A CRITICAL ANALYSIS OF THE EVIDENCE

CONSIDERED PROOF THAT NEVIRAPINE PREVENTS

MOTHER-TO-CHILD TRANSMISSION OF HIV
Eleni Papadopulos‑Eleopulos
Valendar F.Turner
John M Papadimitriou
Helman Alfonso
Barry A. P. Page
David Causer
Sam Mhlongo
Christian Fiala
Todd Miller
Anthony Brink
Neville Hodgkinson

www.virusmyth.net/aids/perthgroup
www.theperthgroup.com

PLEASE REFER TO LAST SLIDE BEFORE PROCEEDING

http://aidsmyth.addr.com/report/
news/newperthpaper.htm
 EVIDENCE REQUIRED

• Proof of HIV infection of mothers and babies

• Proof of drug efficacy

• High benefit/risk profile

DIAGNOSIS OF HIV INFECTION

MOTHERS

ANTIBODY TESTS

• Blood sample

• HIV proteins

• Technique (ELISA and Western blot)

 HIV PROTEINS

Montagnier 1983 & Gallo 1984

On the basis of isolation/purification of a unique,

novel retrovirus from supernatant obtained from
cell co-cultures of tissues of AIDS patients and
banded in a sucrose density gradient

1.16 gm/ml band = “Purified virus”

Barré-Sinoussi, F et al. (1983). “Isolation of a T-lymphotropic retrovirus from a patient at risk for
acquired immune deficiency syndrome (AIDS).” Science 220: 868-71.
Gallo, RC et al. (1984). “Frequent detection and isolation of cytopathic retroviruses (HTLV-III)
from patients with AIDS and at risk for AIDS.” Science 224: 500-503.
 HIV PROTEINS

“...analysis of the proteins

demands mass
production
and purification”

Montagnier interview at Pasteur Institute July 1997

Continuum (1998) 5: 30-34. www.virusmyth.com/aids/data/dtinterviewlm.htm
 MONTAGNIER DID NOT ISOLATE/PURIFY HIV

“I repeat, we did not purify”

Montagnier interview at Pasteur Institute July 1997

Continuum (1998) 5: 30-34. www.virusmyth.com/aids/data/dtinterviewlm.htm
 HIV PROTEINS IN NORMAL HUMAN PLACENTA
p18/p24/p120

“Placentae from 25 normal term pregnancies were collected

by vaginal delivery...Antigens gp120 and p17 were identified
in normal chorionic villi…Antigen p24…in villous
mesenchymal cells...localized to HLA-DR positive cells”

Faulk, WP et al (1991). “HIV proteins in normal human placentae.” American

Journal of Reproductive Immunology 25: 99-104.
 THE “HIV” PROTEINS p41/p120/p160

Montagnier considers p41 to be cellular actin

p160, p120 in “HIV” WB are oligomers of p41

Pinter AW et al (1989). “Oligomeric structure of gp41, the transmembrane protein

of human immunodeficiency virus type 1 Journal of Virology 63: 2674-9.
Zolla‑Pazner S et al (1989). Reinterpretation of Human Immunodeficiency virus
Western Blot patterns. NEJM 320:1280‑1281.
0
MONTAGNIER ON
MONTAGNIER AND GALLO

No particles “typical of retroviruses” in “purified virus”

“Did Gallo purify?

“Gallo?..I don’t know if he really purified.

I don’t believe so”

Montagnier interview at Pasteur Institute July 1997

Continuum (1998) 5: 30-34.
11

Gluschankof P et al. (1997). Cell membrane vesicles are a major contaminant of

gradient-enriched human immunodeficiency virus type-1 preparations. Virology
230: 125-133.
12
13
Bess et al
National Cancer Institute USA

“We agree that you can come to the conclusion from gel
electrophoresis patterns that there are only quantitative
differences between HIV and [cellular] microvesicles”

“We have been unsuccessful in separating microvesicles from HIV”

Bess, J. W., R. J. Gorelick, et al. (1997). Email correspondence August 2000 re

Microvesicles are a source of contaminating cellular proteins found in purified HIV-1
preparations. Virology 230: 134-144
4
Western blot strip

p160

ENV
p120
p41
p68
POL p53
p32

p55
GAG

p39
p24
p18
15 AUTO-ANTIBODIES IN HIV/AIDS PATIENTS

Immune complexes, rheumatoid factor, anti‑cardiolipin,

anti‑nuclear factor, anti‑cellular, anti ‑platelet, anti ‑red cell,
anti‑actin, anti‑DNA, anti‑tubulin, anti‑thyroglobulin,
anti‑albumin, anti‑myosin, anti‑thymosin, anti-lactoferrin, anti-
TNF-α, anti-beta-2 glycoprotein I, anti-prothrombin, anti-
neutrophil cytoplasmic, anti-ssDNA, anti-RNA, anti-histones,
anti-nuclear antigen SS-A, anti-mitochondrial,anti-reticulin, anti-
smooth muscle, anti-gut epithelial cell, anti-lymphocytic
ganglioside, anti-Fab, anti-protein S, anti-brain proteins, anti-
synthetic peptides of ubiquitinated histone H2A, anit-Sm-D
antigen, anti-U1-A RNP antigen, anti-60 kD SSA/Ro antigen,
anti-histone H1 and anti-histone H2B antibodies.

Anti‑lymphocyte auto‑antibodies in 87% of seropositives.

16

ANTIBODY CROSS-REACTIVITY

• Hypergammaglobulinaemia (predicts seropositivity)*

• Antibodies directed against fungi and mycobacteria

cross-react with HIV proteins

• Fungal and mycobacterial diseases are the indicator

diseases present in 90% of AIDS patients

• Kashala et al 1995 advised caution using Western blot

in high prevalence mycobacterial areas

*Brenner, B., S. Schwartz, et al. (1991). “The prevalence and interaction of human
immunodeficiency virus and hepatitis B infections in Israeli hemophiliacs.” Israel journal
of medical sciences 27: 557-561.
7
 HIV
18
AFR AUS FDA RCX CDC CDC CON GER UK FRA MAC
WESTERN 1 2
BLOT STRIP

3 WEAK BANDS OR ANY STRONG BAND

p160 p160/ p160/ p160/
ENV

p120 ANY ANY ANY ANY p120 p120 p120 ANY ANY ALL
2 1 1 1 AND OR OR 1 1 3
p41 p41 p41 p41

p68
NONE ESSEINTIAL
POL

ANY 3 GAG OR POL

ANY 1 GAG OR POL

ANY ANY
p53 p32 1 p32 p32 1
p32
AND AND AND OR AND OR
p55
p39
GAG

p24 ANY p24 p24 p24 ANY

p24 1 1
p18
19

GOLD STANDARD

HIV ITSELF

HIV ISOLATION/PURIFICATION
20

“HIV” positive

What may a scientist conclude?

• Present or likely illness; similar to raised ESR or C-reactive protein

• No proof = HIV infection

21

ANTIBODY DIAGNOSIS IN CHILDREN

Additional problem

Persistent of maternal antibodies in infant

22
23

Mother-to-child transmission of HIV infection. The European Collaborative Study.

(1988). Lancet ii: 1039-43.
24 ANTIBODY TESTS
WHO “Currently available HIV antibody tests
are extraordinarily accurate, both in terms of
sensitivity and specificity”
www.niaid.nih.gov/spotlight/hiv00/default.htm

Abbott Laboratories
“At present, there is no recognized standard for
establishing the presence or absence of antibodies
to HIV-1 and HIV-2 in human blood”

Packet Inserts Abbott Axsym system (HIV-1/HIV-2. Abbott Laboratories,

Diagnostics Division. 100 Abbott Park Rd. Abbott Park. Illinois, USA
25

PROBLEMS WITH PCR

• Primers and probes not obtained from purified material

• No proof that particles in unpurified material are HIV or even RVPs

• No proof of specificity for HIV infection

26 OWENS et al 1996

REVIEW OF 379 STUDIES FROM 5698 PUBLICATIONS

"Our investigation produced two main findings. First, the false-

positive and false-negative rates of PCR that we determined are too
high to warrant a broader role for PCR in either routine screening or
in the confirmation of diagnosis of HIV infection. This conclusion is
true even for the results reported from more recent, high-quality
studies that used commercially available, standardized PCR
assays...We did not find evidence that the performance of PCR
improved over time”

Owens DK et al. (1996). Polymerase chain reaction for the diagnosis of HIV
infection in adults. A meta-analysis with recommendations for clinical practice and
study design. Annals of Internal Medicine 124:803-15.
27

PROBLEMS WITH HIV PCR

“Those laboratories which undertake HIV screening and confirmation

assays understand fully the technical problems associated with PCR
and other amplification assays and it is precisely for those reasons that
PCR is NOT used as a confirmatory assay (as discussions with any
competent virologist would have informed them)” (emphasis in original).

Chrystie IL. (1999). Screening of pregnant women: the case against. The Practising
Midwife 2:38-39.
28

CDC 2000 Revised AIDS Surveillance Definition

“This revised definition of HIV infection, which applies to any

HIV (e.g., HIV-1 or HIV-2), is intended for public health
surveillance only…This definition is not presented as a guide to
clinical diagnosis” (emphasis in original).

Centers for Disease Control and Prevention. Mortality and

Morbidity Weekly Reports 1999;48 (RR-13):1-27, 29-31
29
CDC 2000 Revised AIDS Surveillance Definition

“In adults, adolescents, and children infected by other

than perinatal exposure, plasma viral RNA nucleic
acid tests should NOT be used in lieu of licensed HIV
screening tests (e.g., repeatedly reactive enzyme
immunoassay)” (emphasis in original).

“HIV nucleic acid (DNA or RNA) detection tests are

the virologic methods of choice to exclude infection
in children aged <18 months” (“Positive results on
two separate specimens) (emphasis added).

Centers for Disease Control and Prevention. Mortality and Morbidity

Weekly Reports 1999;48 (RR-13):1-27, 29-31.
30

Guidelines for the Use of Antiretroviral Agents in

Pediatric HIV Infection December 14, 2001 with
74 authors

“…data are more limited regarding the sensitivity and

specificity of HIV RNA assays compared with HIV
DNA PCR for early diagnosis”.

www.hivatis.org/guidelines/Pediatric/Dec12_01/peddec.pdf
 31

Coste J et al. (1997). Effect of HIV-1 genetic diversity on HIV-1 RNA quantification in plasma: comparative
evaluation of three commercial assays. Journal of Acquired Immune Deficiency Syndromes and Human
Retrovirology 15: 174.
32

Roche Laboratories

“The Amplicor HIV-1 [RNA] Monitor test is not intended to be

used as a screening test for HIV-1 or as a diagnostic test to
confirm the presence of HIV-1 infection”

Roche Diagnostic Systems, 06/96, 13-08088-001. Packet Insert

33

EVIDENCE REQUIRED

• Proof of HIV infection of mothers and babies

• Proof of drug efficacy

• High benefit/risk profile

34
PROOF OF DRUG EFFICACY

The most reliable evidence regarding the effects of a drug on

a disease are obtained by conducting randomised, double
blind, placebo controlled clinical trials.

“The placebo effect is assumed to occur in patients taking

active drugs and therefore to account for some fraction of
that drug’s total therapeutic effect”.*

“A placebo control group is important in drug trials because

it allows researchers to determine that fraction of the overall
treatment effect that is attributable to the drug’s specific,
pharmacological activity”.*

*Barksy AJ et al. 2002. JAMA 287: 622-627.

35
THE HIVNET 006 STUDY
Musoke P et al. (1999). A phase I/II study of the safety and
pharmacokinetics of nevirapine in HIV-1-infected pregnant
Ugandan women and their neonates (HIVNET 006). AIDS
13:479-86.
Cohort 1: 8 women; 200mg NVP “when in active labour”

Cohort 2: 13 women; 200mg NVP

Infants 2mg/Kg “at 72 h of age”
36

THE HIVNET 006 STUDY

Diagnosis

Women: ELISA and WB

Infants: Detectable RNA on 2 separate specimens
ELISA/WB at 18 months
Single RNA = “probable” infection
“Where possible” infant infection “confirmed” by culture

TRANSMISSION = 19% (4/21)

Musoke P, Guay LA, Jackson JB et al. (1999). “A phase I/II study of the safety and
pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and
their neonates (HIVNET 006).” AIDS 13: 479-86.
37
HIVNET 012 STUDY

“Intrapartum and neonatal single-dose nevirapine compared with

zidovudine for prevention of mother-to-child transmission of
HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial”.

Guay LA et al. (1999). Lancet 354: 795-802.

38

HIVNET 012 REGIME

Mothers: 200 mg NVP “at the onset of labour”

Infants: NVP 2mg/Kg within 72 hours of birth

39

HIVNET 012

645
m oth ers as s ig n ed

313 313 19
as s ig n ed A Z T as s ig n ed N V P as s ig n ed p lac eb o
40
REPORTED TRANSMISSION HIVNET 012

Birth 6-8 weeks 14-16 weeks

AZT 10.40% 21.30% 25.10%
NVP 8.20% 11.90% 13.10%
p value 0.354 0.0027 0.0006

Efficacy NCP vs AZT = (25.1-13.1)/25.1 = 48%

41
CONSEQUENCES OF HIVNET 012 STUDY

In August 2000 12 international experts advised:

“At the present time the most practical, effective and safe
antiretroviral intervention is nevirapine, one dose to the
mother at the time of delivery and one dose to the newborn”

Furthermore:

“In high seroprevalence areas the drug intervention should

be proposed to all seropositive pregnant women, to those
who refuse testing, and possibly to those who lack access to
testing”.

Akue, Babaki, Barre-Sinoussi, Charpak, de The, Rea, Huraux, Ndiaye, Pratomo,

Samuel, Wilfert, Zetterstrom-Italy August 2000
42

There are many scientific reasons to question the

validity of this conclusion and these
recommendations
43

PROBLEMS WITH HIVNET 012 STUDY

#1. Diagnosis of infection
Diagnosis of HIV infection in infants:

1. One qualitative RNA “confirmed” by one quantitative

RNA or culture on a second blood sample. (Data
reported only for RNA PCR RNA, not culture)

2. “One positive RNA” + death

Test used Roche = AMPLICOR MONITOR

44

LABORATORY versus COMMITTEE

“HIV-1 infection was defined as a positive qualitative test for

HIV-1 RNA assay confirmed by quantitative HIV-1 RNA assay
or HIV-1 culture on a second blood sample”.

“In addition all available clinical, serological, and virological

data were reviewed by the protocol chairperson, cochairpersons,
biostatisticians, and the data manager to confirm HIV-1
infection”.
45

TWO ROCHE AMPLICOR RNA ASSAYS

Before November 1998 “with 1.0 version kit, with

additional primers”

After November 1998 “with 1.5 version primers”.

46

Roche Laboratories Amplicor Monitor

“The Amplicor HIV-1 [RNA] Monitor test is not intended to be

used as a screening test for HIV-1 or as a diagnostic test to
confirm the presence of HIV-1 infection”

Roche Diagnostic Systems, 06/96, 13-08088-001. Packet Insert

47

PROBLEMS WITH HIVNET 012 STUDY

#2. Randomisation
48
HIVNET 012

13 839
tes ted

2144
w ith p os itive H IV -1 tes t

1499
exc lu d ed 1499/2144=70% excluded

645
m oth ers ran d om is ed

313 313 19
as s ig n ed A Z T as s ig n ed N V P as s ig n ed p lac eb o
49

REASONS FOR EXCLUSION

“did not return for HIV-1 test results, did not want
to give blood samples, were enrolled in other trials,
delivered before they could be enrolled, or had an
indeterminate or negative western blot”
50

DIFFERENCES BETWEEN GROUPS

In table 1 differences between mothers and children in the two

groups some of which are significant:

Duration of labour AZT 8.0 (5.3-12.8) vs NVP 9.3 (6.1-13.5)

hours; p=0.042

Median birth weight AZT 3200 (2900-3500) vs NVP 3100

(2800-3400); p=0.001

Well known inverse relationship between risk of transmission

and birth weight
51

PROBLEMS WITH HIVNET 012 STUDY

#3. Numerical inconsistencies

52
Numerical inconsistencies

Figure 1 shows 302 (AZT) plus 307 (NCP) = 609 “assessable for
HIV-1 infection” infants

HIV free survival measured at 14-16 weeks in 496/616 assessable

infants. Thus 19% of assessable infants not assessed.

Discrepancy in numbers because 5 children in the AZT

group and 2 in the NVP group died before they could be
tested for HIV infection
53
12 sets of twins
1 set of triplets

“If all babies from multiple births were included, HIV-1-

infection outcomes were concordant in all cases other than in
three sets of twins”

Why exclude 14 additional infants? Are the outcomes of

treatment not considered important in siblings?

Why not report their HIV status? Especially since 9 were in

the nevirapine arm

Effect on results of study if concordant and infected

54

PROBLEMS WITH HIVNET 012 STUDY

#4. Not double blind

55

NOT DOUBLE BLIND

“After randomisation, on-site study staff and investigators became

aware of the treatment and infection status of the mother-baby pairs.
Mothers also knew to what study group they had been assigned after
randomisation and were told the infection status of their babies during
the studies”.
56

PROBLEMS WITH HIVNET 012

#5. No placebo

"No researcher can assess a drug's effectiveness with scientific

certainty without testing it against a placebo. That's the only
way we can know for sure if a short course of AZT or
nevirapine is better than nothing”*.
J Brooks Jackson. Senior author of the HIVNET 012 study.

*1. Swingle AB. The pathologist who struck gold. Hopkins Medical News
2001;Spring/Summer 2001. www.hopkinsmedicine.org/hmn/S01/feature.html
57
PROBLEMS WITH HIVNET 012

Problem #5

NO PLACEBO

Without ARVs transmission rates vary considerably

15-20% in Europe; 16-30% in USA

25-40% in Africa; 13-48% Asia and SE Asia

58

NO PLACEBO

Among the reasons for large variations in MCT are “methodological

differences between studies”.

Thorne C, Newell ML. (2000). Epidemiology of HIV infection in the newborn.

Early human development. 58: 1-16
59
NO PLACEBO

Different hospitals of same study

TR Hospital A 14.3% vs Hospital B 23.7% (both placebo)

Different times during the same study

14.4% vs 23.5% before and after study mid-point

In the same hospitals A and B

TR placebo 18.6% vs no drug treatment placebo 24.2%

CDC (1998). “Administration of zidovudine during late pregnancy and delivery to prevent perinatal HIV transmission--
Thailand, 1996-1998.” Morbidity and Mortality Weekly Reports 47: 151-4.
Shaffer, N., R. Chuachoowong, et al. (1999). “Short-course zidovudine for perinatal HIV-1 transmission in Bangkok,
Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group.” Lancet 353:
773-80.
60

NO PLACEBO

Transmission rate for nevirapine of 13.1% in HIVNET

012 is higher than the 12% transmission rate reported in
a prospective study of 561 African women given no
antiretroviral treatment

Ladner, J., V. Leroy, et al. (1998). Chorioamnionitis and pregnancy outcome in

HIV-infected African women. Pregnancy and HIV Study Group. Journal of the
Acquired Immune Deficiency Syndrome and Human Retrovirology 18: 293-8.
61

PROBLEMS WITH HIVNET 012 STUDY

#6. Reporting of transmission rates

62
REPORTED INFECTION RATES

“Blood samples were collected at 24 h, 6 weeks, and 14 weeks after

birth for all babies”

Infection rates estimated at 3 days, 8 weeks, and 16 weeks using KM

method

Data used to calculate the efficacy of nevirapine

Why estimate infection rates?

Why not give the actual data without statistical manipulation?

63

“The drug regimens in this trial were specifically

designed to provide antiretroviral prophylaxis to
the neonate during labour, delivery, and in the first
week of life”.

YET

25 of the 37 children (68%) were “infected” between “Day 1-3”

when the pharmacological effect of NVP was most pronounced

This fact alone casts serious doubt over the efficacy of nevirapine
64

IS IT POSSIBLE FOR NEVIRAPINE

TO DECREASE THE RATE OF
MOTHER TO CHILD
TRANSMISSION OF HIV?
65

Viral Load and Transmission

“…elevated maternal viral load is a strong risk factor for both in

utero and intrapartum transmission”. Mock PA et al. (1999). AIDS 13:407-
14.

“The most important maternal factor is viral load…maternal viral

load has been found to predict vertical transmission” Thorne and
Newell (2000) Early human development 58 1-16.

“ 2.07-fold increase (1.57-2.72) [in risk of HIV transmission] for

every log10 increment in HIV-1 RNA copy number” (HIVNET 012)
66

NECESSARY CONDITIONS TO REDUCE MTCT ACCORDING

TO HIVNET AUTHORS

“…maternal viral load must be substantially decreased by the time

of labour or the baby must have systemic concentrations of active
drug present at the time of HIV-1 exposure to successfully lower
risk of transmission”
67

HIVNET 012 and maternal viral load

“Quantitative plasma HIV-1 RNA measurements were done before

entry, at delivery, and at 7 days and 6 weeks after delivery”

Reported only baseline value

“…nevirapine can reduce plasma HIV-1 RNA concentration by at

least 1.3 log after a single dose13”

Reference 13 is the authors’ HIVNET 006 study

68
HIVNET 006 and viral load

19 women, median = 1.3 (95% CI; -1.46 -1.17) log

reduction 7 days after single dose of nevirapine

2 had VLs of 556 and 672

Unspecified number < 400

Viral load < 400 is considered zero

At six weeks viral load same as baseline

69

HIVNET 006 RESULTS NOT REPRODUCIBLE

20 patients: NVP 200 mg daily 2 weeks; then 400 mg daily

“A mean decline of 0.46  0.47 log RNA copy numbers was

observed after 4 weeks of treatment, with a return to baseline
values within 12 weeks of treatment”

de Jong, MD et al. (1997). “High-dose nevirapine in previously untreated human

immunodeficiency virus type 1-infected persons does not result in sustained suppression
of viral replication.” Journal of Infectious Diseases 175: 966-70.
70

HIVNET 006 and viral load

MOST IMPORTANTLY

“Maternal plasma HIV-1 RNA levels were also not significantly

different at delivery from baseline”
71

CONCLUSION

“…maternal viral load must be substantially decreased by

the time of labour”*

THUS

Nevirapine cannot “successfully lower risk of transmission”

“during labour and delivery”*

*Authors, HIVNET 012 study

72

“…the baby must have systemic concentrations of active

drug present at the time of HIV-1 exposure to successfully
lower risk of transmission”*

Maternal blood and birth canal

Colostrum and breastmilk

*Authors, HIVNET 012 study

73
HIVNET 006 STUDY
“The target nevirapine plasma
level in the infant one week after
delivery was 100 ng/ml or
higher. This target was chosen
because it is 10 times greater
than the nevirapine IC50 for HIV-
1”

IC50 determined not by 006/012 authors

In vitro, not in vivo
Using synthetic template-primers, not HIV RNA.

Grob PM et al. (1992). Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype
drug. AIDS Research and Human Retroviruses 8:145-52.
74 Infant pharmacokinetics
200 mg nevirapine at “active labour”
Infant 2mg/Kg
PACTG 250 HIVNET 006
Age (hrs) 53.3 (48-77.6) 72
Pre-dose* 541 (141-768) 595 (77-1224)
Cmax* 1335 (644-1607)1279 (736-2120)
Tmax 12 (2-24) 24.6 (22.0-38.3) 13
T½ 36.8 (27.3-49.5) 72.1 (36.6-81.6) 2
Conc 1 w eek* 215 (112-275) 383 (171-757)

Mirochnick et al JID 1998; Musoke et al AIDS 1999 * ng/ml

5
CONCENTRATION REQUIRED IN VIVO FOR
VIROLOGICAL RESPONSE

“4.7 µg/mL [17.7 µM]; range, 3.4-8 µg/mL”

Concentration required NVP = 4700 (3400-8000) ng/mL

Cmax infants = 1279 (736-2120) ng/mL

In no child does Cmax reach the minimum concentration required for

a virological response.
Time between mother’s first dose and delivery:
6.9 (3.0-13.2) hours
*Havlir, D., S. H. Cheeseman, et al. (1995). High-dose nevirapine: safety,
pharmacokinetics, and antiviral effect in patients with human immunodeficiency
virus infection. Journal of Infectious Diseases 171: 537-45.
6

Could nevirapine reduce transmission via breastfeeding?

“…if nevirapine turns out to be efficacious in preventing
vertical transmission at the time of delivery, it is unlikely
to be caused by a reduction in maternal viral load. The
decrease in viral load during colostrum feeding might,
however, impact on postnatal transmission”.

“…findings from HIVNET 006 suggest maternal dose

may primarily act by reducing early breastmilk
transmission”*

*Hudson CP, Moodley J. University of Natal, Durban, South Africa

(1999) Lancet 354: 1817
77

REDUCTION VIA BREASTFEEDING

Even if the in vivo concentration for virological response

is 100 ng/ml, since T½ is 72 hours, the target will be
sustained for a few weeks, at most.

Nevirapine could only reduce HIV transmission via

breastmilk for a few weeks at most.
78
Maximum possible lowering of MTCT by Nevirapine

According to the authors of 012, “a study in Malwai found a

cumulative risk of HIV-1 infection associated with breast feeding of
7.0% at age 11 months and 10.3% at age 23 months”*

Assume:

NVP is 100% effective in preventing BF transmission up till 11 mo

Placebo = 26.2%

26.2% minus 7.0% =19.2% = TR with NVP (vs AZT 25.1%)

Maximum efficacy NVP vs AZT = (25.1-19.2)/25.1 = 24%

*Miotti, P. G., T. E. Taha, et al. (1999). “HIV transmission through breastfeeding: a study in
Malawi.” Journal of the American Medical Association 282: 744-9.
79

If placebo TR = 26.2% AND AZT TR = 25.1%

then AZT transmission rate = Placebo transmission rate

Yet the authors claimed that “short-course zidovudine may

have had some benefit”
80

DOES NEVIRAPINE PASS THE HIVNET 012 AUTHORS’ TEST?

“Maternal viral load must be substantially decreased by the time of

labour or the baby must have systemic concentrations of active drug
present at the time of HIV-1 exposure to successfully lower risk of
transmission”

• Does not reduce maternal viral load “during labour and

delivery”

• Concentration in infant is less than that necessary for a

virological response in vivo

• Cannot prevent transmission during pregnancy

81

CONCLUSION

“…CIs for their estimate of efficacy are wide, with a lower value of 20%.
Further studies are needed, and are in progress, to confirm their findings”*

Where are these studies?

No study valid without manufacturers’ guarantees that tests are specific

*Hudson CP, Moodley J. University of Natal, Durban, South Africa

(1999) Lancet 354: 1817
82

EVIDENCE REQUIRED

• Proof of HIV infection of mothers and babies

• Proof of drug efficacy

• High benefit/risk profile

83
TOXICITIES IN CHILDREN

HIVNET 006

4/22 infants died (sepsis in one child, remainder not given)

12 “serious adverse events”
1 “possibly, but not likely, study drug related”.
84 TOXICITIES IN CHILDREN
HIVNET 012

38 babies died. 22 AZT vs 16 NVP.

Pneumonia, gastroenteritis, diarrhoea, dehydration,
sepsis.
59 serious adverse events in the first 8 weeks of life
Sepsis, pneumonia, fever, congenital anomaly,
asphyxia, dyspnoea.
4 in AZT, 2 in NVP “possibly, but unlikely to be,
related to the study drug”.
No placebo: AZT and NVP have equal toxicities
Nevirapine reduces non-HIV deaths?
5 Guidelines for the use of antiretroviral agents in
pediatric HIV infection. CDC December 2001
Major toxicities (continuous dosing, not single dose regimens)
More common: (similar to adults) Skin rash (some severe, requiring
hospitalization, and life-threatening, including Stevens-Johnson
syndrome, toxic epidermal necrolysis), fever, nausea, headache, and
abnormal liver function tests.
Less common: Inflammation of the liver (hepatitis), which rarely may
lead to severe and life threatening and in some cases fatal liver
damage, and very rarely fatal liver failure and granulocytopenia.
Hypersensitivity reactions (including, but not limited to, severe rash or
rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial
edema, muscle or joint aches, general malaise and/or significant
hepatic abnormalities).

www.hivatis.org/guidelines/Pediatric/Dec12_01/peddec.pdf
86 TOXICITIES IN ADULTS

CDC
Nevirapine is toxic so much so that the CDC have advised doctors not
to prescribe it for needlestick injuries, that is, healthy individuals.
Toxicities may be “severe and life-threatening” and include Stevens
Johnson syndrome, toxic epididermal necrolysis, hypersensitivity
reactions and hepatotoxicities. Some fatal and at least one requiring
liver transplantation. Gottlieb, BMJ (2001) 322: 126

EAEMP
European Agency for the Evaluation of Medicinal Products-only for
combination therapy and only for “infected patients with advanced or
progressive immunodeficiency” (2000)
www.emea.eu.int/pdfs/human/press/pus/1126000EN.pdf
 THE PERTH GROUP APRIL 18th 2002

THIS IS THE SECOND EDITION OF THIS PRESENTATION

IT DOES NOT HAVE AN ACCOMPANYING AUDIO FILE*

THIS PRESENTATION COMES WITH SPEAKER NOTES

PLEASE ENSURE YOU EITHER PRINT THESE NOTES

OR ARE IN THIS MODE BEFORE PROCEEDING

*The first edition with streaming audio is at www.virusmyth.net/aids/perthgroup