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- NeonatologyWhere Myths Persist

For instance: « Efavirenz is teratogenic »

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.

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

« 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

Spurious « contra-indications »:

• A luxury for the rich• A burden for the poor

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 (Strategies for Manage-ment of anti-retroviral therapies)

Patients with > 350 CD4 cells, mostly on treatment, willing to be randomized to

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

Curves diverge after

4 months

STI groupCT group

SMART: Confirmed Events

Event STI CT RR PN /100py N /100 py

AIDS/death 118 3.3 46 1.3 2.63<10-4

Death 55 1.5 30 0.8 1.840.007

SMART: Type of AIDS Events

Event STI CT

Esophageal candidiasis 24 7PCP 8 2Recurrent bacterial pneumonia 7 2Kaposi’s 6 1Persistent herpes simplex 3 2Lymphoma 4 1Disseminated zoster 3 1TB 2 2All others 7 2

Patients with any event 54 17

Few Deaths are AIDS-Related

Type STI CT

Cancer (excluding AIDS-related) 11 5Cardiovascular 7 4Substance abuse 3 5Accident, suicide, violence 3 4AIDS-related opp. disease 4 3Other infections 3 1Various 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 PN /100py N /100 py

MI, major CAD,stroke, RF, LF 63 1.8 38 1.0 1.68 0.01

What if Treatment Was Re-started at Higher CD4 Counts ?

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

* 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

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

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

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.