Interruptions thérapeutiques: Pour ou contre?

Interruptions thérapeutiques: Pour ou contre? Lausanne, 19 avril 2007 Bernard Hirschel, Division of Infectious Diseases, Geneva University Hospital, Geneva, Switzerland. Bernard.hirschel@hcuge.ch

The Giant (SMART) And The 7 Dwarfs: Trivacan, Dart, Staccato, Windows, ISS, Basta, Salto

STI Update Overview A Detailed Look at SMART Confirmation: Trivacan and DART Opposition: Staccato and Windows Reconciliation Is there a way to make STIs «safe»? The cost-effectiveness of continuous therapy

SMART (Strategies for Management of anti-retroviral therapies) Patients with > 350 CD4 cells, mostly on treatment, willing to be randomized to 1. Drug conservation (DC or STI) arm: Treatment stopped if CD4 > 350, started at < 250 2. Virologic suppression (VS or CT) arm: Keep VL < 50 at all times

SMART: As Planned NIH, CPCRA 6000 patients, planned follow-up of 5 to 9 years 900 endpoints expected in 2009, with power to detect difference of approximately 20% between arms

SMART: As It Turned out Recruitment suspended on January 11, 2006, after 5472 patients had been recruited, and 164 endpoints observed Excess of endpoints in the STI (DC) arm

Primary endpoint of OI/death STI group CT group Curves diverge after 4 months

SMART: Confirmed Events Event STI CT RR P N /100py N /100 py AIDS/death 118 3.3 46 1.3 2.63 <10-4 Death 55 1.5 30 0.8 1.84 0.007

SMART: Type of AIDS Events Event STI CT Esophageal candidiasis 24 7 PCP 8 2 Recurrent bacterial pneumonia 7 2 Kaposi s 6 1 Persistent herpes simplex 3 2 Lymphoma 4 1 Disseminated zoster 3 1 TB 2 2 All others 7 2 Patients with any event 54 17

Few Deaths are AIDS-Related Type STI CT Cancer (excluding AIDS-related) 11 5 Cardiovascular 7 4 Substance abuse 3 5 Accident, suicide, violence 3 4 AIDS-related opp. disease 4 3 Other infections 3 1 Various other causes 9 5 Unknown 15 3 Total 55 30

SMART: (Supposedly) Drug-Related AEs Are Also Worse in STI Group Event STI CT RR P N /100py N /100 py MI, major CAD, stroke, RF, LF 63 1.8 38 1.0 1.68 0.01

Start of HAART

Years later, starting SMART SMART: Let s see whether we can save fuel by letting them swim a while. We can always pick them up downstream.

January 11, 2006 I don t want to wait until 2009!

«Trivacan» Ivory Coast, 840 patients, ARV-naïves, CD4 count 150-350 Treated > 6 mos until VL < 300, CD4 > 350 1. CT 2. 2 months off / 4 months on 3. CD4-guided STIs: Stop if CD4 > 350, start if CD4 < 250

Trivacan: probability of remaining free from serious mobidity. Lancet 2006; 367: 1981 89

Trivacan: Premature stop of the CD4-guided STIs Incidence per 100 years of follow-up Event CD4- CT arm p STI arm Bacteremia 5.1 0 < 0.001 Oral candida 6.4 2.3 0.05 TB 2.3 3.6 NS

«DART» Uganda/Zimbabwe Treated with ZDV/3-TC plus either NVP, TFV or ABC until CD4 > 300 813 patients randomized, median CD4 351 1. CT 2. 12 weeks on / 12 weeks off

DART: Premature Stop of the STI Arm Incidence per 100 years of follow-up Event 12 wowo CT arm p STI arm AIDS (WHO stage 4) 8.3 3.2 0.003 ART change for toxicity 0.5 3.1 0.02

DART: Premature Stop of the STI Arm Number of cases Event 12 wowo CT arm STI arm Esophageal candidiasis 17 4 Extrapulmonary TB 4 2 Cryptococcosis 2 2 Herpes simplex 2 1

Staccato (Lancet 2006; 368:459) Swiss (19%) Thai (80%) Australia (1%) 430 patients, 24 mos Randomized 2:1 1. CD4 guided: ART to stop if CD4 > 350 2. Continuous therapy Re-treatment for 12-24 weeks in all at end

Staccato: Clinical events 1 death in each arm No AIDS-defining events Excess of candida stomatitis/vaginitis in STI arm (4% versus 1%) Approximately 60% drug savings No problems with resistance during and after re-treatment

Median length of STIs: 18 weeks 1.00 Probability to re-start ART.75.50.25 Probability to re-start: 50% at 18 weeks 75% at 90 weeks 0.00 0 18 36 54 72 90 108 126 144 162 180 Time from randomization (in weeks)

Staccato: Conclusions In pts treated mostly with boosted PI-based HAART: No excess in AIDS-defining OIs/deaths Little or no resistance Substantial drug savings Less adverse events ascribed to drugs May depend on type of regimen used

ANRS 106, "Windows" France, 403 patients Fully suppressed, CD4 > 450 (median 741), nadir > 100 (median 281) 1. Continuous therapy 2. 8 wks off / 8 weeks on for 96 weeks

Windows: Results at week 96 2 deaths (cirrhosis and violence) in STI group Excess of candida stomatitis (10 in STI vs 6 in CT), and thrombocytopenia (11 cases, all in patients who interrupted treatment) Marchou B et al., CROI 2006

Windows: Results at week 96 Primary Endpoint STI group CT group p CD4 < 300 3.6% 1.5% NS CD4 < 450 25% 8% 0.02 Little resistance was observed Marchou B et al., CROI 2006

Windows: Conclusions A fixed STI strategy of 8-wk-off/8-wk-on appeared clinically and immunologically safe over 96 weeks. Marchou B et al., CROI 2006

SMART Trivacan DART N of pts 5472 326 813 PY FU (in STI arm) 3062 275 388 CD4 at Stop median (min) 598 (350) 460 (350) 358 (300) CD4 at Start 250 250 12 wowo AIDS, death/100py STI 3.1 17.6 8.3 CT 1.4 6.7 3.2 Time on ARV before study (mo) 72 7 15

SMART Windows Staccato N of pts 5472 390 430 PY FU (in STI arm) 3062 360 490 CD4 at Stop median (min) 598 (350) 741 482 (350) CD4 at Start 250 500 350 Median age (years) 46 41 35 AIDS, death/100py STI 3.1 0.4 0.2 CT 1.4 0 0.4 Oral and vaginal candidiasis STI? 2.8 2.28 CT? 1.7 0.34 Mos on ARV before study 72 62 15 Length of STIs (median, in months) 18 2 4.5

Are the Different Results due to the Differences in Size? None of the trials other than SMART were powered to detect differences in AIDS/death Were the trials too small and therefore succumbed to a type beta error (concluding that there is no difference whereas in fact there is)

Comparison of Staccato and SMART (2) Is the difference between Staccato and SMART «real»? - In SMART s DC (STI) arm, the incidence of disease progression was 3.5/100 PY - In Staccato s STI arm, 490 years of experience accumulated. At a rate of 3.5/100 PY, this would have produced 17 events, but only 1 was observed - The difference between 17 and 1 is unlikely to be due to chance (p < 0.001)

SMART is large enough to permit meaningful analyses of subsets In almost all subgroups CT is favored 0.1 1 10 Favors STI Favors CT

Duration of HAART Before Study Favors STI Favors CT Hazard Ratio

Nadir of CD4 Cells before Trial Favors STI Favors CT Hazard Ratio

Baseline CD4 Cells Favors STI Favors CT Hazard Ratio

Latest CD4 Cells During Trial STI patients with OD/death Min Median Max 25th 75th

Medians: 341 (STI), 515 (CT) STI Group CT Group Pts with OD/death All patients Pts with OD/death All patients

If none of the patients had had CD4 counts lower than 350, approximately half of AIDS/deaths in the STI group, but only a quarter of AIDS/deaths in the CT group, would have been eliminated. STI Group CT Group STI pts with OD/death CT pts with OD/death

What if Treatment Was Re-started at Higher CD4 Counts? STI* CT* RR Delta NNP CD4 strata < 250 7.6 10.5 0.72 250-349 4.2 2.3 1.83 1.9 32 350-499 2.7 1.4 1.93 1.3 47 >499 2.0 1.2 1.67 0.8 76 * Number of patients with endpoints (AIDS or death) per 100 patientyears of follow-up. **NNP = number of patient years of treatment needed to prevent 1 event, considering that patients in the STI group were treated during 33 percent of days, compared to 94 percent in the CT group

The Cost-Effectiveness of HAART Numbers from Switzerland: - Before HAART, approx. 800 AIDS/Deaths per year - After HAART, approximately 100 - Approximately 5000 patients are being treated - 5000/700 or approximately 7 years worth of treatment to prevent one event

I would like to stop. Can I do so safely?

STI* CT* RR Delta NNP Last CD4 < 250 7.6 10.5 0.72 250-349 4.2 2.3 1.83 1.9 32 350-499 2.7 1.4 1.93 1.3 47 >499 2.0 1.2 1.67 0.8 76 The Future of STIs (1): At higher CD4 counts: 500 to stop, 400 to start again

The Future of STIs (2): Limited in time to 4-6 months Caveats: although the curves looks suggestive, the hypothesis of no excess risk in short STIs has not been formally tested Further follow-up of SMART, to extend for 18 months, will determine how quickly the risk of re-treated patients in the STI group returns to the risk of the CT group

Further Research SMART suggests that events occur at appreciable frequency even though CD4 count is high a trial of earlier start of ARV Comparison of the trials suggests that disease rates are higher in Africa maybe CD4 levels that are safe in Europe are dangerous in Africa

Thank you! The Staccato Study - HIVNAT, Jintanat Ananworanich, Michelle LeBraz Swiss HIV Cohort Study Swiss National Science Foundation SMART State of Geneva Private donors Corporate sponsors, particularly Roche - James Neaton, Waffa El-Sadr and Jens Lundgren

The End

I feel like shit but I'm so happy that I don't have to take those pills anymore!