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. 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 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. 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 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 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." 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 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) 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." 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 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 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: 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 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. ? 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 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". 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 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 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; 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 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. ______________________________ 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 2