Anthony Brink: The trouble with nevirapine

PART FOUR 

There is no expedient to which man will not resort to avoid 
the hard work of thinking. 

Thomas Edison

In January 2001 nevirapine was approved by the South African Medicines Control Council for use as a single drug to prevent mother to child transmission of HIV. On the strength of a study so inept you can’t believe your eyes – the one that founded the Treatment Action Campaign’s successful application to the High Court for an order compelling our government to forget about the cautious exploratory trials that the Medical Research Council was conducting at pilot sites around the country, and to supply nevirapine to every HIV-positive pregnant woman showing up at government hospitals without further ado. 

Laura Guay, an ambitious staff-doctor in the Pathology Department of Johns Hopkins University School of Medicine, in the city of Baltimore, Maryland, US, got the bright idea that nevirapine would be her ticket to stardom if she could show that it saved babies from their mothers. In 1997 she flew in to Kampala, Uganda with a team of researchers to conduct an experiment on pregnant black women there. Her idea was to compare the effectiveness of nevirapine versus AZT versus placebo for preventing mother to child transmission of HIV. All treatments commencing at labour.

 The study was reported in Lancet on 4 September 1999 in all the usual posh language: 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. South African ‘AIDS experts’, activists, pharmaceutical regulators, health officials, opposition politicians, journalists, human rights lawyers and judges were all tremendously wowed. Here was rock-solid proof of nevirapine’s efficacy for saving babies’ lives. Summed up in the assertions of our Medicines Control Council’s Dr Jonathan Levin in a disgracefully inadequate answering affidavit that he made in the TAC's nevirapine case: “NVP would save 10 out of every 100 babies born to HIV-positive mothers” and “HIVNET 012 provides conclusive evidence of the efficacy of NVP.” With friends like these on your side, who needs enemies? Is it any wonder our government lost the case?

 Guay’s nevirapine study was an unbelievable mess. To read her referring to the drug’s “potent antiviral activity” and “safety profile”, i.e. very effective against HIV and perfectly safe in pregnancy, contrary to what was already known, was just a foretaste of what was to follow.

 It’s elementary that a drug trial should be randomised, placebo-controlled, and double-blind – meaning its subjects should be treated or not treated on the basis of a random assignment; test drugs and dummies should be equally distributed; and neither the hospital doctors nor the patients should know who’s on what. There should also be an untreated control group in the trial, given neither the test drugs nor placebos, in order to exclude the possibility of outcomes hoped for by the researchers showing up without any intervention at all – since the administration of placebos can have the strangest effects, as we’re about to see. And of course there should be a big enough number of test subjects on the trial from which to draw meaningful conclusions.

 Guay apparently knew most of these basics when she teed off, because the trial she conceived “was originally designed to be a randomised, placebo-controlled, double-blind phase three trial of 1500 mother-baby pairs to investigate the safety and efficacy of oral zidovudine and oral nevirapine for the prevention of vertical mother to child transmission of HIV-1 from pregnant women to neonates in Uganda.” A fair start, except that Guay didn’t think to study an untreated control group. A not insignificant omission, seeing that the American CDC, studying the effect of AZT for the same purpose, reported that placebos apparently reduced the transmission rate (18.6%) when compared with untreated controls (24.2%) – leading the researchers to observe: “The lower than expected background transmission rate highlights the importance of having included a randomised, concurrently enrolled, untreated control group. Had the test regimen been inactive, a transmission rate of 18.6% may have suggested some efficacy when compared with historical data.” 

From the day Guay’s plane landed, her study began falling to pieces. The system designed to keep the trial blinded immediately collapsed. She reported this fundamental breakdown of control with face-saving delicacy: “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 the infection status of their babies during the study.” She concluded: “Limitations of our study were that investigators and mothers were not masked to treatment status or outcome after randomisation.” She could have put it more plainly: ‘We fucked it up from the word go.’ 

That the unblinding of the trial would have affected its outcome is certain, given the terror of the diagnoses and the inevitability that at least some of the pregnant women given the news that their babies might die would do anything to reduce the chances. Resort to pill sharing between groups, for instance, or swallow other drugs by the handful, or traditional potions, not necessarily benign. Those on experimental nevirapine might have taken ‘proven effective’ AZT as well. Unseen by the trial overseers, because “many doses [of AZT] were given unobserved. Mothers were identified before labour and given the drug to take at home.” And one must consider the possibility that those on old AZT might have gone to any lengths to obtain the hyped new drug instead. The kind of stuff that FDA inspectors discovered went on in the chaotic licensing trial that preceded AZT approval in the US, and thereafter approval everywhere else. The key one that became utterly corrupted (detailed in Just say yes, Mr President: Mbeki and AIDS) but on the basis of which GlaxoSmithKline still claims AZT extends lives. Being liars of Nazi scale. 

We recall that Guay originally had 1500 mother-baby pairs in mind. Subjects for the study were drawn from pregnant “women attending antenatal clinics at Mulago Hospital in Kampala, Uganda…screened for HIV-1 infection by EIA [ELISA] for HIV-1 antibody. If a woman tested positive, she received post-test counselling about her infection status and was informed about the opportunity to enrol in HIVNET 012…” In other words, women lighting up a single ELISA HIV antibody test were considered infected, told so, and offered the chance to save their babies with free medicine for them if they joined the drug trial. In her next sentence however, Guay states that, “Women were eligible for the study if: they…were positive on EIA and western blot for HIV-1 antibody…” So which is it? By what criterion did Guay define HIV infection? 

Nearly all ‘AIDS experts’ agree that a single reactive ELISA antibody test is insufficiently reliable a basis upon which to make an HIV-positive diagnosis – notwithstanding that the manufacturers of these state-of-the-art, third-generation, recombinant protein-based test kits typically claim 99.6 per cent specificity for HIV, that is, only 4 mistaken positive diagnoses per thousand. As the figure would suggest. It’s a claim made on an essentially fraudulent basis however, because the sensitivity and specificity of these tests has never been assessed by observing how they perform in relation to groups of confirmed HIV-infected, as against confirmed HIV-free individuals – HIV-infected meaning the virus isolated from the HIV-positive patient’s blood or tissues. The reason is startlingly simple. HIV has never, in the history of the AIDS era, been isolated from anyone – by ultracentrifugal purification and then electron photomicrograph verification (the standard procedure for isolating viruses). The existence of the most feared pathogen in history (suddenly with us, say ‘AIDS experts’) is inferred instead from indirect ambiguous biochemical clues. 

The Medical Underwriters Committee of the Life Offices Association for our life insurance industry sees things differently. They’re really with it, these guys. And just waiting to be cleaned out in a ‘class action’ for damages for psychic shock. Its Informed Consent form for folk like you and me taking a compulsory ‘AIDS test’ for a life policy anticipates our question, “Is the test always accurate? Can there be mistakes?”, answering: “…the tests used are very accurate.” Underscored by: “What does it mean if the test is positive?: …this means that you have been infected with the AIDS virus.” However when I taxed the pathologist drawing my own blood about this, he disagreed with these statements on the form, and claimed that pathologists had been conducting “a running battle with the Life Offices Association for years” regarding the sufficiency of a single ELISA test as a basis for an HIV-positive diagnosis. But the machine just rolls on, as lives are crushed daily. Who gives a damn when there’s money to be made, and certainly none in rocking the boat? How many doctors do you know who have ever taken a risky principled stand against abusive and harmful practices of their profession? Or are likely to? 

Guay’s Trial Profile schematic tells us that 13 839 women were “tested for HIV-1.” 2144 were described as: “…with positive HIV-1 test.” Whether Guay meant positive according to a single ELISA – like the women just referred to – or positive according to an ELISA ‘confirmed’ by western blot, is simply left in the air. We’re left to wonder. 1499 of those 2144 women were excluded from the trial, leaving just 645 mothers (not the 1500 intended). Among the reasons for excluding the 1499, Guay mentions “an indeterminate or negative western blot.” But since women lighting up a single ELISA “received post-test counselling about [their] infection status and [were] informed about the opportunity to enrol in HIVNET 012”, it’s quite possible that some of these women came aboard the trial without further testing. And since further testing always leads to the exclusion of the majority of single ELISA positives, the necessary conclusion is that most of these single ELISA positive women were not infected. We are staring into a massive crack in the trial’s foundations that nothing can patch. 

Simple logic dictates that repeating an ELISA can’t confirm the initial positive result, because whatever triggered the first test (such as TB bacilli, and about 60 other documented conditions) can just as well set off the second. Even if it’s made by a different manufacturer. (This point has never occurred to University of Cape Town ‘AIDS expert’ virologist Dianna Hardie, because according to her, speaking on John Perlman’s prime-time AM Live radio show (“for the well-informed”) on 4 April 2002, two positive ELISAs do just fine.) Guay may or may not have been alive to the problem just stated, because we see that she wasn’t content with a second reactive ELISA: “We screened plasma from mothers for HIV-1 antibody with a licenced assay (HIV type 1 Vironostika, Organon-Teknika…). If the test was reactive, a second HIV-1 antibody test was done on the same sample with the Murex 1+2 assay… For women with blood samples that were reactive on both tests, we took a second sample and did an HIV-1 western blot analysis (Cambridge Biotech…) for confirmation of HIV-1 infection.”

As your doubts begin rising like bile, you might wonder whether those mothers ‘confirmed’ infected by western blot retesting were really ‘living with HIV’ anyway. See, you can’t intelligently confirm positive ELISAs with a western blot either. Most ‘AIDS experts’ regard western blot results for HIV antibodies as decisive – as the absolutely reliable last word. But not in England and Wales, where western blots are not used to confirm positive ELISAs precisely because they are regarded as too unreliable. (Hello? Welcome to AIDS.) The spuriousness of a ‘confirmatory’ positive western blot test for one or more positive ELISAs got a close look in a lengthy landmark review, Is a positive western blot proof of HIV infection? by Papadopulos-Eleopulos et al, published in a prominent scientific journal, Bio/Technology (now Nature Biotechnology), in June 1993, and it makes a staggering read. (It’s archived on the Internet). It points out that all the proteins used in these tests as antigens to fish for ‘HIV antibodies’ are not unique bits of ‘HIV’ as had always been imagined by ‘AIDS experts’, but are actually ubiquitous cellular proteins, or clumps of them (oligomers). Bits of us, in other words, or bits of common bugs. What’s more, the performance of the test has never been gauged by reference to the gold standard of confirmed viral infections. Because oddly enough, as mentioned, ‘HIV’ has never been isolated. But we don’t have to get into all that. It’s surely enough to know that ‘AIDS experts’ apply completely different criteria from place to place when interpreting western blot results. In their western blot paper, Papadopulos-Eleopulos and colleagues describe eleven distinct currently applied official sets of criteria for diagnosing HIV infection with western blot, varying radically from continent to continent, institution to institution and even between laboratories in the same city. So that whether you’re ‘infected’ or not, and condemned by doctors to die soon, or told with relief that you’ve a long life ahead, is really the luck of the draw. Being all about how your test result is interpreted. Which criteria are applied. Infected with a deadly virus here, but free of it according to a different interpretation there. It’s unbelievable but true. But as I say friends, this is AIDS, and in AIDS anything goes. Don’t bother asking ‘AIDS experts’ about any of this stuff though, let alone your family doctor. They’ll huff and puff with dismissals and haughty assurances, but in truth won’t have a clue as to what you’re even talking about. (Been there, got the tee shirt.) You’ll have to read up for yourself. 

By February 1998, only 49 women had been enrolled on Guay’s trial – 19 of whom were assigned placebos, 15 AZT and 15 nevirapine – when Shaffer’s pleasing report came through of the results of his short-course AZT trial in Thailand (Lancet 353: 773-80). So Guay thought the hell with placebos, and simply dropped the placebo arm of her study. No doubt because she figured it would be unethical to deny pregnant women antiretrovirals any longer. Although she didn’t find anything morally troublesome about treating HIV-positive pregnant women with the experimental drug, nevirapine. Before calling off the placebo wing however, she noted that the transmission rate among women given placebos was 26.1%. But also that the rate among women given AZT was a “similar” 25%. 

Amazing: when it comes to saving babies, placebos are as good as AZT. But of course that’s not what the ‘AIDS experts’ tell you. Being ‘AIDS experts’. Indeed, recording these substantially identical numbers, Guay said in the same breath that “short-course zidovudine may have had some benefit.” Except that placebos wouldn’t have caused the kind of toxic shock that resulted in the vomiting and premature labour contractions that Guay reported among some of the women given AZT. We’ll return to deal with her toxicity data shortly. 

Abandoning the placebo wing of the study made it impossible to claim a benefit for the test drug – nevirapine being the new one under investigation – since not only do untreated mother to child transmission rates vary hugely from place to place according to all the reports (ranging from approximately one in two cases to one in ten) but even placebo administration has magical reported effects: For instance in the Shaffer study of the effect of short-course AZT administration on mother to child transmission, placebo administration reduced ‘transmission’ at one hospital 14.3% and at another 23.7%. 

 But not only does placebo administration have mysterious benefits; so does taking nothing at all. A study by Ladner and Leroy published in Journal of the Acquired Immune Deficiency Syndrome and Human Retrovirology in 1998 (18:293-8) reported that the transmission rate among 561 African women given neither antiretroviral drugs nor placebos was 12%. That’s lower than the 13.1% rate triumphantly claimed by Guay as the benefit of administering nevirapine. In short, the Ladner study provides evidence for the contention that pregnant African women left to have their babies unmolested by white missionary ‘AIDS experts’ like Guay actually do best of all.

 Apart from a theoretical grasp of some of the basics for the proper conduct of a clinical drug trial – even as she watched her study fall apart – Guay was wise to a couple more things. Like: “…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.” But without batting an eyelid, she went on to report: “Maternal plasma HIV-1 RNA levels were…not significantly different at delivery from baseline.” Which is kind of hard to reconcile with her claim that the drug worked as hoped. To lower transmission risk by lowering the concentration of viruses in the mother. Since it turned out not to. Does anyone have any bright ideas?

 We’ll just accept for now that a ‘viral load’ test result indicates the number of HIV particles in your blood. We’ll block our ears to Nobel Prize-winning biochemist Kary Mullis’s complaint that it doesn’t, and that the test is an abuse of the PCR technology that he conceived, for which he won the Swedish honour. (He wouldn’t know what he’s talking about, right? He only invented the thing.)

 With the effectiveness of nevirapine for the purpose of reducing maternal ‘viral load’ in the can – Guay’s first condition for efficacy – let’s turn to the second one: “…the baby must have systemic concentrations of active drug present at the time of HIV-1 exposure to successfully lower risk of transmission.” What she means by a “systemic concentration” is enough of the drug in blood to equal or exceed its inhibition concentration (IC50) – that is, a concentration high enough to inhibit viral replication by half, as determined by the usual indices. Guay whimsically picked a generous figure of 100 ng/ml – ten times the IC50 of nevirapine asserted by the manufacturer in 1990. Although two years later, other scientists reported nevirapine’s IC50 value as being double that – both values determined however in highly artificial laboratory conditions, with no relevance to the real world whatsoever. Guay happily told us that a pill of nevirapine given to pregnant mothers going into labour achieved drug concentrations surpassing her arbitrary 100ng/ml concentration. The trouble is that Havlir et al reported in 1995 (JID 171: 537-45) that in vivo (as opposed to tricks in test tubes) the minimum concentration of nevirapine for a virological response is 3.4 to 8mg/ml. But in no case did the nevirapine plasma concentrations that Guay achieved come anywhere even close to that. Meaning that with the dose that she gave, Guay was unable to achieve systemic concentrations of nevirapine in the babies sufficient to prevent HIV replication and thereby reduce the risk of HIV transmission from mother to child. Either before or during birth. Or after it during breastfeeding. Which is another way of saying that nevirapine given as described could not possibly be doing what Guay claimed it was.

 But at the end of the study, Guay’s exciting bottom line was this: The transmission rate (assessed at 14-16 weeks) among mothers on AZT was 25.1%. On nevirapine it was 13.1%. On this basis, nevirapine was declared 48% more effective than AZT. And Christ, we’ve never heard the end of it.

 Having heard ‘AIDS experts’ forswearing HIV antibody tests for ascertaining mother to child transmission, since it's accepted that babies inherit their mothers’ antibodies when born, you would be right to wonder how the “transmission rate” was determined.

 Guay tells us: “HIV-1 infection [among babies] was defined as a positive qualitative HIV-1 RNA assay confirmed by a quantitative HIV-1 RNA assay or HIV-1 culture on a second blood sample. If babies died after only one positive RNA assay on the sample, we classified the baby as being infected.” No matter what caused the baby’s death – an adverse drug reaction, a bad heart, whatever. It’s a pity that Guay never got around to reading the instruction manuals that came with her PCR-based RNA test kits. Had she done so she would have read Roche stating in regard to its qualitative RNA test used in her study: “For research use only. Not for use in diagnostic procedures.” Not being reliable enough to hang a diagnosis on. Too hit and miss. Our very own National Institute for Virology goes along with the FDA about this. Such assays are hopelessly inaccurate for HIV diagnosis – the US Centers for Disease Control agrees with everyone. But inexplicably, without rhyme or reason – and unable to explain why when asked – the CDC relaxes the rule for babies. For them, the CDC says, they’re as true as an atomic clock. Sometimes: When diagnosing babies putatively infected by their mothers – but not by blood transfusions; in which latter case the CDC reverts to its ban on RNA assays for diagnosing HIV infection in babies. Lovely stuff.

 If you’re not already gagging on the stench, here’s some rotten cabbage to add: To confirm neonate HIV infection indicated by the qualitative RNA test result, Guay tells us she used a quantitative RNA test, commonly referred to as a ‘viral load’ test. But this is a use of the assay explicitly forbidden by the manufacturer: “The Roche Amplicor HIV-1 Monitor Test v1.5 is not intended to be used…as a diagnostic test to confirm the presence of HIV-1 infection.” But hang on, we’re ‘AIDS experts’. Are you suggesting we’re illiterate and incompetent morons?

 In his answering affidavit to the TAC’s nevirapine case, the MCC’s Levin alluded clumsily to some of the trouble with diagnosing babies with PCR tests – in doing so, missing all their basic problems. On the use of PCR for diagnosing babies, the statistician shared his wisdom with us as follows: “It is also possible that the PCR test used at 6 weeks gave some false positives. A study by Glenda Gray on the influence of breastfeeding on MTCT found a number of indeterminate PCR results. A paper by Zijenah et. al., states that the use of PCR for diagnosis of HIV infection has been hampered by a lack of suitable primers for clade C viruses. In addition in September 2000 (after the Petra and SAINT PCR tests were done) Roche announced the development of an improved PCR kit. Thus virologists should be consulted to comment on the reliability of PCR particularly at 6-8 weeks.” As if they’d know better than the manufacturer of such tests. The fact is, all you have to do is read the instruction book that comes with any PCR-based HIV-RNA assay. It says it all. You cannot diagnose HIV infection with PCR tests. Period.

 These most basic problems aside, let’s dwell for a moment on the sense and wisdom of giving pregnant women nevirapine as they go into labour to prevent mother to child transmission of HIV. A very poisonous chemical, it’s well known. Even just a little bit, the FDA warned doctors and nurses on 5 January 2001 – banning it for even a couple of weeks of treatment in HIV needlestick injury prophylaxis.

 ‘AIDS experts’ tell us that unlike other viruses, HIV is a retrovirus that burrows into and actually becomes part of our DNA. That infected pregnant women can infect the babies they are carrying. And that, according to Guay, a single pill of nevirapine administered just before birth can prevent this. If the mother’s virus has had nine months to reach the baby through the placenta, the umbilical cord, and all those shared fluids, and thereafter ingratiate itself into the baby’s DNA, would someone care to explain the value of the magic pill? How it can possibly prevent anything? Particularly since administration of nevirapine alone has no effect on CD4 cell counts, and no significant effect on ‘HIV RNA’. Since its putative activity is reverse transcriptase inhibition, the drug is notionally only able to prevent the infection of new cells – not eradicate HIV from already infected cells, or prevent such cells from expressing new HIV particles. So if the child is ‘infected’ by the mother while in utero during the nine months it is being carried, administering nevirapine as she goes into labour is completely pointless. As is giving it to the neonate: The drug concentration in the neonate’s blood achieved by the recommended dose of 2 mg/kg following birth is much lower than the concentration determined to be necessary for an antiretroviral action, anyway. Likewise the concentration of the drug found in breast milk, so it can’t prevent infection via breastfeeding either.

 But Guay claimed: “Most vertical transmission occurs during active labour because of maternal blood transfusions to neonates [?!] and direct exposure to virus during passage through the birth canal [nasty place that – to ‘AIDS experts’]”, citing a couple of speculative studies proposing that mothers infect their babies during labour and birth. Which makes it hard to understand why in the West AZT is administered for many weeks before it. Especially since it doesn’t reduce maternal ‘viral load’. British ‘AIDS experts’ aren’t too sure about this last-minute stuff anyway. Certainly not in all cases. In Reducing Mother to Child Transmission of HIV in the United Kingdom, a report put out in April 1998 by the Royal College of Paediatrics and Child Health, hooked up with other top boffs, they state, “Indirect evidence suggests that in the absence of breastfeeding about two thirds of infections are acquired around the time of delivery.”

 We recall that the ostensible benefits of administering nevirapine (per CD4 counts) were observed only in people “with HIV infection who have experienced clinical and/or immunological deterioration.” But the overwhelming majority of pregnant women who light up HIV antibody tests are healthy. (In fact the Guay study excluded women with health problems.) And nobody looks at whether their CD4 cell counts are within what ‘AIDS experts’ consider (arbitrarily) to be within a normal range. What’s more: “…nevirapine is only recommended for use in combination with at least one other antiretroviral agent in the nucleoside analogue class…” Because notwithstanding how allegedly “potent” it is (per Boehringer Ingelheim’s The Role of Nevirapine in HIV Therapy information release), the manufacturer admits that it’s ineffective on its own no matter how much of it and for how long you take it. Yet it is claimed by ‘AIDS experts’ to work its magic solo with a single dose when given to pregnant women. Irrespective of their CD4 cell count or clinical health status. With perhaps one or two given to the infant too. Brilliant.

In Mother to child transmission of HIV and its prevention with AZT and nevirapine: a critical analysis of the evidence,published as a monograph on 1 October 2001, Papadopulos-Eleopulos and her colleagues point out another basic problem with giving nevirapine to women entering labour. It takes an average of 4.6 hours for an oral dose of 200 mg to reach its maximum concentration in the blood. Since women generally deliver at between 0.9 and 10.5 hours after dosing, and nevirapine takes between 1-8 hours to reach maximum plasma concentration, an unascertained number must give birth before the target concentration can be reached. In fact, as we’ve discussed, it never is.

 Nevirapine may be completely useless, but does it do any harm to give it? I mean just to keep the AIDS activists happy. The doctors full of high purpose. Saving babies’ lives. Mothers and children always being a cuddly cause. Guay’s take on it was this: “Although the zidovudine and nevirapine regimens we used seemed safe, long term follow up of the babies remains a high priority to find out about possible long-term toxic effects.” But what did her data say? About the immediate short-term ones? About the safety of the drugs? About evidence of poisoning with the poisons?

 Nevirapine, we read in Part One, is extremely toxic. Would it come as a surprise then to learn that in HIVNET 006, the toe-in-the-water trial that preceded the Guay study, a chilling four babies out of the twenty-two treated with nevirapine died? Twelve “serious adverse events” were reported, but the researchers (including Guay) didn’t connect them with the drug. But then we’ve read enough already to know that this bird wouldn’t recognize a toxic reaction if it hit her between the eyes.

 In Guay’s HIVNET 012 study “The rates of maternal serious adverse events were similar in the two groups (4.4% in the zidovudine group, 4.7% in the nevirapine group). One mother in the zidovudine group died 2 weeks after delivery and had bronchopneumonia. One serious event, anaemia, was possibly associated with zidovudine, but excessive blood loss at delivery may have accounted for the anaemia. The occurrence of clinical or laboratory abnormalities in mothers was similar in the two groups (82.2% in the zidovudine group and 80.7% in the nevirapine group had at least one such event). The most frequent adverse clinical event was bacterial or viral infection, occurring in 18.2% of women receiving zidovudine and 20.4% of those receiving nevirapine, followed by parasitic infection in 12.4% and 15% respectively, followed by anaemia in 10.5% and 13.1% respectively. Nine mothers (four in the zidovudine group, five in the nevirapine group) had maculopapular rash, but no case was serious.” The “laboratory abnormalities” – at a sky-high rate – detected after the drugs were given were not specified in the report; Guay didn’t think it important to identify them. The development of infectious illnesses in about one in five women on the trial following ingestion of the general metabolic poisons didn’t draw any comment either. Even though the FDA itself pointed out in a press release on 5 March 1990 concerning AZT that it “may reduce white blood cell counts to the point where the drug has to be discontinued to avoid infections.” Incredible.

 As for the effect of the poisonous drugs on the babies, Guay reported that, “The rate of serious adverse events in the two groups [of babies] was similar up to the 18-month visit (19.8% in the zidovudine group. 20.5% in the nevirapine group), with the median age at last visit being 183 days… The most frequent cause of serious adverse events within 56 days of birth were sepsis, pneumonia, fever, congenital anomaly, asphyxia, and dyspnoea.” 18 babies suffered maculopapular rash, and 22 anaemia. “The frequency and severity of laboratory-detected toxic effects, including neutropenia [depleted immune cells], thrombocytopenia [depleted clotting platelets], and abnormalities in creatinine [energy metabolism] or bilrubin [breakdown product of haemoglobulin], were similar in the two groups.” But again, Guay didn’t think to share the numbers with us. “38 babies (6.8%) died (22 (7.9%) in the zidovudine group, 16 (5.7%) in the nevirapine group). The most frequent causes of death were pneumonia, followed by gastroenteritis, diarrhoea, dehydration and sepsis.” 

 On the basis of a one in five incidence of serious adverse events and a seven per cent death rate among the babies treated with nevirapine and AZT, would you also have deduced – especially without placebo and untreated controls for comparison purposes – that “zidovudine and nevirapine regimens…used seemed safe”? Being a person in your right mind? In your sound and sober senses? Compos mentis?

 Following publication of the Guay study, South African AIDS activists and journalists dropped AZT for pregnant women like a hot plate. From now on the roar was for nevirapine. In every newspaper, every day. John Perlman managed to cram in no less than three interviews plugging nevirapine on his radio show one morning in early 2002. Everyone joined in the feel-good campaign: Mandela, Tutu, Billy Carter, Bill Gates, the lot. But it was only in only South Africa that this unreal drive took off, like the great 1857 Xhosa cattle slaughter. Because American and European ‘AIDS experts’ didn’t see it the way the aforementioned nevirapine fans did – as the ANC pointed out in a press release on 9 March 2002, deploring Carter’s criticism of the government’s reservations about the drug, after meeting Mbeki and Tshabalala-Msimang the day before, during his tour with Bill Gates’s father to turn up the heat on the government to give nevirapine to all HIV-positive pregnant women: "We find it alarming that president Carter is willing to treat our people as guinea pigs, in the interest of pharmaceutical companies, which he would not do in his own country. We do not understand why US citizens urge this drug upon us when the health authorities in their own country do not allow its use for mother-to-child-transmission. One of the reasons for this is that these authorities say that there is insufficient data about issues of the safety of the drug. For this, we do not need the interference and contemptuous attitude of president Carter or anybody else. As South Africans, we have the possibility to find solutions to our problems, as the people of the US have. We are not arrogant to presume that we know what the US should do to respond to its many domestic challenges. Nobody from elsewhere in the world should presume they have a superior right to tell us what to do with our own challenges. We are therefore very surprised at the public comments made by president Carter after this meeting.” Carter hit back from Kenya saying, “In most countries where presidents stand aloof, the rate of infection continues to increase.” In other words Mbeki stands aloof, doesn’t care. But Kenyan President Arap Moi, he said, has the right idea – having asked Kenyans in 2001 to abstain from having sex for at least two years to combat AIDS: “It is often not realised in Kenya the extraordinary leadership that President Moi has taken in declaring several years ago that HIV is a national disaster." Sure. Something new from doctors for us to shudder over, since hardly any of us take the fire and brimstone of priests seriously any more. As we admire the curves.

 Hoping to cash in on the vast market opportunities generated by the publication of Guay’s paper, Boehringer Ingelheim lodged an application to the FDA for permission to market the drug in the US for the new indication suggested by the study. It probably wished it hadn’t. An audit of Guay’s data by researchers at the National Institute of Allergy and Infectious Diseases (a branch of the National Institutes of Health) found problems – described by FDA spokesman Jason Brodsky as “potentially quite serious.” As the company put it in a press release on 22 March 2002: "Boehringer Ingelheim is aware that questions have been raised regarding reporting and documentation in a study conducted in Uganda for prevention of the transmission of HIV from mother-to-child during birth called HIVNET 012." NIAID’s simultaneous press statement put it this way: "Although no evidence has been found that the conclusions of HIVNET 012 (the Uganda trial) are invalid or that any trial participants were placed at an increased risk of harm, certain aspects of the collection of the primary data may not conform to FDA regulatory requirements." This statement by the trial’s sponsor was something of a snow job, having regard to NIAID’s John LaMontagne’s disclosure that there were often "professional differences of opinion" between the American researchers and the Ugandan hospital staff concerning what constituted a "serious adverse event." The “irregularities”, as Reuters called them, appear to have concerned in part the under-reporting of toxic reactions to the test drugs. NIAD’s soft soap line cannot wash: LaMontagne’s revelation about “differences of opinion” concerning the critical issue of toxic reactions is indeed “evidence that the conclusions [of Guay’s study] are invalid” – calling as they do the claimed safety of nevirapine for babies very pertinently into question.

 Anybody who hasn’t by now appreciated, in the light of our discussion above, that ELISA and western blot test results for ‘HIV antibodies’ are irrelevant, and who still wants to know whether the women on the trial were single ELISA positive, or ‘confirmed’ positive with a second ELISA and a western blot, is in for a hard time finding out. According to a report in the Kampala Monitor on 3 April 2002, Guay’s Ugandan sidekick, Professor Francis Mmbiro, had been able to find only 100 of the source documents that the FDA wanted to audit; the rest, he said, were “stacked up in a container due to the ongoing rehabilitation at the hospital.” Sounds like lost to me. To LaMontagne too, if you read between his lines: There are “differences in the way hospitals in Uganda keep records and the requirements of the FDA”, which, he said, "quite rightly has a rigorous standard." But this was a study conducted by American ‘AIDS experts’. His attempt to blame the Ugandans for the shambles is transparently dishonest.

 The missing original case records also mean that we’ll never know what happened to the Ugandan women who were single ELISA positive, “received post-test counselling about [their] infection status and [were] informed about the opportunity to enrol in HIVNET 012” but chose not to. Were they were offered a second ELISA and then a western blot? Or just packed home believing that they were HIV-infected? To suffer under the false curse. Put on them by the American doctors. In spooky white robes, dangling stethoscopes in place of crucifixes.

 The upshot of it was that Boehringer Ingelheim immediately withdrew its application to the FDA for a licence to sell nevirapine to pregnant women in the US. The drug is not currently licensed for marketing to prevent mother to child HIV transmission in that country or in Europe. But in developing countries it’s different: Spokesman John Wecker said, “Boehringer Ingelheim continues to donate nevirapine to programs in some 23 countries where the drug is used to help prevent mother-to-child HIV transmission.” That’s how the company operates in penetrating new markets in the Third World: It gives its drug away. Until such time as it becomes established by usage as ‘the standard of care’. Then of course everything changes. Do you think we’re in this for charity?

 The striking frequency of severe toxic reactions in Guay’s study, disclosed in the Lancet report – those that were actually recorded – we have noted already. But the Treatment Action Campaign’s activists evidently didn’t get as far as reading the Adverse events and toxic effects bit on page 799. Because in response to a contemporaneous public announcement by Health Minister Tshabalala-Msimang concerning the reported trouble with the integrity of the Guay study data, the TAC released a characteristically histrionic press statement containing this gem: “Not a single serious side-effect to mother or child has been reported from this study.”

 The TAC statement went on: “In a speech today in Alexandria, Johannesburg, the Minister of Health once more called into question the safety and efficacy of nevirapine. Yet again she has done so without any scientific basis. The inflammatory nature of her speech and the continued baseless attacks on life-saving medicines that have been proven safe and effective are highly irresponsible. This is a desperate attempt to create smokescreens and red herrings to divert public attention from her department's failure to accept the Pretoria High Court's decision on mother-to-child transmission prevention.” But the Medicines Control Council took a different view from that of the TAC’s drama queens. In a letter to Tshabalala-Msimang it said, "We are to review nevirapine in the light of these developments [the discovery by the NIH of irregularities in the records of the study, and the consequent withdrawal by Boehringer Ingelheim of its licensing application] and will inform you of the decision as soon as information is available."

 Guay herself seems to have had some quiet doubts about her study. Her modest intervention – safe she claims – would spare mothers and babies in the First World the horrible AZT toxicities that have been showing up in paper after paper in the medical journals, especially the permanent foetal ones discussed in Debating AZT, and the latest in Just say yes, Mr President. But Guay pulled back from recommending nevirapine instead: “…we cannot judge the efficacy of the nevirapine regimen used in our study compared with the full three-part zidovudine regimen that is currently the standard for prevention of transmission in more-developed countries. The data from our trial do not change recommendations in the USA, Europe for…use of the three-part zidovudine regimen for prevention of transmission.” Why not, if a pill or two of nevirapine was so stunningly effective? And perfectly safe too. Why not?

 Guay concluded the report of her drug trial with some self-promoting sales-spin: “Single-dose nevirapine given to the mother and the baby is likely to be one of the few deliverable and sustainable strategies for prevention of perinatal HIV-1 transmission in resource-poor settings. The challenge is to rapidly translate our findings into public-health policy to bring an effective HIV-1 intervention within the reach of millions of HIV-1 infected pregnant women.”

 We see it differently, Laura. We think you should be struck off for dangerous incompetence. And the identities of the anonymous peer-reviewers who approved your pathetic paper for publication in Lancet should be revealed, so that they can be publicly shamed for doing so. Perhaps marched down the journal’s nearest high street in dunce caps, along with those twenty-two “top names in South Africa’s scientific and medical community” (reported by the Cape Times on 22 March 2002), including Salim Abdool Karim, Hoosen Coovadia, and Carolyn Williamson, who co-signed a ‘”declaration” published in Lancet in the same week to the effect that “the fundamental scientific evidence in favour of nevirapine is incontrovertible” and that the government should accordingly “distribute the drug without delay.” Joined in the parade in the same hats we’d like to see nevirapine advocates like Zachie Achmat, Nathan Geffen, Mark Heywood (they like marching), Nicoli Nattrass, and the rest of the mediocrities who supported the TAC's application to the High Court to force the government to supply the drug, followed by Edwin Cameron, Costa Gazi, Glenda Gray, James MacIntire and Mathew Cherish, along with Howard Barrell, Belinda Beresford, John Perlman, Sally Burdett, Lynne Altenroxel and the rest of their fellow white journalists who’ve had so much to say, and who love getting righteously indignant in interviews and articles, knocking recalcitrant black health officials who don’t share their enthusiasm for giving cell-poisons to black babies. Not forgetting former radical Catholic priest and struggle hero, Father Cosmas Desmond – latterly a pharmaceutical industry pimp – who asked in the Mail and Guardian on 8 March 2002: “Can Manto Tshabalala-Msimang really be as abysmally stupid as her actions suggest?” in view of her reservations about nevirapine toxicity in the long term (shared by Guay), in the absence of any available data. “In the meantime, the rather short-term effects of her – and puppeteer-in-chief Thabo Mbeki's – policy of not providing the drug to all HIV-positive pregnant women is killing tens of thousands of babies every year.”

 The extraordinary thing about this popular notion is that there is nothing in the medical literature to support the idea that babies born to untreated mothers have a worse prospect of survival than those treated. (Nor is there any good evidence for the root belief among most whites that babies born to HIV-positive mothers are doomed to an early death.) To the contrary, a host of recent studies (canvassed in Debating AZT and Just say yes, Mr President) show that babies exposed to these chemicals in utero have far higher rates of death, disease, immunological disorders and ‘birth defects’ than the unexposed. An unpalatable reality unfortunately, but not a surprising one to folk who take the trouble to look at the pharmacology of such drugs for themselves. Instead of asking the doctor. Whose knowledge of such matters derives from what the visiting bimbo from the drug company told him, or what he read in the glossy advertisement on the inside cover of his professional journal.

 The real “challenge”, we think, is to keep American ‘AIDS experts’ like Laura Guay out of our country. And as far away from our people as possible. We note that, “During screening for our trial, many women refused to be counselled or tested or did not return for their test results.” Good on them! Spurning the doctors’ inherently ridiculous new dogmas, just as their ancestors drove out missionaries along with their equally horrible ideas. Our local ‘AIDS experts’ and activists would do well to eat some humble pie and return to basics, taking a tip from Socrates:“The only good is knowledge and the only evil is ignorance.” Bearing in mind Will Rogers’s observation: “The trouble with ignorant people is not what they don’t know; it’s that they know what ain’t.” And Treatment Action Campaign boss Zachie Achmat’s statement during an interview in Rapport on 10 February 2002:“With great honesty the TAC has always tried to understand medical science. And this is something with which all South Africans have always struggled. We are scientifically illiterate.” Our impression exactly.

 But not only of Zachie Achmat and his TAC. News of the FDA’s scowl at the trouble with the Guay study data, and of our own MCC’s in turn, sent the TAC into a flat spin. On 24 March 2002 it issued,  “FOR WIDEST DISTRIBUTION”, Five Critical Statements on the Safety and Efficacy of Nevirapine for Mother-to-Child Transmission Prevention by the WHO, NIAD, CDC, Elizabeth Glazer Foundation and Boehringer Ingelheim “that affirm the safety and efficacy of nevirapine for the prevention of mother-to-child transmission.” Not one of them had picked up any of Guay’s study’s glaringly obvious radical flaws.

 The right thing to do, “with great honesty”, would be for the TAC to file a notice of withdrawal of opposition to the government’s appeal against Judge Chris Botha’s nevirapine order, and for the organisation’s patron, Supreme Court of Appeal Judge Edwin Cameron, to take a tip from Alexander Pope – “A man should never be ashamed to admit that he has been in the wrong, which is but saying, in other words, that he is wiser today than he was yesterday” – and issue a simultaneous public apology along the following lines:

 ‘We meant well but we were wrong: we weren’t thinking, we got carried away, and we wasted everybody’s time. We uncritically accepted a bad study and all the propaganda spun around it, and in so doing, we endangered the lives and health of babies born to poor black mothers in public hospitals. I would like to convey my personal apologies to President Thabo Mbeki and Minister of Health Dr Tshabalala-Msimang for having been at the forefront of local and international condemnation of their well-justified concerns about nevirapine. And about AZT too. I realize that by suggesting that they have been both lacking in judgement and uncaring I have needlessly besmirched their personal reputations, and indeed I have damaged our whole country’s standing in the eyes of the international community. I feel most embarrassed about the role I’ve played in this fiasco, and particularly for having abused my status as a senior judge to promote this harmful chemical, which I used to believe was ‘a very good drug’. I’m really terribly sorry.’

For a comprehensive critique of Guay’s HIVNET 012 trial, presented as a Powerpoint slide show, see www.leederville.net/aids/nevppsn.ppt  It is crucial viewing for anybody with an opinion to state concerning the merits of nevirapine for preventing mother to child transmission of HIV. Part Four above should be considered as an introduction only to some of the radical flaws in the Guay study. Many more are detailed in the Powerpoint presentation – itself a summary, with an expanded focus on nevirapine, of Mother to child transmission of HIV and its prevention by AZT and nevirapine: A critical analysis of the evidence, published as a stand-alone monograph on 1 September 2001. It can be ordered from Dr Valendar Turner, Consultant Emergency Physician, Department of Emergency Medicine, Royal Perth Hospital, GPO Box S1400, Perth WA 6845, Western Australia; vturner@cyllene.uwa.edu.au; fax: 0961892243511. Co-authors Professor Sam Mhlongo, Head of the Department of Family Medicine at MEDUNSA, and the author of this article, Advocate Anthony Brink, also have copies. To contact the latter for perusal of the ‘mother to child’ monograph or to discuss any matters raised in this article: write to arbrink@iafrica.com or telephone 083 6260945 weekdays before 10 am or after 4 pm, or in the weekend any time.

 The trouble with nevirapine will appear in the appendices to the author’s new book in preparation, Just say yes, Mr President: Mbeki and AIDS, a sequel and companion to Debating AZT: Mbeki and the AIDS drug controversy, available from good bookshops in South Africa, or from the author at cost if not in stock. The text of the book is also posted on the Internet at www.debating-azt.co.za and on the www.virusmyth.net and www.aidsmyth.com websites.

Papadopulos-Eleopulos’s et al papers are archived at www.virusmyth.net/aids/perthgroup/ and  www.leederville.aids   Theirseminal AZT review, A Critical Analysis of the Pharmacology of AZT and its Use in AIDS,published in Current Medical Research and Opinion (1999) Volume 15, Supplement 1,  is archived by Librapharm online at:

www.librapharm.co.uk/cmro/vol_15/supplement/main.htm

 I thank: David Crowe in Calgary, Canada for procuring a wad of confidential internal government memoranda by means I didn’t care to ask, and for telefaxing them on to me, to enable me to write Part Two; Vivienne Vermaak in Johannesburg for information from her investigation notes for Part Three; and Eleni Papadopulos-Eleopulos and Valendar Turner at Royal Perth Hospital for vetting Part One and Part Four for scientific accuracy.

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