Transcript Efavirenz and pregnancy

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

For instance: « Efavirenz is
teratogenic »
Efavirenz and pregnancy
Teratogenicity/Developmental Toxicity Animal Studies
Malformations 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
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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 contraindicated »
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
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
AIDS/death
Death
STI
CT
N
/100py
N
/100 py
118
55
3.3
1.5
46
30
1.3
0.8
RR
P
2.63
1.84
<10-4
0.007
SMART: Type of AIDS Events
Event
STI
CT
Esophageal candidiasis
PCP
Recurrent bacterial pneumonia
Kaposi’s
Persistent herpes simplex
Lymphoma
Disseminated zoster
TB
All others
24
8
7
6
3
4
3
2
7
7
2
2
1
2
1
1
2
2
Patients with any event
54
17
Few Deaths are AIDS-Related
Type
STI
CT
Cancer (excluding AIDS-related)
Cardiovascular
Substance abuse
Accident, suicide, violence
AIDS-related opp. disease
Other infections
Various other causes
11
7
3
3
4
3
9
5
4
5
4
3
1
5
Unknown
15
3
Total
55
30
SMART: (Supposedly) Drug-Related AEs Are
Also Worse in STI Group
Event
MI, major CAD,
stroke, RF, LF
STI
CT
N
/100py
N
/100 py
63
1.8
38
1.0
RR
P
1.68
0.01
What if Treatment Was Re-started at Higher CD4
Counts ?
STI*
CT*
RR
Delta
NNP
7.6
4.2
2.7
2.0
10.5
2.3
1.4
1.2
0.72
1.83
1.93
1.67
1.9
1.3
0.8
32
47
76
Last CD4
< 250
250-349
350-499
>499
* 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
7.6
4.2
2.7
2.0
10.5
2.3
1.4
1.2
0.72
1.83
1.93
1.67
1.9
1.3
0.8
32
47
76
Last CD4
< 250
250-349
350-499
>499
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.