDV
    • HIV RNA <400 ever since (and in 8/00, <50)
    • Last CD4: 304 (5/00), 362 (8/00)
    • Calls Friday late afternoon from London to say that he’s flying to Katmandu tomorrow for a two week trek in the Himalayas and has lost his IDV
question 1
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

common reasons for stopping antiretrovirals
Common Reasons for Stopping Antiretrovirals
  • access
  • intercurrent illness
  • toxicities
  • surgery
  • first trimester of pregnancy
  • futility (virologic) in late-stage disease
  • non-adherence
comet study
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 <200 maintained
treatment interruption 1
Treatment Interruption (1)
  • 837 subjects took 2 nucs + EFV or IDV on Dupont 006
  • 170 had d/c >2d for adverse event, then restarted later
  • for 82 with VL <400, ~70% reached <50
  • for 88 with VL >400, ~40% reached <50
treatment interruption 2
Treatment Interruption (2)
  • 78 of 1246 clinic patients UAB had treatment interruption >30d, then resumed for >30d
  • 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
case 1 follow up
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.”
question 11
QUESTION #1
  • Have you had a patient ask to “do an STI”?
  • Yes
  • No
question 2
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

clinical rationale for sti
Clinical Rationale for STI
  • Issues with antiretroviral regimens
    • adherence
    • toxicity
    • quality of life
    • cost
  • viral eradication not possible
sti the hypothesis
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.
clinical settings for sti
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
sti in acute hiv infection
STI in Acute HIV Infection
  • 8 patients with acute/recent HIV infection treated with antiretrovirals (VL <50 X >8 months)
  • All underwent STI and all experienced viral rebound; 3 pts had VL <5000 and remained off rx
  • Other 5 underwent second STI after resuppression and 2 maintained VL <500 X 5-6 months off meds
  • HIV-specific CD4 responses maintained/augmented and CTL responses augmented/broadened

Rosenberg, Nature 2000

sti in chronic hiv suppression
STI in Chronic HIV Suppression
  • SSITT study: The Swiss-Spanish Intermittent Trial
  • 122 subjects on HAART, VL <50 and CD4 >300
  • STI cycles: d/c X 2 wks, rx X 8 wks (4 cycles)
  • 9 of 54 (17%) had VL <5K, 3 of 54 (6%) VL <50
  • 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

sti risks
STI: Risks
  • repopulate reservoirs
  • virologic rebound and resistance
  • CD4 decline
  • clinical
    • acute antiretroviral syndrome
    • AIDS-defining illness
antiretroviral therapy conclusions 1
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.
antiretroviral therapy conclusions 2
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.
antiretroviral therapy conclusions 3
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 STI’s.
  • Further research is needed.
ad