Limitations of Current Antiretroviral TherapyInability to eradicate HIV Limited number of agents/classesDevelopment of HIV resistance Occurrence of serious side effectsDifficulty with long-term adherence

Short-term trialsObservational studiesExpert opinionBasis for Antiretroviral GuidelinesOnly partially evidence-based

2001 DHHS GuidelinesSymptomaticTreat!! Plasma HIVClinical Category CD4+ Count RNA Recommendation

Asymptomatic > 200/mm3Any Treat. But and < 350/mm3

Asymptomatic< 200/mm3AnyTreat!

A Large, Randomized Trial Comparing Two

Strategies for Management of Anti-Retroviral Therapy

Countries Participating in SMART

SMART Study DesignDrug Conservation (DC) Strategy[Stop or defer ART until CD4+ < 250; then episodic ART based on CD4+ cell count to increase counts to > 350] Virologic Suppression (VS) Strategy[Use ART to maintain viral load as low as possible throughout follow-up]

Participants with CD4+ > 350 n = 3000n = 3000Expected follow-up period: 7-8 years

The SMART Study QuestionsWhat is the optimal way to use ART to achieve longest disease-free survival?

Which treatment strategy is associated with Better adherence Fewer drug side effectsFewer metabolic complications Better quality of lifeLess drug resistance?

Which strategy is more cost effective?

Study Treatment ComparisonViral Suppression Strategy Continuous Antiretroviral Therapy

VS

Drug Conservation StrategyEpisodic Antiretroviral Therapy

Primary Objective

To compare the VS and DC strategies in prolonging survival without progression of disease.

Other Major Clinical OutcomesDeathMajor cardiovascular and metabolic complicationsSerious HIV progression eventsCombined endpoint of death, HIV disease progression, and major cardiovascular and metabolic eventsGrade 4 adverse events

SMART Target Population HIV-infected patients CD4+ cell counts > 350 cells/mm3 Older than 13 years of age Willing to initiate, modify, or stop antiretroviral therapy, in accordance with the randomized assignment.

Viral Suppression (VS) Strategy

GoalMaintain maximum possible suppression of viral load

Treatment StrategyUtilize any available HIV treatments irrespective of CD4 cell count

Viral Suppression Strategy PotentialRISKS

More cumulative side effects Adherence more difficult Resistance to more agents with virologic failuresFewer active anti-HIV agents available when risk of disease is higherPotentialBENEFITS

Maximal suppression of viral load more likely Lower risk of resistance due to viral suppressionLower risk of lasting CD4 depletionPotential lower risk of HIV transmission

Drug Conservation (DC) Strategy

GoalConserve anti-HIV drug options while the risk of disease progression is low

Treatment StrategyDefer use of anti-HIV agents until CD4 cell count is < 250 then treat episodically to maintain CD4 > 350 using any available HIV treatments

Drug Conservation StrategyPotential RISKS

Stopping and restarting anti-HIV agents may increase the risk of drug resistance

Risk of lasting damage to immune systemPotential increased risk of HIV transmissionPotentialBENEFITS

Potent anti-HIV agents available when risk of disease increasesFewer side effectsLess anti-HIV drug use may reduce the risk of drug resistance Adherence may be better with episodic therapy

Enrollment from 8 January 2002 to 11 January 200633 countries318 sites5,472 patients Date randomization screens closed: 11 January 2006Mean follow-up: 15 months

SMART Participants and Timetable

Canadian Participation

Canadian Enrolment(to 11 January 2006)

Canadian Sites

SMART Enrollment by Quarter

Total Number Enrolled240243186153117127170250292240293351503623547942195

Enrollment by Geographic Region57%26%10%3%3%1%

SMART Study: Enrollment Through11 January 2006 DCVSTotalNumber EnrolledStudy Main272027525472

Baseline Characteristics Patients with data available as of 10 Dec 2005Number244324644907

Age (years; mean)464646

Female (%)252726

Race:Black (%)303231 White (%)575556Other (%)131313

Likely mode of infection:Sexual contact, same sex (%)535052Sexual contact, opposite sex (%)424443Injection drug use (%)101010Other/ unknown (%)898DC GroupVS GroupTotal

Baseline Characteristics Patients with data available as of 10 Dec 2005Number244324644907

CD4+ (cells/mm3; median)599598598(466, 792)

CD4+ nadir (cells/mm3; median)253253253(153, 364)

HIV RNA 400 copies/mL (%)69.869.469.6

HIV RNA < 1000 copies/mL (%)74.373.974.1

Highest log HIV RNA (log copies/mL; median)4.84.84.8DC GroupVS GroupTotalIQR

Baseline Characteristics Patients with data available as of 10 Dec 2005Number244324644907

Prior AIDS-related illnesses (%)24.423.423.9

Hepatitis B co-infection (%)2.52.32.4

Hepatitis C co-infection (%)16.114.915.5

DC GroupVS GroupTotal

Baseline Characteristics Patients with data available as of 10 Dec 2005Number244324644907

ART HistoryART nave (%)4.75.14.9PI experienced (%)68.966.567.7NNRTI experienced (%)64.664.364.5On ART at baseline (%)83.382.582.9

Time since first prescribed ART(years; median)666(3, 8)DC GroupVS GroupTotalIQR

Mean: 661 Median, [ 25th ; 75th ]: 598[ 466 ; 792 ]Distribution of Baseline CD4+ Cell CountNo. of Patients

Mean: 270 Median, [ 25th ; 75th ]: 253 [ 153 ; 364 ]Distribution of CD4+ Nadir Prior to Enrollment No. of Patients

Intent-to-treatDC versus VS comparisonsKaplan-Meier survival curves and Coxs proportional hazard models used to compare treatment groups for:Progression to AIDS or deathSurvivalMajor cardiovascular and metabolic eventsSerious disease progression eventsGrade 4 eventsData cutoff date used in clinical events analyses: 10 December 2005; at that time 5,007 patients were randomized.

SMART Statistical Methods

Follow-up by Treatment GroupNumber of follow-up 761 (4.6%) 1,061 (6.4%) visits missed (%)

Number lost to 48 (1.9%) 55 (2.2%) follow-up (%)

Median months of 10 (4,23) 10 (4,23) follow-up (IQR)

Average follow-up (months)14.7 14.7

Total person years 3062 3077 through 10 Dec 2005DC GroupVS Group

Hypothetical CD4+ Cell Count Patterns Over Follow-up

CD4+ cell count

CD4+ cell count

Year of Follow-up

CD4+ cell count

Possible Patterns of CD4+ Cell Counts During Follow-up for the DC and VS group:(a) no difference in CD4+ cell count after 5 years; (b) CD4+ cell count in the DC and VS group do not converge; and (c) CD4+ cell count greater in the DC than VS group after 5 years. For each of these possible patterns the long-term clinical implications are uncertain.

(a)

(b)

(c)

Confirmed Clinical Events+ - 1through 10 December 2005DC GroupVS GroupRR (DC/VS)P-valueNRateNRate[95% CI]Progression of disease or death (primary endpoint)933.1441.42.15 [1.50, 3.08]

Time to Disease Progression or DeathConfirmed events through 10 December 2005

Time to DeathEvents through 10 December 2005

SMART Primary Composite Endpoint (Disease Progression or Death) and Components; Confirmed Events Through 10 Dec Favors VS No. of Patients with EventsEndpointsRelative Risk (95% CI)Progression of Disease or Death137 Death76 Serious Progression Event19 Other Progression Event46Serious Progression of disease or death91 >2.21.65.82.91.9

Chart1

90.90.7

710.6

514.44.1

32.61.4

110.7

Sheet1

POD or death92.21.53.10.70.9

Death71.612.60.61

Serious POD55.81.720.24.114.4

Other POD32.91.55.51.42.6

Serious POD or death11.91.22.90.71

Time to Group I Event1Confirmed events through 10 December 20051Fatal or non-fatal MI (reported as supplemental event or diagnosed by ECG), stroke, CAD requiring surgery, kidney failure, cirrhosis.

SMART Group I Events and Components:Confirmed Events Through 10 December

No. of Patients with EventsSubgroupsTotal96Cardiovascular78Liver15Renal9Favors VS Relative Risk (95% CI)1.61.51.52.0

Chart1

4.50.80.5

30.80.6

22.81

161.5

Sheet1

4.51.61.12.40.50.8

31.50.92.30.60.8

21.50.54.312.8

120.581.56

Confirmed Clinical Events+ - 2through 10 December 2005DC GroupVS GroupRR (DC/VS)P-valueNRateNRate[95% CI]

Serious progression of160.530.15.82 [1.68, 20.2]0.01 disease1

Serious progression of disease1 or death591.9321.01.88 [1.22, 2.90]0.003

Grade 4 events1575.41334.51.19 [0.94, 1.49]0.15

Total follow-up time (person-years)30623077

+ Reviewed and adjudicated by Endpoint Review Committee.1Progressive multifocal leukoencephalopathy, lymphoma, visceral Kaposis sarcoma, AIDS dementia complex, toxoplasmosis, histoplasmosis, cryptococcosis, MAC, wasting syndrome, cytomegalovirus disease.

Rate of AIDS-related Illnessesthrough 10 December 2005DC GroupVS GroupEvents1Rate2Aspergillosis, invasive0010.0Candidiasis, esophageal170.650.2Candidiasis of bronchi, trachea, or lungs 20.100CMV disease 10.000Cryptococcosis, extrapulmonary 10.000Encephalopathy, HIV-related, stage 2 or higher 10.000Herpes simplex30.120.1Herpes zoster, disseminated30.110.0Kaposis sarcoma60.210.0Lymphoma40.110.0TB, pulmonary or extrapulmonary20.120.1MAC, extrapulmonary10.010.0PCP60.220.1Pneumonia, bacterial370.220.1Wasting syndrome due to HIV30.100Patients with any AIDS-related event541.8170.61One patient may have several illnesses. Each occurrence is counted, but recurrent illnesses of the same type are counted only once.2Per 100 person-years.3Recurred within 1 year.Events1Rate2AIDS related event

Causes of DeathDeaths through 10 December 2005DC GroupVS GroupDeaths1%AIDS-related36.413.4Hepatic complications36.4413.8Pancreatic/ GI complications12.100Cancer, excluding AIDS-related714.9517.2Cardiovascular complications1123.41034.5Violent/ Accident919.1931.0Other, none of the above2612.826.9Unknown919.126.9

Total number of deaths47100.029100.0Patients may have multiple causes of death.Other includes the following causes: DC (cerebral empyema, renal failure 2 patients, ARDS/septic shock, bacterial meningitis, COPD/pneumonia) and VS (intra-abdominal sepsis/multi-organ failure, pneumonia).Deaths1%Death Classification

Progression of Disease or Death by Baseline CD4+ Confirmed Events Through 10 December 2005 0.07 350 - 44921.7213.36172.401.4 0.30 [0.7,2.7] 450 - 54920.4233.8060.964.0

Progression of Disease or Death for Baseline CD4+ Subgroups

No. of Patients with EventsSubgroupsTotal137CD4 (cells/mm3)350 - 44938450 - 54929550 - 64920 65050Favors VS Relative Risk (95% CI)2.21.44.02.42.3

Chart1

70.90.7

41.30.7

35.92.4

23.81.5

11.81.1

Sheet1

POD or death72.21.53.10.70.9

Death41.40.72.70.71.3

Serious POD341.69.92.45.9

Other POD22.40.96.21.53.8

Serious POD or death12.31.24.11.11.8

Progression of Disease or Death by Nadir CD4+ Confirmed Events Through 10 December 20050.42 < 10016.4183.6461.133.2 0.01 [1.3,8.2]100-19918.4162.79101.981.4 0.38 [0.6,3.1]200-29925.621 3.09111.402.2 0.03 [1.1,4.6]300-39920.0254.09111.842.1 0.04 [1.1,4.4] 40019.5132.0160.932.1 0.13 [0.8,5.6]Nadir CD4+ (cells per mm3) % of patients in sub-groupEventsRate1EventsRate1RR2 (DC/VS) [95%CI]P-Value3 Inter-actionP-Value2 for RR1 Per 100 person-years, time to first event. 2 Cox proportional hazards model within subgroup 3 Subgroup by treatment group interaction, Cox proportional hazards modelDC GroupVS Group

Progression of Disease or Death for Nadir CD4+ Subgroups

No. of Patients with EventsSubgroupsTotal137Nadir CD4 (cells/mm3)100 19926200 29932300 39936 40019< 10024Favors VS Relative Risk (95% CI)2.23.21.42.22.12.1

Chart1

80.90.7

551.9

41.70.8

32.41.1

22.31

13.51.3

Sheet1

82.21.53.10.70.9

53.21.38.21.95

41.40.63.10.81.7

32.21.14.61.12.4

22.11.14.412.3

12.10.85.61.33.5

Progression of Disease or Death by Baseline Viral Load for those on ARTConfirmed Events Through 10 December 2005

Progression of Disease or Death for Baseline HIV RNA Subgroups among Those Taking ART

No. of Patients with EventsSubgroupsTotal137HIV RNA (copies/ mL)(only patients on ART at baseline) 40072> 40037Favors VS Relative Risk (95% CI)2.23.21.1

Chart1

50.90.7

2.52.41.3

10.90.5

Sheet1

52.21.53.10.70.9

2.53.21.95.61.32.4

11.10.620.50.9

Percent of Patients on ART at each Month of Follow-up and Treatment Group

CD4+ Change from Baseline, Mean + 2SE (in cells/mm3) by Month of Follow-up and Treatment Group

Hypothetical CD4+ Cell Count Patterns Over Follow-up

CD4+ cell count

CD4+ cell count

Year of Follow-up

CD4+ cell count

Possible Patterns of CD4+ Cell Counts During Follow-up for the DC and VS group:(a) no difference in CD4+ cell count after 5 years; (b) CD4+ cell count in the DC and VS group do not converge; and (c) CD4+ cell count greater in the DC than VS group after 5 years. For each of these possible patterns the long-term clinical implications are uncertain.

(a)

(b)

(c)

Percent with HIV RNA 400 copies/mL by Month of Follow-up and Treatment Group

Summary - 1There is an increased risk in the DC group compared to the VS group of:Progression to AIDS, including deathDeathSerious disease progression eventsMajor cardiovascular, renal and liver events

Summary - 2The increased risk of the DC group compared to the VS group did not differ according to subgroups defined by baseline and nadir CD4+ cell count.

For the subgroup of patients who entered with a viral load < 400 copies/mL on treatment, risk of progression was over 3-fold higher in the DC group compared to the VS group.

For other subgroups examined, risk was always greater in the DC group than the VS group.

Conclusion of the SMART executive committee Episodic use of ART based on CD4+ cell count levels as per the SMART study design is inferior to continuous ART for the management of treatment experienced patients and thus should not be routinely recommended.

Questions:Do you agree with the conclusion of the executive committee?

Questions:Do you agree with the DSMB's recommendation to: (a) stop enrolment?

(b) consider changing the therapy for patients in the DC arm?

Questions:Given that the relative risks between the 2 arms change over time, how should patients who are 1 year into the study be managed? At 2 years? 3 years?

Questions:Can the original question (long term comparison) still be answered by, say, re-designing the study?

If so, how? Any suggestions?

SMART BaselineCVD Risk factors (to Nov 2005)Current smoker 41.8 %Diabetes mellitus 7.6 %Prior MI 1.8 %Prior stroke 1.6 %Peripheral vascular disease 1.7 %

SMART BaselineCVD Risk (cont.)Major ECG abnormalities7.9 %Coronary artery disease 2.8 %Congestive heart failure 0.9 %Antihypertensive drugs 20.3 %Cholesterol >= 240 or lipid lowering drugs 23.3 %

NIAID Stops Intermittent HAART TrialReuters Health Information 2006. 2006 Reuters Ltd.NEW YORK (Reuters Health) Jan 18 - The National Institute of Allergy and Infectious Diseases has halted enrollment in a large international trial comparing continuous highly active antiretroviral therapy (HAART) with intermittent therapy, guided by CD4+ cell counts.

The trial, known as Strategies for Management of Antiretroviral therapy (SMART), quickly showed that patients do better on continuous HAART, according to a statement released by the NIAID on Wednesday.

Patients in the intermittent arm had twice the risk of dying or progressing to AIDS. "Furthermore, there was an increase in major complications such as cardiovascular, kidney and liver diseases in the participants on the drug conservation arm," the statement continued.

"These complications have been associated with (HAART), and it was hoped that they would be seen less frequently in those patients receiving less drug," it added.

NIAID Stops Intermittent HAART Trial(Continued)"We were surprised to learn that in the short-term, episodic antiretroviral therapy carries such an increased risk without evidence of sparing patients the known side effects associated with ART," said co-investigator Dr. Wafaa El-Sadr of the Harlem Hospital Center and Columbia University in New York.

The patients in the drug-sparing arm stopped treatment when CD4+ counts reached 350 cells per microliter and resumed treatment when CD4+ counts dropped below 250 cells per microliter.

When the trial was stopped, it had enrolled 5472 of a target of 6000 patients at 318 clinical sites in 33 countries. The trial was halted January 11, 2006 after an average follow-up of 15 months.

As you can see the acronym SMART stands for strategies for management of anti-retroviral therapy.This international, randomized trial was developed by the CPCRA (the equivalent to the CTN in Canada) in the US and is funded by the national institutes of health, Division of aids.Here is a quick look at the international sites that are involved, this international collaboration of sites was developed during the IL2 studies (ESPRIT and SILCAT). Each circle is the regional coordinating centre and Canada is managed by the CPCRA regional centre in baltimore.The study was designed for HIV + people with a CD4 count greater than 350 cells and was originally designed to enrol 6000 patients with a 7-8 year follow-up. Half the patients were to be allocated to the VS arm or the virologic suppression strategy which allows for the use of any antiretroviral therapy combination to ideally maintain an undetectable viral load. The DC arm or drug conservation strategy is CD4 guided approach. Patients stop or defer antiretroviral therapy until their CD4 count drops below 250 and then they take antiretroviral therapy until their CD4 cell counts returns to greater than 350 cells. It was expected that patients in this arm would cycle on and off therapy as it was required.The hypothesis of the original study design was to determine the optimal way to use therapy to achieve the longest disease-free survival, to determine which strategy was associated with better adherence, fewer drug side effects and metabolic complications, promotes a better quality of life, which strategy is associated with less drug resistance and of course which is more cost effective.I will now discuss each arm in more detail.As you can see the primary objective was to compare the two strategies abilities to prolong survival without disease progression.Secondary clinical outcomes included: death, major cardiovascular and metabolic complications, serious progression events, the combination of these endpoints and grade 4 AEsAll HIV positive patients with a CD4 above 350 and who are older than 13 were eligible if they were willing to accept their allocation, were not pregnant or breast feeding and were not involved in studies such as ESPRIT, SILCAT or OptimaPatients in the VS arm were allowed to use any available HIV treatment, irrespective of their CD4 cell count to maintain maximum suppression of viral load.

The protocol lists the benefits of this arm as: maximal suppression of VL, due to viral suppression a lower risk of resistance, less risk of a lasting CD4 depletion and possibly a lower risk of HIV transmission. The risks include: more side effects, adherence difficulties, resistance to more agents with viroligc failures and eventually fewer active antiretorvirals available when risk oif disease is higher. Patients in the DC arm were only using antiretrovirals when their CD4 count fell below 250, once they were able to maintain a CD4 of 350 they once again stopped therapy. The goal was to conserve drug options while the risk of disease progression was low.The protocol lists potential benefits of this arm as: more availibility of potent meds when risk of disease increases, fewer side effects, potentially reduce the risk of drug resistance and the possiblity of better adherence when on meds. Potential risks associated with this arm were: potential for increasing the risk of drug resistance, damage to the immune system and increased HIV transmission.Enrolment was open for 4 years before randomization was closed on January 11. As you can see 33 countries are involved with 318 sites and 5472 patient were randomized. As you watch the rest of the presentation keep in mind that the mean time for follow-up was 15 months.Canada had 13 sites, of which 10 were open to enrolment when randomization was stopped. We were involved in randomization for about a year.Here is a list of sites that randomized patients and our goal in Canada was 150.These three sites had completed the ominous amount of paperwork to open and were on the verge of opening or enrolling patients by January 11.This slide is interesting because it shows from January 2002 to the 3rd quarter of 2004 most patients enrolled were from the US (Canada was the first country in the CPCRA RCC to begin enrolling patient s after the Americans), the large spike of randomizations in the last quarter of 2004 is due to the fact that Brazil, the red bar and thailand, the blue bar opened for enrollment.

Here is the same information presented in a different format.Remember when you view this slide that < 400 copies is considered undetectable in this study.When you view this slide keep in mind that 83 % of patients enrolled were on ART when they were randomized and the median time on therapy is 6 years.Just under half the patients have a baseline CD4 count between 350 and 450Half the patients had a nadir CD4 count less than 250 which means they would have been at risk for opportunistic infections and may have had a prior AIDS -related illnesses