IN THE HIGH COURT OF SOUTH AFRICA
(TRANSVAAL PROVINCIAL DIVISION)
In the matter between
TREATMENT ACTION CAMPAIGN AND OTHERS Applicants
MINISTER OF HEALTH AND OTHERS Respondents
AFFIDAVIT: PROFESOR ROBIN WOOD
I, the undersigned
ROBIN WOOD
hereby make oath and state as follows:
1. I previously deposed to an affidavit in this matter.
2. The facts deposed to in this affidavit are again within my personal
knowledge except where I indicate otherwise. To the extent that I
rely on information supplied by others, I believe that such
information is true and correct.
2
3. I have read the affidavits of Dr Ayanda Ntsaluba, Dr Princess
Nothemba Simelela, Dr Jonathan Levin and Dr Philip Chukwuka
Onyebujoh and respond to these affidavits to the extent that they
deal with scientific and clinical matters pertaining to the reduction
and prevention of mother-to-child transmission of HIV.
HIV/AIDS EPIDEMIOLOGY
4. Dr Ntsaluba (ad paras 19 and 45) and Dr Simelela (ad para 76)
admit that HIV constitutes “a major public health problem” but they
apparently dispute the relevance of the evidence in the antenatal-
survey. This survey (also attached by the Respondents) illustrates
that at least 2.5 million women aged 15-49 have HIV. The majority
of the women are of reproductive age and will benefit from
counseling, testing, advice on HIV and reproductive health,
nutritional supplements, the provision of antiretroviral medicines
such as Nevirapine to reduce mother-to-child HIV transmission,
advice on breastfeeding and formula feed where appropriate.
5. As a clinician specialist working in the public sector, it is my
opinion the facts contained in paragraph 11 of my original affidavit
are relevant because an MTCT prevention programme including
the use of Nevirapine is a health intervention needed by millions of
women with HIV and their future offspring.
6. I disagree with the negative constructions of certain of the
deponents for the Respondents regarding the safety, efficacy and
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resistance of a single dose Nevirapine for the reduction of mother-
to-child HIV transmission, for the reasons set out below.
NEVIRAPINE SAFETY
7. There is no medicine which does not have possible adverse
effects. For example, I attach (RW 18) a package insert for
Panado, a well-known medicine which can be bought over the
counter in supermarkets, without prescription, to deal with fevers
and pains. The list of possible adverse effects speaks for itself.
8. In deciding whether a medicine is safe, the question is therefore
not whether a medicine has possible adverse side-effects. The
question is the likelihood and severity of those side-effects.
Regard must obviously also be had to the seriousness of the
condition which it treats.
9. The World Health Organisation (WHO) unequivocally states in its
recommendations that antiretrovirals such as Nevirapine are safe
to use in mothers and infants to reduce intrapartum mother-to-child
HIV transmission. On the “Safety of ARV prophylactic regimens” it
says: “Conclusion: The WHO Technical Consultation concluded
that benefit of these drugs in reducing mother-to-child HIV
transmission greatly outweighs any potential adverse effects of
drug exposure. “ This is contained at page 215 (RW17) of my
orginal affidavit.
4
10. Dr Simelela was a party to this consensus statement. Neither
she nor Dr Ntsaluba has produced any evidence to the contrary.
11. In her comment on the WHO Consensus statement, Dr
Simelela misrepresents the position in her affidavit at paragraph
113.5. She denies that the WHO Cunsultation considered the
safety of Nevirapine for MTCT prevention. “The WHO was
concerned with antiretroviral drugs in general and not only with
Nevirapine. None of the clinical trials referred to by WHO in the
paragraphs addressing safety of antiretroviral prophylactic
regimens include trials where Nevirapine was used. The
conclusion by the WHO Technical Consultation on safety does not
apply, and cannot be applied, to Nevirapine. …” (emphasis added)
This is not a mistake by Dr Simelela because she also refers to it
in paragraphs 113.1 to 113.4.
12. Where the WHO statement concludes: “Short-term safety and
tolerance of the effective antiretroviral prophylactic regimens has
been demonstrated in all the controlled clinical trials,1-4,6-8,10-12
while collection of long-term safety data is ongoing”, it does in fact
include Nevirapine. The following studies that address the use
and safety of Nevirapine in clinical trials are referred to and
prominently footnoted in the WHO statement:
12.1. Endnote 10: Owor M et al “The one year safety and
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efficacy data of the HIVNET 012 trial” 13th AIDS
Conference, Durban South Africa 9-14 July 2000.
Abstract LbOr1
12.2. Endnote 11: McIntyre J. et al “Evaluation of the safety of
two simple regimens for prevention of mother-to-child
transmission (MTCT) of HIV infection: Nevirapine (NVP)
versus zidovudine (ZVD) + lamivudine (3TC) in prevention
of peripartum HIV transmission, Abstract LbOr2, 13th
International AIDS Conference, Durban, South Africa, 9-
14 July 2000.
12.3. Endnote 8: Moodley, D et al The SAINT Trial: Nevirapine
(NVP) versus zidovudine (ZVD) + lamivudine (3TC) in
prevention of peripartum HIV transmission, Abstract
LbOr2, 13th International AIDS Conference, Durban,
South Africa, 9-14 July 20
12.4. Endnote 7: Guay L et al “Intrapartum and neonatal single
dose nevirapine compared with zidovudine for prevention
of mother to child transmission of HIV-1 in Kampala,
Uganda: HIVNET 012 randomized trial” Lancet 1999;
354:795-802.
13. The HIVNET results by Owor et al concluded that the “Study
results continue to indicate that a single dose of NVP given to
HIV+ women in labor and to the newborn within 72 h of birth was
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safe and significantly reduced mother-to-child HIV transmission
rate compared with a short course AZT regimen in a breast
feeding population.”
14. Even although the Respondents (through Dr Levin) have
disputed the efficacy of Nevirapine in the SAINT Study, they have
not questioned the safety data of that study.
15. In a report on the SAINT study, Dr. Glenda Gray concluded
that: “Both NVP and ZDV+3TC regimens were safe and well-
tolerated and equally effective. She reports that “all potentially
drug-related adverse events were rashes”. Of the 661 women
enrolled for the study, only 7 or 1.2% had rashes. Only one
woman had a rash that lasted 25 days. Of 649 infants 13 or 2.1%
had rashes. Of these only “two infants had rash after NVP, one
day after the dose.” (RW19)
16. Dr Simelela herself acknowledges the efficacy and safety of
Nevirapine at paragraph 29 of her affidavit, where she states:
“Although the WHO technical consultation concluded that “the
implementation of the ARV drug regimens (including Nevirapine)
could be recommended for general implementation; the WHO
recommendations only relate to the efficacy and safety issues of
the drugs, but do not relate to the operational and implementation
issues.”
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17. Background papers for the WHO Consultation were prepared
by experts, and were presented in plenary sessions and discussed
in groups at the Consultation. They included a paper by Dr. Lynne
Mofenson (National Institute of Health, USA) and Dr. Paula
Munderi (UN AIDS, Geneva) on “Safety of Antiretroviral
Prophylaxis of Perinatal Transmission on HIV-Infected Pregnant
Women and Their Infants” (RW20)
18. This paper shows that Nevirapine safety was discussed, and it
contains the following conclusion: “The Data and Safety
Monitoring Board interim review of 869 mother/infant pairs in the
study conducted earlier this year [2000] identified no safety
concerns, with no significant difference identified between
nevirapine and placebo groups in terms of rash, clinical,
hematologic or liver toxicity in either women or infants.” Safety in
women in the SAINT and HIVNET 012 was confirmed: “No woman
receiving nevirapine had hepatic toxicity in either study; rash
occurred in less than 2% of women in both studies and was non-
serious in all cases. (Mofenson and Munderi page 17).
19. In fact, the evidence presented by Dr Ntsaluba and Dr Simelela
indicates that NVP is safe to use as long-term treatment in infants
and children.
20. The Medicines Control Council approved package insert states
the following: “Paediatric Patients: Safety has been assessed in
361 HIV-1 infected paediatric patients between the ages of 3 days
8
to 19 years. … The most frequently reported adverse events
related to Viramune [NVP] were similar to those observed in
adults.”
21. Dr Ntsaluba misrepresents facts presented in my original
affidavit at paragraphs 24-26 and in the founding affidavit by
Siphokazi Mthathi at paragraph 72-74. There I drew attention to
serious potentially life-threatening adverse effects seen in a
minority of patients who use NVP as long-term chronic medication
in association with other antiretroviral agents. Together with the
MCC, the WHO and other agencies nationally and internationally, I
differentiate between long-term treatment and a single once-off
dose with NVP.
22. However, Dr Ntsaluba confuses the adverse effects of long-
term treatment with prevention by a single-dose of NVP. At
paragraph 56.3 of his affidavit he says: “Furthermore, even though
the risk/benefit ratio of Nevirapine as an anti-retroviral agent has
been found to be in favour of continued use of Nevirapine, serious
safety issues have been picked up after registration of Nevirapine
not only in South Africa but all over the world. … Although these
undesirable effects are worse with prolonged use of Nevirapine,
some of them especially skin reactions have the potential to occur
with the first exposure to and the short-term use of Nevirapine in
MTCT of the HIV.” (emphasis added)
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23. Later, Dr Ntsaluba repeats this allegation and says: “Thus far,
serious safety issues pertaining to the use of Nevirapine have
emerged, for example serious localised and systematic skin
reactions, for example the Steven Johnson Syndrome,
Anaphylaxis and Hepatitis. Although these problems are more of
a risk with the continued use of Nevirapine, they are also likely to
occur with short-term use of that medicine, for example in order to
treat MTCT of HIV.” (excerpted from para 110.1.1)
24. From the letter of the manufacturer of Nevirapine, Boehringer
Ingelheim attached to Dr Ntsaluba’s affidavit (“AN8” pages 923-4),
it is evident that the MCC and the manufacturer understand the
severe adverse reaction to refer to treatment with Nevirapine as a
chronic medication. For instance, it refers to the “first 8 weeks of
therapy” with Nevirapine as the “critical period”. It is of course
common cause that NVP used to reduce mother-to-child HIV
transmission relies on a single dose to the mother and a single
dose to the infant.
25. Scientific logic would suggest that if a medicine is considered
safe for long-term daily use, a single once-off dose would be much
safer. That must be one of the reasons why the MCC endorsed
the claim on the package insert that: “Pregnancy and lactation:
The safety of Viramune [NVP] in pregnant or lactating women
except when used as a single dose during labour has not been
established.”
10
26. A similarly pragmatic and cautious approach is followed by the
Respondents in their pilot research and training sites. At page
1397-1398 and elsewhere in the affidavit of Dr Simelela, an
informed consent form is attached. This form is used to counsel
patients who participate in the government “research sites”. It
reads: “There are side effects that can be expected from taking
many tablets of Nevirapine. These are skin rash, fever, nausea,
headache and abnormal liver functions tests. In this programme,
you will receive only one tablet, and these side-effects have not
been commonly reported for one dose.” (1397)
27. In fact, as Mofenson and Munderi show, apart from non-serious
rash, Nevirapine did not cause any adverse reactions when used
to reduce mother-to-child HIV transmission.
28. There can be no other scientific conclusion than to say that the
MCC registered Nevirapine because on all the available evidence,
it is safe to use for the reduction in risk of intrapartum transmission
of HIV-1 from mother to child in patients who have been tested for
HIV and appropriately counseled.
EFFICACY OF NEVIRAPINE
29. In my previous affidavit, I expressed the opinion that the
efficacy of Nevirapine to reduce mother-to-child HIV transmission
during labour and at birth was established by two clinical trials,
HIVNET 012 in Uganda and the SAINT trial in South Africa. I
11
endorsed the statements of Ms Mthathi at paragraphs 57-71 of the
her affidavit in this matter.
30. Dr Ntsaluba agrees that Nevirapine is effective. He says: “It is
further noteworthy that Nevirapine has been proven to be effective
in intrapartum transmission of HIV-1. It has only been approved
and licenced for this reason. Thus, Nevirapine does not address
the other aspects of a comprehensive programme of prevention of
MTCT of HIV.” (para 56.4)
31. I agree with Dr Ntsaluba’s conclusion that Nevirapine is
effective in reducing mtct HIV transmission intrapartum. However,
I add that Nevirapine is also approved for the chronic treatment of
HIV-1 in adults and children by the MCC.
32. Dr Levin is of the same opinion. He states: “The efficacy of
intrapartum and neonatal single dose Nevirapine (NVP) in the
prevention of mother-to-child transmission (PMTCT) of the HIV
was established by the HIVNET 012 randomised trial in Uganda.”
He repeats this and states that: “HIVNET 012 provides conclusive
evidence of the efficacy of Nevirapine.” (para 7)
33. In November 2000, the National Steering Committee of the
South African Programme for PMTCT, chaired by Dr Simelela,
prepared its protocol for the research and training sites. That
document states: “The use of antiretroviral therapy to reduce
mother to child transmission of HIV has become the standard
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treatment in developed countries. Recent results showing that the
use of both short course AZT and single dose Nevirapine
administered in labor to the mother and a dose to the infant can
reduce transmission has led to recommendations for the
widespread introduction of antiretroviral interventions for this
strategy in developing countries, in parallel with the provision of
replacement feeds. “ It continues further: “There is enough
evidence to support the efficacy of antiretroviral drugs in the
reduction of HIV transmission from mothers to infants.” (pages
1265 and 1266 Simelela annexures)
34. “General efficacy of Nevirapine not in doubt. Clinical
effectiveness not the key objective of the pilot programme. “ This
statement is made in a Department of Health presentation entitled
“Developing a research framework for the National Pilot
Programme for Prevention of Mother to Child Transmission of HIV”
on 4th June 2001. It appears at page 1181 as an annexure to Dr
Simelela’s affidavit.
35. Dr Levin agrees that HIVNET012 showed that Nevirapine
reduces intrapartum transmission by 47%, but only after a 6 to 8
week period. He further states "it could be argued from a public
health point of view that the month 20 result is more relevant than
the 14-16 result."(para 7) Dr Levin ultimately concludes that: "NVP
does reduce MTCT, but probably considerably less than the
relative reduction of 50% as claimed by the Applicants." Dr Levin
has conflated separate two interventions as I will explain below:
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35.1. Nevirapine is effective for intrapartum transmission
prevention and does reduce mother-to-child transmission
by almost 50% with alternative feeding during the first
weeks of life; and
35.2. Transmissions that occur post-partum are almost entirely
due to breastmilk transmission. This can lead to
significant reversals. The reversal can be reduced with
the parallel provision of alternative feeds.
36. Dr Ntsaluba acknowledges the WHO Consultation Consensus
“that the long-term efficacy of short-term Nevirapine regimens has
been demonstrated by infant status through 12-24 months.” (para
90.1)
37. Dr Levin (either in his capacity as a member of the MCC or
some other capacity) has had access to SAINT data that is not in
the public domain, and that he has not attached to his affidavit.
He analyses the SAINT data and concludes that this trial cannot
provide any “statistically” relevant evidence that Nevirapine is
effective. Without access to this data, I cannot comment
intelligently on his analysis. If the data is made available, I will be
able to express a professional opinion on it.
38. However, regardless of whether the SAINT study provides this
evidence, I believe that it is indisputable (and apparently common
14
cause) the HIVNET 012 study has prove the evidence of efficacy
for reducing or preventing intrapartum transmission of HIV..
NEVIRAPINE RESISTANCE
39. The detection of a Nevirapine-resistant strain of HIV after a
single dose in a minority of mothers and infants concerned every
public health expert. Evidence from the different clinical trials
showed however that every mother and infant who had resistant
virus reverted to wild-type virus, thus allaying the concerns of
public health experts. Therefore, the WHO Technical Consultation
concluded that: “the benefit of decreasing mother-to-child HIV
transmission with these antiretroviral drug prophylaxis regimes
greatly outweighs concerns related to development of drug
resistance”.
40. The WHO Consultation agreed the following:
“Selection of resistant viral populations
Selection for pre-existing resistant viral populations or
development of new mutations may occur with all antiretroviral
drugs or drug regimens that do not fully suppress viral
replication. However, this is more likely to rapidly occur with
drugs in which a single mutation is associated with
development of drug resistance; such drugs include 3TC (with
and without concomitant ZDV treatment) and Nevirapine.22-24
Virus containing drug resistant mutations decreases in amount
once antiretroviral drug prophylaxis is discontinued, and wild
type virus dominates.25 However, the mutant virus may remain
present in an individual at very low levels.
15
This could decrease antiviral effectiveness of future
treatment with antiretroviral regimens that contain the same
drug, or drugs within the same class, as that used for
prophylaxis.
It is unknown if such low-level drug resistance would affect
the efficacy of the antiretroviral prophylaxis regimen if used
in a subsequent pregnancy.
There is currently no evidence that drug-resistant viruses are
more transmissible than non-resistant viruses.
There are currently no data to indicate that drug-resistant
viruses are more virulent than non-resistant viruses.
Conclusion: The WHO Technical Consultation concluded that
the benefit of decreasing mother–to-child HIV transmission with
these antiretroviral drug prophylaxis regimens greatly
outweighs concerns related to development of drug resistance.
(page 215-216 of record).
41. Dr Ntsaluba and Dr Simelela repeatedly exaggerate the
scientific and public health impact of Nevirapine-resistant virus.
They use descriptions such as “catastrophic consequences”,
“devastating”, “potentially catastrophic for public health”. There is
no evidence of such impact or potential impact. If there had been,
the WHO would not have made the recommendations which it did.
42. The MCC has requested that the manufacturer of Nevirapine
monitor the emergence of resistant virus. This is sensible and a
step I would support.
43. Dr Simelela states that “as part of the research and training
programme the First to the Ninth Respondents have undertaken a
prospective study of the selection of resistant variants of HIV-1
following the use of intrapartum and post-partum Nevirapine
16
therapy.” The plan is annexed as “NS6” and can be found at page
1131 of the Respondents’ papers. This plan is commendable.
44. The scientists and clinicians involved in this study state the
following in Annexure NS6 (1131-1144):
44.1. HIV is genetically variable. It replicates at a very high rate:
viral turnover in an infected individual is approximately 10
billion viral particles per day.
44.2. The replication process is inaccurate and even without
drugs it results in the generation of multiple variants of the
original (“wild type”) strain.
44.3. Drug pressure exposes HIV to intense selective pressure.
Viral strains that have “reduced susceptibility” to the drug
“have a reproductive advantage and replicate”. Drug
sensitive strains decrease.
44.4. When the viral population is no longer exposed to the
antiretroviral (e.g. if therapy is halted), “wild type” strains
become dominant again.
44.5. “Virus containing drug resistant mutations decreases in
amount once antiretroviral drug prophylaxis is
discontinued, and wild type virus dominates”.
17
44.6. Persistent Nevirapine resistant variants of HIV were not
found in any of the women who received the drug as part
of a mother-to-child programme.
44.7. Drug resistant HIV virus was not circulating in HIV-
infected drug naïve women attending the ante-natal clinic
at Chris Hani Baragwanath Hospital.
44.8. The Respondents’ study will only involve 200 women.
45. These expert opinions are at variance with the claims of Dr
Ntsaluba and Dr Simelela.
46. I reiterate that there is a much greater public health danger in
denying pregnant women and their infants Nevirapine, than in
mass-scale provision.
47. I have read the expert affidavit of Dr. Pierre Schoeman and
agree with its analysis and conclusions.
BREASTFEEDING
48. Reversals of all mother-to-child HIV prevention interventions
occur in a breastfeeding population.
49. In my previous affidavit, I said: “HIV can be transmitted from
mother-to-child through breastmilk. Alternative feeding options
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such as formula feed reduce this risk. Since 1992, it has been
recommended that where feasible, women be counseled to
formula feed. However, breastfeeding is the cheapest and
nutritionally most desirable way to feed infants. In poor
communities women often do not have access to clean water or
high-cost formula feed. In all contexts, women should be given the
clear information to make informed choices and provided with
formula feed when she chooses alternative feeding. “
50. It is a tragedy that almost a decade after these facts were
known, no systematic programme exists to ensure that safe
alternatives to breastfeeding exist for women with HIV/AIDS, even
leaving aside the question of an antiretroviral intervention.
51. Women and their infants must be given a choice on feeding
options that will promote their rights to healthcare and life.
OPERATIONAL CONCERNS
52. I appreciate the operational concerns faced by the
Respondents’. After all, I am an employee in the public sector with
expertise in developing programmes on Infectious Diseases.
53. Because of its low cost; its proven safety and efficacy; and its
relative ease of use, I believe that Nevirapine provides the public
sector with an ideal opportunity to create the requisite
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infrastructure to use more complex regimens that will eliminate
paediatric HIV infections.
54. There are no easy answers to operational challenges. I urge
the Respondents to adopt a two-fold incremental approach to
create the capacity and operational conditions for such
comprehensive programme:
54.1. First, adopt an incremental approach, that allows doctors
and other health-care professionals to prescribe and
administer Nevirapine anywhere in the public sector
where capacity exists to counsel and where patients have
given informed consent. This can be promoted in a clear
policy guideline that does not undermine the Essential
Drug List or impact negatively on the fiscus. It is only an
interim solution.
54.2. Second, I urge the Respondents to plan and implement a
comprehensive programme that will deal with among
others the following:
54.2.1. A programme and budget for the training of health
care professionals;
54.2.2. A programme and budget for the training and
provision of counselors for VCT;
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54.2.3. A programme and budget for HIV testing;
54.2.4. A programme and budget to provide the nutritional
supplements needed by pregnant women with
HIV/AIDS;
54.2.5. A programme for the acquisition of the dosages of
Nevirapine needed for women and their new-born
infants (currently available for free);
54.2.6. A programme and budget for the formula feed
needed by women who choose this alternative.
This could also include a plan to reduce the cost of
formula feed;
54.2.7. A programme and budget for appropriate
infrastructural support, such as modification of
buildings and storage facilities; and
54.2.8. Appropriate managerial training, monitoring and
evaluation of the programme.
I do not say that all of these things can be done instantly throughout
our country. They plainly can not. But if our country is going to deal
with the HIV/AIDS crisis, we have to get on with planning and
implementing a comprehensive programme of this kind without
further delay. What distresses me most, as a clinician who deals
21
every day with the consequences of this epidemic, is that we still do
not even have a decision to plan and implement such a programme,
let alone the programme itself. This is leading and will continue to
lead to avoidable human suffering and death, on a vast scale.
CONCLUSION
55. In my professional opinion antiretroviral therapy, such as
Nevirapine or AZT, for use in the prevention of mother-to-child
transmission of HIV, significantly reduces the risk of HIV
transmission from mother to child; nothing which has been said on
behalf of the Respondents have changed my opinion.
56. The provision of Nevirapine is safe for both mother and infant;
and it is a critical public health care measure that enhances the
choices of all women of reproductive age.
57. The use of Nevirapine for this indication is simple, cheap and
consistent with the latest recommendations of international health
authorities.
58. To prevent mother-to-child transmission of HIV, the a package
that includes voluntary counseling and testing, antiretroviral
therapy such as Nevirapine, and the option of using formula milk is
an essential public health measure.
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______________________________
ROBIN WOOD
I CERTIFY THAT THE DEPONENT HAS ACKNOWLEDGED THAT HE KNOWS AND
UNDERSTANDS THE CONTENTS OF THIS AFFIDAVIT WHICH WAS SIGNED AND
SWORN TO BEFORE ME AT CAPE TOWN ON THIS ----- DAY OF NOVEMBER 2001
AND THAT HE HAS NO OBJECTION TO TAKING THE PRESCRIBED OATH AND
CONSIDERS SAME TO BE BINDING ON HIS CONSCIENCE.
______________________
COMMISSIONER OF OATHS