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The Cafeteria Test

The Cafeteria Test. Good policy – and a good research protocol – can be explained to your surgeon colleague in the noisy hospital cafeteria, between two beepers beeping, and over a cup of coffee. Pregnancy – Fetotoxicity- Neonatology Where Myths Persist.

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The Cafeteria Test

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  1. The Cafeteria Test • Good policy – and a good research protocol – can be explained to your surgeon colleague in the noisy hospital cafeteria, between two beepers beeping, and over a cup of coffee

  2. Pregnancy – Fetotoxicity- NeonatologyWhere Myths Persist • For instance: « Efavirenz is teratogenic »

  3. Efavirenz and pregnancy Teratogenicity/Developmental Toxicity Animal StudiesMalformations were observed in three of 20 infants born to pregnant cynomolgus monkeys receiving efavirenz from gestational days 20 to 150 at a dose of 30 mg/kg twice daily (resulting in plasma concentrations comparable to systemic human therapeutic exposure). The malformations included anencephaly and unilateral anophthalmia in one; microphthalmia in another; and cleft palate in the third. Primate teratogenicity studies have not been conducted for delavirdine or nevirapine.

  4. Antiretroviral Pregnancy Register • Overall, the prevalence of birth defects in 2427 live births was 3.0 percent. The CI of 2.4-3.8 includes the prevalence in patients not exposed to ARVs (2.7) indicating no significant difference • For abc, lpv, efv, nvp, tfv, rtv, sufficient births have accrued to exclude a two-fold increase, and for 3-TC and zdv, a 1.5-fold increase can be excluded • Regarding efv 7 defects in 281 first trimester exposures, i.e. 2.5% (confidence interval 1.0 – 5.1), none of which resembled the CNS lesions in monkeys • 3 cases of myelomeningocoele reported in the literature www.apregistry.com, accessed December 15, 2007. Last interim report June 2007

  5. « Ciprofloxacin is contra-indicated » • Bone problems in puppies, not reproduced in other species • In dogs, some quinolones do, others don’t. The most powerful of all: nalidixic acid, a precursor drug used widely in the 1970ies • Follow-up of these children, now adults: No bone problems. • Inadvertent exposure: Nothing • Inspite of this, the pediatric c.-i. to cipro still exists

  6. Spurious « contra-indications »: • A luxury for the rich • A burden for the poor

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

  8. 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

  9. 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

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

  11. 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

  12. 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

  13. 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

  14. 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

  15. What if Treatment Was Re-started at Higher CD4 Counts ? STI* CT* RR Delta NNP Last CD4< 250 7.6 10.5 0.72250-349 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 patient-years 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

  16. 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

  17. “I would like to stop. Can I do so safely?”

  18. STI* CT* RR Delta NNP Last CD4< 250 7.6 10.5 0.72250-349 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

  19. Summary: Harmful to Stop ? • SMART participants started HAART at CD4 counts of approx. 200 (median, large range) • Intermittent treatment is inferior to continuous treatment • Holds true at all CD4 counts • At high CD4 counts, NNP exceeds 50 years of treatment to prevent one event SMART does not show that intermittent treatment is inferior to no treatment

  20. When To Stop ?(in women who started ART for PMCT) • Women who had an indication for treatment (CD4 < 350): SMART says: Don’t stop ! • Women who did not have an indication: Treat for one year, then stop. • If treatment started without CD4 count measured: Stop after 1 year. Measure CD4 counts after three months, treat if < 350.

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