Structured Treatment Structured Treatment Interruption in HIV Interruption in HIV

Positive PatientsPositive Patients

Leah Jackson, Leah Jackson, BScPhmBScPhmPharmacy Resident Pharmacy Resident

HIV RotationHIV RotationJanuary 23, 2007January 23, 2007

ObjectivesObjectives

To become reTo become re--acquainted with the basics of acquainted with the basics of HAART for HIV infectionHAART for HIV infectionTo list reasons why a patient may want to To list reasons why a patient may want to interrupt HAARTinterrupt HAARTTo describe the appropriateness of structured To describe the appropriateness of structured treatment interruption based on the findings of treatment interruption based on the findings of the SMART studythe SMART study

HAARTHAART

Highly Active AntiHighly Active Anti--Retroviral TherapyRetroviral TherapyOften involves the use of 3 or more antiOften involves the use of 3 or more anti--retroviralsretrovirals ((ARVsARVs) acting at different stages of ) acting at different stages of the HIV life cycle (the HIV life cycle (ieie/ PIs, / PIs, NNRTIsNNRTIs, , NRTIsNRTIs, , etc)etc)Combination therapy provides potent viral Combination therapy provides potent viral suppression leading to good immune system suppression leading to good immune system recoveryrecoveryLifeLife--long uselong useHIV now considered a chronic diseaseHIV now considered a chronic disease

Pharmacotherapy basics Pharmacotherapy basics

AbacavirAbacavir (ABC)(ABC)LamivudineLamivudine (3TC)(3TC)ZidovudineZidovudine (AZT)(AZT)StavudineStavudine (d4T)(d4T)DidanosineDidanosine ((ddIddI))**TenofovirTenofovir (TDF)(TDF)

EfavirenzEfavirenz (EFV)(EFV)NevirapineNevirapine (NVP)(NVP)**EtravirineEtravirine (TMC (TMC 125)125)

Lopinavir/rLopinavir/rFosamprenavirFosamprenavirAtazanavirAtazanavirNelfinavirNelfinavir**Darunavir/rDarunavir/r(TMC 114)(TMC 114)

Nucleoside reverse Nucleoside reverse transcriptase inhibitors transcriptase inhibitors ““NRTIsNRTIs””

NonNon--nucleoside reverse nucleoside reverse transcriptase inhibitors transcriptase inhibitors ““NNRTIsNNRTIs””

Protease inhibitorsProtease inhibitors“PIs”“PIs”

Other agentsOther agents

EnfuvirtideEnfuvirtide (fusion inhibitor)(fusion inhibitor)MaravirocMaraviroc, , vicrivirocvicriviroc (CCR5 receptor (CCR5 receptor antagonists)antagonists)MKMK--0518 (0518 (integraseintegrase inhibitor)inhibitor)22

DHHS GuidelinesDHHS Guidelines33

http://http://AIDSinfo.nih.govAIDSinfo.nih.gov

Adverse EffectsAdverse Effects

NRTI backboneNRTI backboneNauseaNauseaPeripheral neuropathy (often “d” drugs)Peripheral neuropathy (often “d” drugs)Lactic acidosisLactic acidosisHepatic Hepatic steatosissteatosisPancreatitisPancreatitisLipodystrophyLipodystrophy (d4T)(d4T)Renal insufficiency (TDF)Renal insufficiency (TDF)Hypersensitivity (ABC)Hypersensitivity (ABC)Bone marrow suppression, headache, insomnia (AZT)Bone marrow suppression, headache, insomnia (AZT)

Adverse EffectsAdverse Effects

NNRTIsNNRTIsRash Rash →→ StevensStevens--Johnson syndrome (esp. NVP)Johnson syndrome (esp. NVP)↑↑ liver liver transaminasestransaminases →→ hepatitis, hepatic necrosishepatitis, hepatic necrosisCNS effects with EFV (insomnia, abnormal dreams, CNS effects with EFV (insomnia, abnormal dreams, dizziness, confusion, abnormal thinking, dizziness, confusion, abnormal thinking, hallucinationshallucinations…….).)TeratogenesisTeratogenesis (EFV)(EFV)++ potential for drug interactions++ potential for drug interactions

Adverse EffectsAdverse Effects

PIsPIsN/V/DN/V/D↑↑ liver liver transaminasestransaminasesHyperlipidemiaHyperlipidemia (esp. (esp. ↑↑ TG)TG)HyperglycemiaHyperglycemiaFat Fat maldistributionmaldistributionHyperbilirubinemiaHyperbilirubinemia ((atazanaviratazanavir, , indinavirindinavir))NephrolithiasisNephrolithiasis ((indinavirindinavir))Oral Oral paresthesiaparesthesia ((ritonavirritonavir))Intracranial hemorrhage (Intracranial hemorrhage (tipranavirtipranavir))++ potential for drug interactions++ potential for drug interactions

Potential reasons for interruptionPotential reasons for interruption

Adverse events!Adverse events!Pill burden and necessity of adherencePill burden and necessity of adherenceResistanceResistanceCostCost

Question:Question:

Can we safely interrupt ARV treatment???Can we safely interrupt ARV treatment???

““CD4+ CountCD4+ Count--Guided Interruption of Guided Interruption of Antiretroviral Treatment”Antiretroviral Treatment”44

The SMART study group. NEJM 2006;335:2283The SMART study group. NEJM 2006;335:2283--9696

Enrolment began Enrolment began January 2, 2002January 2, 2002318 sites in 33 countries 318 sites in 33 countries →→ incl. TGH!incl. TGH!Ambitious target of 6000 patientsAmbitious target of 6000 patientsFollowFollow--up planned for 6+ yearsup planned for 6+ years

BackgroundBackground

Despite Despite ↓↓ morbidity and mortality with morbidity and mortality with HAART, its effectiveness is limited by adverse HAART, its effectiveness is limited by adverse events (metabolic and cardiovascular events (metabolic and cardiovascular complications), problems with adherence, and complications), problems with adherence, and viral resistance (incl. multiviral resistance (incl. multi--drug resistance)drug resistance)Lifelong treatment Lifelong treatment

PurposePurpose

To study a treatmentTo study a treatment--sparing strategy in hopes sparing strategy in hopes of providing the benefits of ARV therapy while of providing the benefits of ARV therapy while minimizing the adverse events and other risks of minimizing the adverse events and other risks of longlong--term useterm use

InterventionIntervention

5472 patients randomized:5472 patients randomized:•• Drug conservation arm: episodic drug Drug conservation arm: episodic drug txtx based on based on

CD4 count; start CD4 count; start txtx if <250, and stop when >350if <250, and stop when >350•• Viral suppression arm: uninterrupted Viral suppression arm: uninterrupted txtx with goal with goal

of maximal and continuous suppression of HIV of maximal and continuous suppression of HIV replication (standard care)replication (standard care)

Inclusion criteriaInclusion criteria

>13 years of age (median age 43)>13 years of age (median age 43)Not pregnant/breastfeedingNot pregnant/breastfeedingEligible whether or not they had received or Eligible whether or not they had received or were currently receiving were currently receiving ARVsARVs (84% on (84% on txtx at at baseline)baseline)Willing to initiate, modify or stop Willing to initiate, modify or stop ARVsARVsaccording to the guidelinesaccording to the guidelines

Case example: CCCase example: CC

44 44 yoyo ♂♂ diagnosed at age 38diagnosed at age 38Sexual transmission (homosexual)Sexual transmission (homosexual)At At dxdx: CD4=620, VL=115 795: CD4=620, VL=115 795Started treatment during Started treatment during seroconversionseroconversion illness illness →→ EFV EFV and and CombivirCombivir (AZT/3TC)(AZT/3TC)Numbness in fingertips, mild Numbness in fingertips, mild lipoatrophylipoatrophy, bad dreams, bad dreams++ interested in stopping treatment++ interested in stopping treatmentEnrolled in SMART July 2005; CD4 800, VL <50Enrolled in SMART July 2005; CD4 800, VL <50Randomized to discontinue medicationsRandomized to discontinue medications

Case example: RCCase example: RC

42 42 yoyo ♂♂ diagnosed at age 28diagnosed at age 28Sexual transmission (heterosexual)Sexual transmission (heterosexual)ARV history: AZT, AZT/3TC study (impotence, fatigue, h/a, ARV history: AZT, AZT/3TC study (impotence, fatigue, h/a, nausea, anemia); nausea, anemia); ddIddI; ; ddCddC and and saquinavirsaquinavir; EFV, d4T, ; EFV, d4T, nelfinavirnelfinavir19981998--present present Has experienced opportunistic infections (Has experienced opportunistic infections (OIsOIs) including ) including disseminated zosterdisseminated zosterTingling extremities, significant abdominal obesity and buffalo Tingling extremities, significant abdominal obesity and buffalo hump, ++ vivid dreams (requires sleeping pill), hump, ++ vivid dreams (requires sleeping pill), dyslipidemiadyslipidemia (TC (TC 13.48, TG 11.45 prior to lipid 13.48, TG 11.45 prior to lipid txtx))Enrolled in SMART July 2005; CD4 1001, VL <50Enrolled in SMART July 2005; CD4 1001, VL <50Randomized to continue HAARTRandomized to continue HAART

DemographicsDemographics

Similar at baseline, incl. CV risk factorsSimilar at baseline, incl. CV risk factorsWomen (27%), hepatitis B and C coWomen (27%), hepatitis B and C co--infection, infection, various races (white 56%, black 29%, other various races (white 56%, black 29%, other 15%)15%)Median CD4 = 597Median CD4 = 597VL < 400 in 72% of patientsVL < 400 in 72% of patientsMedian 6 years since first Median 6 years since first ARVsARVs24% had prior AIDS24% had prior AIDS--related illnessrelated illness55

Monitoring and followMonitoring and follow--upup

Scheduled visits @ 1 mo and 2 Scheduled visits @ 1 mo and 2 mosmos, q2mos , q2mos thereafter for 1thereafter for 1stst year, then q4mos in 2year, then q4mos in 2ndnd and and subsequent yearssubsequent yearsMore frequent if clinical care requiredMore frequent if clinical care requiredIndependent data and safety board to review Independent data and safety board to review interim analyses at least yearlyinterim analyses at least yearlySTOPPED EARLY: mean followSTOPPED EARLY: mean follow--up only 16 up only 16 mosmos; 26% of pts followed > 2 years; 26% of pts followed > 2 years

EndpointsEndpoints

PrimaryPrimaryNew or recurrent opportunistic diseaseNew or recurrent opportunistic disease5,65,6 or death or death from any causefrom any cause

SecondarySecondaryDeath from any causeDeath from any causeSerious opportunistic diseaseSerious opportunistic disease77

Major cardiovascular, renal, or hepatic diseaseMajor cardiovascular, renal, or hepatic disease66

Grade 4 adverse eventsGrade 4 adverse events88 (not incl. opportunistic (not incl. opportunistic disease) or death from any causedisease) or death from any cause

ResultsResults

Median duration of 1Median duration of 1stst interruption=17 interruption=17 mosmosN=343 stopped N=343 stopped ARVsARVs a 2a 2ndnd timetimeN=62 stopped N=62 stopped ARVsARVs ≥3 times≥3 timesCD4 count ↓ 87 cells/mmCD4 count ↓ 87 cells/mm33 per month x 2 per month x 2 mosmos, , then ↓ at lower rate (drug conservation group)then ↓ at lower rate (drug conservation group)CD4 count was 206 cells/mmCD4 count was 206 cells/mm33 lower in drug lower in drug conservation groupconservation groupWithin 2 Within 2 mosmos, patients with VL ≤ 400 , patients with VL ≤ 400 copies/copies/mLmL ↓ from 72% to 6%↓ from 72% to 6%

CD4 count changesCD4 count changes66

% patients with VL ≤ 400% patients with VL ≤ 40066

ResultsResults

After After reinitiationreinitiation of of ARVsARVs, time to VL ≤ 400 , time to VL ≤ 400 copies/copies/mLmL was 3.1 was 3.1 mosmosCD4 count ↑ 166 cells/mmCD4 count ↑ 166 cells/mm33 within 8 within 8 mosmos

ResultsResults

72.3%72.3%28.8%28.8%VL ≤ 400 VL ≤ 400 copies/copies/mLmL (% (% time)time)

1.8%1.8%8.6%8.6%CD4 count < 250 CD4 count < 250 (% time)(% time)

92.7%92.7%67.9%67.9%CD4 count ≥ 350 CD4 count ≥ 350 (% time)(% time)

93.7%93.7%33.4%33.4%Received Received ARVsARVs(% time)(% time)

Viral suppression Viral suppression (VS) group(VS) group

Drug conservation Drug conservation (DC) group(DC) group

ResultsResults44

ResultsResults

Hazard ratio (HR) for primary endpoint Hazard ratio (HR) for primary endpoint (opportunistic disease of death from any cause) (opportunistic disease of death from any cause) = 2.6 (95% CI 1.9= 2.6 (95% CI 1.9--3.7; P<0.001)3.7; P<0.001)Most common individual eventsMost common individual events

DC group: death from any cause (39%), esophageal DC group: death from any cause (39%), esophageal candidiasiscandidiasis (20%), and PCP (7%)(20%), and PCP (7%)VS group: death from any cause (57%) and VS group: death from any cause (57%) and esophageal esophageal candidiasiscandidiasis (15%)(15%)

ResultsResults

Number of deaths = 85Number of deaths = 85Only 8% due to opportunistic diseaseOnly 8% due to opportunistic diseaseCommon causes of death outside of Common causes of death outside of opportunistic disease:opportunistic disease:

Cancer (DC>VS)Cancer (DC>VS)CVD (DC>VS)CVD (DC>VS)Substance abuseSubstance abuseAccident, violence, or suicideAccident, violence, or suicideUnknown for 18 patients (15 DC, 3 VS)Unknown for 18 patients (15 DC, 3 VS)

ResultsResults

Sensitivity analysis on primary endpoint:Sensitivity analysis on primary endpoint:New opportunistic disease (OD) or death from any New opportunistic disease (OD) or death from any cause HR=2.6 (95% CI 1.8cause HR=2.6 (95% CI 1.8--3.7, P<0.001)3.7, P<0.001)Fatal and nonFatal and non--fatal cases of OD (excl. deaths from fatal cases of OD (excl. deaths from other causes) HR=3.6 (2.2other causes) HR=3.6 (2.2--5.9, P<0.001)5.9, P<0.001)All reported cases of ODs and deaths irrespective of All reported cases of ODs and deaths irrespective of classification after review by endpoint review classification after review by endpoint review committee HR=2.5 (1.9committee HR=2.5 (1.9--33, P<0.001)33, P<0.001)

(Note: HR reported for DC group (Note: HR reported for DC group vsvs VSVS group)group)

ResultsResults

Secondary endpoints (DC group Secondary endpoints (DC group vsvs VSVS group)group)Death from any cause: HR=1.8 (95% CI 1.2Death from any cause: HR=1.8 (95% CI 1.2--2.9)2.9)Serious opportunistic disease: HR=6.6 (1.5Serious opportunistic disease: HR=6.6 (1.5--29.1)29.1)Major CV, renal, or hepatic disease: HR=1.7 (1.1Major CV, renal, or hepatic disease: HR=1.7 (1.1--2.5)2.5)Grade 4 event or death from any cause: HR=1.3 Grade 4 event or death from any cause: HR=1.3 (1.0(1.0--1.6)1.6)

Clinical ApplicationClinical ApplicationContinuous use of Continuous use of ARVsARVs is superior to episodic is superior to episodic use guided by the CD4 count thresholds used in use guided by the CD4 count thresholds used in the SMART studythe SMART studySMART strategy is deleterious SMART strategy is deleterious →→ eeven patients ven patients with with ““goodgood”” CD4 counts are at risk for bad CD4 counts are at risk for bad clinical events if not on treatment (outside of clinical events if not on treatment (outside of ODs as well)ODs as well)Lack of benefit of interruption on major adverse Lack of benefit of interruption on major adverse eventsevents

Clinical ApplicationClinical Application

Interruption strategies should be viewed Interruption strategies should be viewed with net clinical risk unless proven otherwise with net clinical risk unless proven otherwise in properly powered studiesin properly powered studies

Study limitationsStudy limitations

Overall, very well done!Overall, very well done!FollowFollow--up missing for 73 patients at the close of the up missing for 73 patients at the close of the study (32 in interruption group, 41 in suppression study (32 in interruption group, 41 in suppression group)group)UnblindedUnblinded, but endpoint review committee unaware of , but endpoint review committee unaware of treatment assignmentstreatment assignmentsEqual treatment of groups?Equal treatment of groups?Concomitant diseases and medications unknown, Concomitant diseases and medications unknown, including use of OI treatment and prophylaxisincluding use of OI treatment and prophylaxis

Unanswered questionsUnanswered questions

Is it possible to safely interrupt treatment at Is it possible to safely interrupt treatment at higher CD4 thresholds?higher CD4 thresholds?Smaller studies have attempted to answer some Smaller studies have attempted to answer some of them of them →→ StaccatoStaccato99 (n=284) deferred (n=284) deferred treatment until CD4 < 350; compared to treatment until CD4 < 350; compared to continuous continuous txtx, more oral and vaginal , more oral and vaginal candidiasiscandidiasis

Case examplesCase examples

MrMr CC:CC:Discontinued meds (EFV/Discontinued meds (EFV/CombivirCombivir) July 2005 as ) July 2005 as per SMART randomization; very pleased about thisper SMART randomization; very pleased about thisStudy closed January 2006; CD4 count 912, VL still Study closed January 2006; CD4 count 912, VL still <50<50Did not resume medications upon study closureDid not resume medications upon study closure

Case examplesCase examples

Mr. Mr. RCRC::Long ARV history; randomized to continue Long ARV history; randomized to continue medications in July 2005 as per SMART studymedications in July 2005 as per SMART studyRemains on d4T, Remains on d4T, nelfinavirnelfinavir, EFV (since 1998), EFV (since 1998)Lipids controlled on Lipids controlled on pravastatinpravastatin and and fenofibratefenofibrate (TG (TG 2.5 recently 2.5 recently vsvs 11.45 in 2002)11.45 in 2002)Difficulty with weight loss despite exerciseDifficulty with weight loss despite exercise

ReferencesReferences

1.1. Egger M, May M, Egger M, May M, ChêneChêne G, et al. Prognosis of HIVG, et al. Prognosis of HIV--11--infected patients starting highly active infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119studies. Lancet 2002;360:119--29.29.

2.2. IntegraseIntegrase articlearticle3.3. DHHS Panel of the Office of AIDS Research Advisory Council. GuidDHHS Panel of the Office of AIDS Research Advisory Council. Guidelines for the Use of elines for the Use of

Antiretroviral Agents in HIVAntiretroviral Agents in HIV--11--Infected Adults and Adolescents. October 10, 2006. Infected Adults and Adolescents. October 10, 2006. http://AIDSinfo.nih.govhttp://AIDSinfo.nih.gov

4.4. The SMART study group. CD4+ CountThe SMART study group. CD4+ Count--Guided Interruption of Antiretroviral Treatment. Guided Interruption of Antiretroviral Treatment. NEJM 2006;255:2283NEJM 2006;255:2283--96.96.

5.5. 1993 Revised classification system for HIV infection and expande1993 Revised classification system for HIV infection and expanded surveillance case definition d surveillance case definition for AIDS among adolescents and adults. MMWR for AIDS among adolescents and adults. MMWR RecommRecomm Rep 1992;41:No. RRRep 1992;41:No. RR--17:117:1--19. 19. http://wonder.cdc.gov/wonder/help/AIDS/MMWRhttp://wonder.cdc.gov/wonder/help/AIDS/MMWR--1212--1818--1992.html1992.html

6.6. Supplementary webSupplementary web--only appendix for SMART study available through only appendix for SMART study available through fulltextfulltext article at article at www.nejm.orgwww.nejm.org

7.7. NeatonNeaton JD, Wentworth DN, JD, Wentworth DN, RhameRhame F, et al. Considerations in choice of a clinical endpoint F, et al. Considerations in choice of a clinical endpoint for AIDS clinical trials (CPCRA). Stat Med 1994;13:2107for AIDS clinical trials (CPCRA). Stat Med 1994;13:2107--25.25.

8.8. Adaptation of toxicity table of the Division of AIDS of the NIAIAdaptation of toxicity table of the Division of AIDS of the NIAID. Accessed online at D. Accessed online at http://www.niaid.nih.gov/dmid/clinresearch/DMIDpedtox.dochttp://www.niaid.nih.gov/dmid/clinresearch/DMIDpedtox.doc

9.9. AnanworanichAnanworanich J, J, GayetGayet--AgeronAgeron A, Le A, Le BrazBraz M, et al. CD4M, et al. CD4--guided scheduled treatment guided scheduled treatment interruptions compared with continuous therapy for patients infeinterruptions compared with continuous therapy for patients infected with HIVcted with HIV--1: results of 1: results of the Staccato the Staccato randomisedrandomised trial. Lancet 2006;368:459trial. Lancet 2006;368:459--65.65.