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

Management of Antiretroviral Management of Antiretroviral Therapy – Case PresentationsTherapy – Case Presentations

Roy M. Gulick, MD, MPHRoy M. Gulick, MD, MPHWeill Medical College of Cornell UniversityWeill Medical College of Cornell University

Antiretroviral Therapy: Antiretroviral Therapy: Continuing QuestionsContinuing Questions

• When to start?When to start?

• What to start?What to start?

• When to switch?When to switch?

• What to switch to?What to switch to?

• Can you stop therapy?Can you stop therapy?

When to Start? Case 1When to Start? Case 1

• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• History of oral thrush and zosterHistory of oral thrush and zoster• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120

• Do you recommend treatment?Do you recommend treatment?


• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• AsymptomaticAsymptomatic• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120



• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• AsymptomaticAsymptomatic• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 420CD4 420


Goal of Antiretroviral TherapyGoal of Antiretroviral Therapy

• to suppress HIV RNA (viral load level) as to suppress HIV RNA (viral load level) as low as possible, for as long as possiblelow as possible, for as long as possible

• to preserve or enhance immune functionto preserve or enhance immune function

• to delay clinical progression of HIV diseaseto delay clinical progression of HIV disease

When To Start Treatment? -- When To Start Treatment? -- DHHSDHHS

• symptomaticsymptomatic

• asymptomatic, asymptomatic, HIV RNA >10-20KHIV RNA >10-20Koror CD4 <500 CD4 <500

• asymptomatic,asymptomatic,HIV RNA <10-20KHIV RNA <10-20Kandand CD4 >500 CD4 >500

• treattreat

• offer treatmentoffer treatment

• delay or treatdelay or treat

DHHS Guidelines, 1/28/00

Early vs. Late TreatmentEarly vs. Late Treatment

EARLY RX:EARLY RX:• HIV disease is HIV disease is

progressive.progressive.• Rx decreases VL (and Rx decreases VL (and

resistance) and resistance) and increases CDincreases CD44 (and (and immune function).immune function).

• 3+ years of virologic 3+ years of virologic suppression suppression demonstrated.demonstrated.

DELAYED RX:DELAYED RX:• Risk of clinical Risk of clinical

progression low in progression low in early disease.early disease.

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

• Long term effects Long term effects unknown.unknown.


What to Start? Case 1What to Start? Case 1

• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• History of oral thrush and zosterHistory of oral thrush and zoster• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120

What to start?What to start?Case 1 (cont.)Case 1 (cont.)

• What would you recommend?What would you recommend?1.1. Indinavir + 2 nucsIndinavir + 2 nucs

2.2. Nelfinavir + 2 nucsNelfinavir + 2 nucs

3.3. Efavirenz + 2 nucsEfavirenz + 2 nucs

4.4. Nevirapine + 2 nucsNevirapine + 2 nucs

5.5. Something elseSomething else


• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• History of oral thrush and zosterHistory of oral thrush and zoster• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120• Concerned about her ability to adhere to Concerned about her ability to adhere to

therapytherapy

What to start?What to start?Case 2 (continued)Case 2 (continued)







• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• History of oral thrush and zosterHistory of oral thrush and zoster• Never on treatmentNever on treatment• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120• Recently diagnosed with pulmonary TB, Recently diagnosed with pulmonary TB,

taking INH, RIF, PZA, ETHtaking INH, RIF, PZA, ETH

What to start?What to start?Case 3 (cont.)Case 3 (cont.)






ANTIRETROVIRAL DRUGS ANTIRETROVIRAL DRUGS -- 2000-- 2000

nucleoside RTIsnucleoside RTIs• zidovudine (AZT, ZDV)zidovudine (AZT, ZDV)• didanosine (ddI)didanosine (ddI)• zalcitabine (ddC)zalcitabine (ddC)• stavudine (d4T)stavudine (d4T)• lamivudine (3TC)lamivudine (3TC)• abacavir (ABC)abacavir (ABC)

NNRTIsNNRTIs• nevirapinenevirapine• delavirdinedelavirdine• efavirenzefavirenz

nucleotide RTIsnucleotide RTIs• *tenofovir *tenofovir

(PMPA)(PMPA)

protease inhibitorsprotease inhibitors• saquinavirsaquinavir• ritonavirritonavir• indinavirindinavir• nelfinavirnelfinavir• amprenaviramprenavir• lopinavirlopinavir

(ABT-378/r)(ABT-378/r)

DHHS Treatment Guidelines:DHHS Treatment Guidelines:Strongly RecommendedStrongly Recommended

Column AColumn A

• efavirenzefavirenz• indinavirindinavir• nelfinavirnelfinavir• ritonavir + saquinavirritonavir + saquinavir

Column BColumn B

• d4T + 3TCd4T + 3TC• d4T + ddId4T + ddI• ZDV + 3TCZDV + 3TC• ZDV + ddIZDV + ddI


Combination Rx: 3-Drug RegimensCombination Rx: 3-Drug Regimens

comparable VL comparable VL responsesresponses

d4T/ddI/NVP,d4T/ddI/NVP,

d4T/ddI/IDV,d4T/ddI/IDV,

d4T/ddI/3TCd4T/ddI/3TC

AtlanticAtlantic

(N=298)(N=298)

Durban 2000Durban 2000

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

ZDV/3TC/ABC,ZDV/3TC/ABC,

ZDV/3TC/IDVZDV/3TC/IDV

Glaxo 3005 + Glaxo 3005 + 30143014

ICAAC 1999 + ICAAC 1999 + 20002000

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

ZDV/3TC/EFV,ZDV/3TC/EFV,

EFV/IDV,EFV/IDV,

ZDV/3TC/IDVZDV/3TC/IDV

Dupont 006Dupont 006

(N=450)(N=450)

NEJMNEJM 19991999

Results (48 wk f/u)Results (48 wk f/u)RegimenRegimenStudyStudy

DHHS Treatment Guidelines:DHHS Treatment Guidelines:Recommended AlternativesRecommended Alternatives

Column AColumn A• abacavirabacavir• amprenaviramprenavir• delavirdinedelavirdine• nelfinavir + saquinavirnelfinavir + saquinavir• nevirapinenevirapine• ritonavirritonavir• saquinavir sgcsaquinavir sgc

Column BColumn B

• ddI + 3TCddI + 3TC• AZT + ddCAZT + ddC


DHHS Treatment Guidelines:DHHS Treatment Guidelines:OtherOther

NO RECOMMENDATION; INSUFFICIENT DATANO RECOMMENDATION; INSUFFICIENT DATA• hydroxyurea in combination regimenshydroxyurea in combination regimens

• ritonavir + indinavirritonavir + indinavir

• ritonavir + nelfinavirritonavir + nelfinavir

NOT RECOMMENDED; SHOULD NOT BE OFFEREDNOT RECOMMENDED; SHOULD NOT BE OFFERED• all monotherapiesall monotherapies

• saquinavir HGCsaquinavir HGC

• other 2 NRTIs: d4T + AZT, ddC + 3TC, ddC + d4T, ddC + ddIother 2 NRTIs: d4T + AZT, ddC + 3TC, ddC + d4T, ddC + ddI


When to change?When to change?Case Case

• 35 year old woman35 year old woman• Recently diagnosedRecently diagnosed• History of oral thrush and zosterHistory of oral thrush and zoster• HIV RNA 20,000HIV RNA 20,000• CD4 120CD4 120• Tolerating her current regimen Tolerating her current regimen

(ZDV/3TC/EFV) reasonably well(ZDV/3TC/EFV) reasonably well

When to change?When to change?Case Case

• Which of the following would be the Which of the following would be the STRONGEST reason to change STRONGEST reason to change therapy?therapy?

1.1. HIV RNA 600 cps/ml by 6 months.HIV RNA 600 cps/ml by 6 months.

2.2. CD4 increase of only +10 by 6 months.CD4 increase of only +10 by 6 months.

3.3. Recurrence of zoster by 6 months.Recurrence of zoster by 6 months.

4.4. Persistent mild nausea at 6 months.Persistent mild nausea at 6 months.

Treatment Failure: Treatment Failure: Clinical Cohort StudiesClinical Cohort Studies

50%, 48 wks50%, 48 wks337337UCSFUCSF

38%, 2 yrs38%, 2 yrs

20%, 2 yrs20%, 2 yrs

1517 exp1517 exp

1157 naïve1157 naïve

SwissSwiss

63%, 1 yr63%, 1 yr273273HopkinsHopkins

53%, 1 yr53%, 1 yr310310ClevelandCleveland

40% , 48 wks40% , 48 wks271271AmsterdamAmsterdam

Failure rateFailure rate

(% above LD, time)(% above LD, time)

NNClinicalClinical

CohortCohort

When to Change Therapy?When to Change Therapy?

• <0.5-0.75 log reduction in HIV RNA by 4 weeks <0.5-0.75 log reduction in HIV RNA by 4 weeks or <1.0 log reduction by 8 weeksor <1.0 log reduction by 8 weeks

• failure to suppress HIV RNA BLD by 4-6 monthsfailure to suppress HIV RNA BLD by 4-6 months• repeated detection of HIV RNA after suppression repeated detection of HIV RNA after suppression

BLDBLD• any reproducible significant increase of HIV RNAany reproducible significant increase of HIV RNA• undetectable viremia in pts taking dual nucsundetectable viremia in pts taking dual nucs• persistently declining CD4 cell countspersistently declining CD4 cell counts• clinical deteriorationclinical deterioration


Why Does Treatment Fail Why Does Treatment Fail Patients?Patients?

• adherenceadherence• side effects – acute and longer-termside effects – acute and longer-term• baseline resistance or cross-resistancebaseline resistance or cross-resistance• use of less potent antiretroviral regimensuse of less potent antiretroviral regimens• sequential monotherapysequential monotherapy• drug levels and drug interactionsdrug levels and drug interactions• tissue reservoir penetrationtissue reservoir penetration• other, unknown reasonsother, unknown reasons

What to change to?What to change to?Case (f/u)Case (f/u)

• At 6 months, you substituted d4T for At 6 months, you substituted d4T for ZDV, with resolution of nausea.ZDV, with resolution of nausea.

• At 9 months of therapy with At 9 months of therapy with d4T/3TC/EFV, patient has HIV RNA d4T/3TC/EFV, patient has HIV RNA 12,000 cps/ml.12,000 cps/ml.

What to change to?What to change to?Case (f/u)Case (f/u)

• You recommend all of the following You recommend all of the following EXCEPT:EXCEPT:

1.1. Review adherence and tolerabilityReview adherence and tolerability

2.2. Confirm HIV RNA levelConfirm HIV RNA level

3.3. Check CD4 countCheck CD4 count

4.4. Substitute 3TC with ddISubstitute 3TC with ddI

5.5. Order genotypeOrder genotype

What to Change To?What to Change To?

• very few clinical data to support specific very few clinical data to support specific strategiesstrategies

• use resistance testinguse resistance testing• change at least two new drugs, and preferably change at least two new drugs, and preferably

at least three drugsat least three drugs• may be prudent to delay change in anticipation may be prudent to delay change in anticipation

of new drugsof new drugs• clinical expertise requiredclinical expertise required


Prospective Studies ofProspective Studies ofResistance Testing in Salvage RxResistance Testing in Salvage Rx

phenotype group phenotype group had superior VL had superior VL responseresponse

phenotype vs. phenotype vs. none; 16 wk f/unone; 16 wk f/u

VIRA 3001VIRA 3001

(N=118)(N=118)

Durban 2000Durban 2000

genotype group genotype group had superior VL had superior VL responseresponse

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

GARTGART

(N=153)(N=153)

AIDS 2000AIDS 2000

genotype group genotype group had superior VL had superior VL responseresponse

genotype vs. none; genotype vs. none;

6 month f/u6 month f/u

VIRADAPTVIRADAPT

(N=108)(N=108)

Lancet 1999Lancet 1999

ResultsResultsInterventionInterventionStudyStudy

DHHS Monitoring GuidelinesDHHS Monitoring Guidelines

• Use of drug resistance assaysUse of drug resistance assays• RecommendedRecommended

• virologic failure on HAARTvirologic failure on HAART• suboptimal HIV RNA suppression after starting rxsuboptimal HIV RNA suppression after starting rx

• ConsiderConsider• acute HIV infectionacute HIV infection

• Not generally recommendedNot generally recommended• chronic HIV infection, prior to rxchronic HIV infection, prior to rx• after discontinuation of drugsafter discontinuation of drugs• HIV RNA <1000 copies/mlHIV RNA <1000 copies/ml


Investigational Drugs: 2000Investigational Drugs: 2000• nucleoside RTI:nucleoside RTI: DAPD/DXG, FTC DAPD/DXG, FTC• NNRTI:NNRTI: emivirine, capravirine, calanolide A, emivirine, capravirine, calanolide A,

DPC 083 and 983DPC 083 and 983• nucleotide RTI:nucleotide RTI: tenofovir tenofovir• protease inhibitors:protease inhibitors: tipranavir, BMS 232,632, tipranavir, BMS 232,632,

Ag 1776, PD 178390, DPC 681 and 689Ag 1776, PD 178390, DPC 681 and 689• entry inhibitors:entry inhibitors:

• fusion inhibitors:fusion inhibitors: T-20, T-1249 T-20, T-1249• chemokine receptor inhibitors: chemokine receptor inhibitors: AMD-3100, TAK-799, AMD-3100, TAK-799,

Schering-CSchering-C• CD4 attachment inhibitors:CD4 attachment inhibitors: PRO 542 PRO 542

• TAT inhibitors:TAT inhibitors: CG 137053 CG 137053• integrase inhibitors:integrase inhibitors:

Current Approach to Salvage RxCurrent Approach to Salvage Rx• Review antiretroviral hx; assess adherence and Review antiretroviral hx; assess adherence and

tolerabilitytolerability• Distinguish first, second, multiple failuresDistinguish first, second, multiple failures• Perform resistance testing while on drugsPerform resistance testing while on drugs• Identify susceptible drugs/drug classesIdentify susceptible drugs/drug classes• Consider PK enhancement (RTV, DLV, HU)Consider PK enhancement (RTV, DLV, HU)• Consider novel strategies Consider novel strategies (mega-HAART; STI)(mega-HAART; STI)• Consider newer agents through expanded access Consider newer agents through expanded access

or clinical trialsor clinical trials• Design a regimen with Design a regimen with >>3 active drugs (if 3 active drugs (if

possible)possible)

STI’s: CASESTI’s: CASE

• 43 yo man, HIV+43 yo man, HIV+• Originally evaluated in 6/96 with CD4 52, HIV Originally evaluated in 6/96 with CD4 52, HIV

RNA 325KRNA 325K• Started d4T/3TC/IDVStarted d4T/3TC/IDV• HIV RNA <400 ever since (and in 8/00, <50)HIV RNA <400 ever since (and in 8/00, <50)• Last CD4: 304 (5/00), 362 (8/00)Last CD4: 304 (5/00), 362 (8/00)• Calls Friday late afternoon from London to say Calls Friday late afternoon from London to say

that he’s flying to Katmandu tomorrow for a that he’s flying to Katmandu tomorrow for a two week trek in the Himalayas and has lost his two week trek in the Himalayas and has lost his IDVIDV

QUESTION #1QUESTION #1• What do you advise?What do you advise?

1. cancel the trip and obtain meds in London 1. cancel the trip and obtain meds in London ASAPASAP

2. take d4T and 3TC on the trip, resume 3 2. take d4T and 3TC on the trip, resume 3 drugs on returndrugs on return

3. take d4T only on the trip, resume 3 drugs 3. take d4T only on the trip, resume 3 drugs on returnon return

4. take nothing on the trip, resume 3 drugs 4. take nothing on the trip, resume 3 drugs on on returnreturn

5. discontinue meds, check labs on return5. discontinue meds, check labs on return

Common Reasons for Common Reasons for Stopping AntiretroviralsStopping Antiretrovirals

• accessaccess

• intercurrent illnessintercurrent illness

• toxicitiestoxicities

• surgerysurgery

• first trimester of pregnancyfirst trimester of pregnancy

• futility (virologic) in late-stage diseasefutility (virologic) in late-stage disease

• non-adherencenon-adherence

Comet StudyComet Study

• Ten antiretroviral naïve patients (baseline VL Ten antiretroviral naïve patients (baseline VL 63K, CD4 414)63K, CD4 414)

• Rx with ZDV/3TC/IDV X 28 daysRx with ZDV/3TC/IDV X 28 days• Interrupted antiretrovirals X 28 days, VL Interrupted antiretrovirals X 28 days, VL

rebound observed, then restarted medsrebound observed, then restarted meds• Viral load decline rate the same, no Viral load decline rate the same, no

resistance-conferring mutations observedresistance-conferring mutations observed• With 4-12 months follow-up, VL <200 With 4-12 months follow-up, VL <200

maintainedmaintained

Treatment Interruption (1)Treatment Interruption (1)

• 837 subjects took 2 nucs + EFV or IDV on 837 subjects took 2 nucs + EFV or IDV on Dupont 006Dupont 006

• 170 had d/c 170 had d/c >>2d for adverse event, then 2d for adverse event, then restarted laterrestarted later

• for 82 with VL <400, ~70% reached <50for 82 with VL <400, ~70% reached <50

• for 88 with VL >400, ~40% reached <50for 88 with VL >400, ~40% reached <50

Treatment Interruption (2)Treatment Interruption (2)

• 78 of 1246 clinic patients UAB had 78 of 1246 clinic patients UAB had treatment interruption treatment interruption >>30d, then resumed 30d, then resumed for for >>30d30d

• prior to interruption, VL 9K, CD4 230prior to interruption, VL 9K, CD4 230

• after interruption, VL 400, CD4 230 (best after interruption, VL 400, CD4 230 (best response)response)

• 59% reached 90% of prior CD459% reached 90% of prior CD4

• 77% reached within 0.3 logs of prior VL77% reached within 0.3 logs of prior VL

CASE #1 FOLLOW-UPCASE #1 FOLLOW-UP

• Patient decides to proceed with the trip, and Patient decides to proceed with the trip, and not to take any antiretrovirals.not to take any antiretrovirals.

• 3 weeks later, he present with no 3 weeks later, he present with no complaints and asks about “doing an STI.”complaints and asks about “doing an STI.”

QUESTION #1QUESTION #1

• Have you had a patient ask to “do an Have you had a patient ask to “do an STI”?STI”?

1.1. YesYes

2.2. NoNo

QUESTION #2QUESTION #2

• Have you used an STI as part of the Have you used an STI as part of the management of an HIV-infected patient management of an HIV-infected patient (to effect virologic/immunologic status)?(to effect virologic/immunologic status)?

1. Yes1. Yes

2. No2. No

Clinical Rationale for STIClinical Rationale for STI

• Issues with antiretroviral regimensIssues with antiretroviral regimens• adherenceadherence• toxicitytoxicity• quality of lifequality of life• costcost

• viral eradication not possibleviral eradication not possible

STI: The HypothesisSTI: The Hypothesis

In patients with virologic suppression on In patients with virologic suppression on therapy:therapy:

• Discontinuing therapy with viral rebound will Discontinuing therapy with viral rebound will re-stimulate HIV specific immune responses.re-stimulate HIV specific immune responses.

• These immune responses will be able to These immune responses will be able to control viremia without antiretroviral therapy.control viremia without antiretroviral therapy.

Clinical Settings for STIClinical Settings for STI

• Acute infectionAcute infection with virologic suppression on with virologic suppression on antiretroviralsantiretrovirals• Preserve/stimulate HIV-specific cellular responsesPreserve/stimulate HIV-specific cellular responses

• Chronic infectionChronic infection with virologic suppression with virologic suppression on antiretroviralson antiretrovirals• stimulate HIV-specific cellular responses and/or stimulate HIV-specific cellular responses and/or

provide a break from therapyprovide a break from therapy

• Virologic failureVirologic failure• promote reversion to wild type virus; improve promote reversion to wild type virus; improve

activity of subsequent regimenactivity of subsequent regimen

STI in Acute HIV Infection STI in Acute HIV Infection

• 8 patients with acute/recent HIV infection treated 8 patients with acute/recent HIV infection treated with antiretrovirals (VL <50 X >8 months)with antiretrovirals (VL <50 X >8 months)

• All underwent STI and all experienced viral All underwent STI and all experienced viral rebound; 3 pts had VL <5000 and remained off rxrebound; 3 pts had VL <5000 and remained off rx

• Other 5 underwent second STI after resuppression Other 5 underwent second STI after resuppression and 2 maintained VL <500 X 5-6 months off medsand 2 maintained VL <500 X 5-6 months off meds

• HIV-specific CD4 responses HIV-specific CD4 responses maintained/augmented and CTL responses maintained/augmented and CTL responses augmented/broadenedaugmented/broadened

Rosenberg, Nature 2000

STI in Chronic HIV SuppressionSTI in Chronic HIV Suppression

• SSITT study: The Swiss-Spanish Intermittent TrialSSITT study: The Swiss-Spanish Intermittent Trial• 122 subjects on HAART, VL <50 and CD4 >300122 subjects on HAART, VL <50 and CD4 >300• STI cycles: d/c X 2 wks, rx X 8 wks (4 cycles)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 <509 of 54 (17%) had VL <5K, 3 of 54 (6%) VL <50• No clear changes in VL rebound levels, p24 specific No clear changes in VL rebound levels, p24 specific

CD4 IR increased, one subject developed 3TC and CD4 IR increased, one subject developed 3TC and PI resistance, 2 had acute retroviral syndromePI resistance, 2 had acute retroviral syndrome

Hirschel, Durban 2000

STI: RisksSTI: Risks

• repopulate reservoirsrepopulate reservoirs

• virologic rebound and resistancevirologic rebound and resistance

• CD4 declineCD4 decline

• clinicalclinical• acute antiretroviral syndromeacute antiretroviral syndrome• AIDS-defining illnessAIDS-defining illness

Antiretroviral Therapy: Antiretroviral Therapy: Conclusions (1)Conclusions (1)

• The optimal time to start rx is not clear.The optimal time to start rx is not clear.

• The optimal initial rx regimen is not clear.The optimal initial rx regimen is not clear.

• There are many effective combination There are many effective combination regimens available.regimens available.

• First line rx fails in 10-60% of patients.First line rx fails in 10-60% of patients.


• Better “salvage therapy” regimens are Better “salvage therapy” regimens are needed.needed.

• Resistance testing demonstrates benefits in Resistance testing demonstrates benefits in selecting antiretroviral therapy.selecting antiretroviral therapy.

• There are a number of new drugs in There are a number of new drugs in development, both in existing classes and development, both in existing classes and drugs with new mechanisms of action.drugs with new mechanisms of action.


• It is too early to recommend the routine use It is too early to recommend the routine use of STI in any clinical setting.of STI in any clinical setting.

• Prospective, randomized, controlled studies Prospective, randomized, controlled studies are needed to establish the risks and are needed to establish the risks and benefits of STI’s.benefits of STI’s.

• Further research is needed.Further research is needed.

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

Documents

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