Anthony Brink: The trouble with nevirapine

PART THREE

A few men think, but all will have opinions.

George Berkley

 

When you consider how easily Boehringer Ingelheim rammed nevirapine past the First World Canadians, just think how soft the defences of developing countries are to the predations of such giants with all their financial and propaganda resources. Countries like ours. So predictably there was none of the initial Canadian trouble here, with annoying government pharmacologists saying, ‘Your drug is pure shit. We don’t want it here. Take it away. Go and push it somewhere else.’

On 22 April 2000 the Independent Online quoted Boehringer Ingelheim’s local corner merch Kevin McKenna telling us that nevirapine had just been approved: “It was very efficient. It was very quick,” he said. We never doubted it would be. Not a question raised. The South African Medicines Control Council being packed with useless dregs. As we saw with how they blew the AZT enquiry ordered by President Mbeki. Being both blind and thick. Disregarding the key literature. All the latest stuff on foetal toxicity especially. Not to mention Papadopulos-Eleopulos’s et al exhaustive review of the molecular pharmacology of AZT, published on 1 September 1999 in Current Medical Research and Opinion a month before Mbeki’s safety enquiry directive (see endnote), which concluded that not only is AZT very poisonous, but that it cannot, and in fact, by all conventional measures, does not have the pharmacological activity claimed for it by GlaxoSmithKline. However, the paper dealt with tricky stuff like whether AZT is triphosphorylated intracellularly to its inhibition concentration in vivo, and frankly, to expect the MCC’s members to exercise their minds around such abstruse technicalities would be asking too much. Because let’s face it: We’re just a bunch of rubber stamps for the drug industry. And if the FDA hasn’t bothered, why should we? Just because the President asked us to. Tipped off by some prick lawyer.

Soon after licensing in South Africa, nevirapine hit a bump in the road. Approval of the drug by the MCC presented a grand opportunity to Triangle Pharmaceuticals, an American pharmaceutical corporation founded by former GlaxoSmithKline Director of Research and AZT promotor, David Barry. Eager to cut a slice of the AIDS-drugs action, it needed some guinea pigs on which to try out its experimental drug Coviracil (Emtricibatine, alias FTC), ahead of a licence application to the FDA. Penurious South African blacks being ideal. Being unimportant and dispensable. Not such a fuss if they get hurt or killed. Nice and cheap too. Compared to what such test subjects cost back home in the US. Fifty rand to each for every hospital visit – about five dollars. Triangle engaged Quintiles Transnational, described at the time by a Yank newspaper, the Raleigh News and Observer, as “the world’s largest pharmaceutical services company”, to conduct a clinical trial with Coviracil in combination with nevirapine and two other drugs, lamivudine (3TC, an AZT lookalike) and stavudine (d4T, another one). Dr Mariette Botes, an ‘AIDS expert’ at the University of Pretoria and head of the AIDS clinic at Kalafong Hospital in Pretoria, was hired to run the trial there, one of sixteen sites at which the study was conducted. Its subjects were drawn from Atteridgeville, a largely impoverished dormitory complex outside Pretoria for Sotho speakers. The study was called FTC 302. It was an abattoir.

Social workers at Kalafong Hospital, who noticed that many people on the drug trial were suffering severe ill effects, tipped off Pan African Congress MP Patricia de Lille. The right politician to get involved, having more go than just about all of them put together. On 6 April 2000 De Lille was reported telling the Natal Witness that she had uncovered “a nest of abuse and exploitation. … One patient developed a rash all over his body and still has marks on the face. He told Dr Botes that this had happened since using the drugs, but the doctor said it was not the drugs causing the rash, but the HI virus.” Severe skin damage being a brand-new AIDS indicator disease, according to Dr Botes. She’d never heard of Toxic Epidermal Necrolysis apparently. For which nevirapine is famous.

Our Minister of Health Dr Manto Tshabalala-Msimang also heard the news, was damned unhappy about it, and told the Medicines Control Council so. The president of the MCC at the time, Helen Rees, responded nonchalantly that “many AIDS medications could cause liver and other problems. But the combination therapy can make a huge difference to people’s lives.” The kind of thinking we expect from a doctor. For whom drug company propaganda passes as medical knowledge – she even speaks as the advertisements do. At Tshababala-Msimang’s insistence, the MCC nonetheless called off the trial. Or tried to because Quintiles Transnational just pushed right on with it. Since we just do what we like in developing countries. The media reported “an uproar in medical circles” over the termination of the trials. But of course. To be expected, as I said.

Several people died on the drugs. Five women at Kalafong hospital according to Tshabalala-Msimang, the Medicines Control Council and Professor Geoffrey Falkson of the University of Pretoria’s Ethics Committee. Only two, Kalafong Hospital sources were later quoted in the press. Actually only one, a man, claimed hospital superintendant Hanli Dafel. In fact none, said Triangle’s Dr Ian Sanne to investigative journalist Vivienne Vermaak – none at Kalafong Hospital, but seven people at other centres.

An official investigation found that two of the dead died of liver failure, one of pancreas failure (both conditions caused by acid lacidosis, a standard side effect of antiretrovirals), and two of neurological damage (likewise). Other trial subjects suffered deafness, impaired speech, anal bleeding, sores that wouldn’t heal, abdominal pains, weight loss, fevers, pneumonia, insomnia, vomiting, and depression. The investigation concluded that nevirapine had probably caused the liver damage that had killed two of the women. Not surprisingly, since of all so-called antiretroviral drugs on the market, nevirapine is top of the pops when it comes to wrecking livers. Even worse than nucleoside analogue drugs in the AZT class, and they’re not shy. Boehringer Ingelheim’s McKenna ducked and dived at the flashing blue light: “My information is that the actual link to nevirapine is inconclusive…” His bosses in Germany backed him up with a formal press release on 10 April 2000: “…in a clinical trial in which patients are taking multiple drugs, it is not possible to determine with certainty, which drug, if any, may have caused the…deaths. [That’s the joy of mixing dangerous toxins made by different companies: A backdoor out when things go wrong.] … According to news reports, there was a higher than expected incidence of liver toxicity in the study. In fact, the incidence of liver toxicity seen in the study is in line with what is commonly seen in similar studies of triple combination antiretroviral therapies in HIV-infected individuals. [A local doctor commenting anonymously in the Mail and Guardian remarked similarly; he didn’t see why there should be any bother about this. We expect a few to peg off on these AIDS-drug trials, he said; it’s normal.] As with all potent antiretroviral treatments, there are known side effects of nevirapine as described in the labelling product.” In all, an exercise in wordplay more fascinating even than Bill Clinton’s about his side-ass jinks in the Oval Office.

Apropos the liver damage observed, since the liver toxicity of nevirapine is the most acute (rapid) relative to the other drugs on trial, it was a fair bet to blame it – on a preponderance of probabilities, as we lawyers say. “Which drug, if any” suggests doubt that the deaths were the result of drug intoxication. But the causes were diagnosed. And they weren’t AIDS indicator infections or malignancies. AIDS journalists Lynne Altenroxel and Anso Thom reported in the Independent Online on 6 April 2000 that, “Experts have questioned whether nevirapine could have caused the deaths, as the drug had already undergone clinical trials of its own before being registered for use in 1998.” To these airheads, registration meant it was safe apparently. Nevirapine being the new drug that gee-whizz journalists of their calibre have switched to advocating, since AZT for babies seems to have got rather messy. All those nasty foetal damage reports in the medical journals. And when ‘AIDS experts’ talk, don’t we just swoon? But we recall Vicky Hogan, Head of the Monitoring and Evaluation Unit for the Canadian Therapeutic Products Programme, stating her agency’s concerns about the fact that in Boeringer Ingelheim’s jubilant communique to doctors after a conditional licence had been granted, “information about the conditions was not highlighted and the prescribing physicians [who] received that information were NOT informed about the outstanding concerns about efficacy associated with this drug. …physicians are under the impression that this drug…is considered…to be both safe and effective.” Boehringer Ingelheim seemed to be conceding that, look, a cocktail of arsenic, cyanide and strychnine is more poisonous than single shots. But we know this. We say so on the label. So what are you complaining about? As for “potent antiretroviral treatments”, Debating AZT will have brought home that their only potency lies in their toxicity. You can’t make a vicious runt with a knife ‘the heavyweight champion of the world’ just by calling him Muhummad Ali. Especially nevirapine, brave only in gangs. But still useless.

The FDA grumbled about the look of things, sending Triangle Pharmaceutical shares into sharp descent in the US, with more than a third of their value shaved. The company’s executive vice president Carolyn Underwood hastened to exculpate her Coviracil, blathering, “The unfortunate part is, it is really hard to sort out how much of this is a political issue. It is escalating and we are caught in the middle of it.” Like Somalia? You would have thought that the deaths were more than a political issue. And that the poisoned were “in the middle of it.” About whom she expressed not a peep of condolence. Instead, after the plug was pulled on the trial, she said, “There are no other drugs in South Africa for them to receive. We are most concerned about the possibility that these patients will be left without therapy.” Right after the news that it was killing and injuring them. Notwithstanding the horrible toxicities that she observed among these adult clinical trial subjects, our favourite MP, Patricia De Lille, nonetheless deplored government’s reticence in exposing babies to the drugs that caused them: “It is unfortunate that [Tshabalala-Msimang] has used the tragic event of deaths during the trials to make a political point that justifies her doing nothing to stop mother-to-child transmission," she said.

Apart from suffering terrible fatigue, abdominal cramps and headache on Dr Botes’s medicines, one woman, Gladys Mamosodi, went blind for two weeks. The doctor told her it was her AIDS coming on. But strangely, she partially recovered her sight after quitting the drugs. Which makes sense since nevirapine is particularly good, Boehringer Ingelheim warns, at rupturing mucosal tissues like those found on the surface of your eyes. The other symptoms won’t be anything new to you, having read Debating AZT, and knowing what you do now about ‘antiretrovirals’. Afraid about what was happening to her, Mamosodi approached Botes, asking for her medical case file. It’s gone missing, she was told. Unconvinced by this excuse, she returned to demand its production again, this time taking her mother along for reinforcement. You can’t have it, Botes responded; why, you tore it up yourself. Hearing this extraordinary news broke Mamosodi’s heart. She passed on from this world to the next soon after. But not before Vermaak had got her story, masquerading as a nun in a borrowed habit to get through the hospital door. As if to administer the last rites, but really to ask questions and peer into closely guarded medical files, when the white madam wasn’t looking. Mamosodi shared her tale kneeling on the floor, emaciated, incontinent in nappies, her head in Vermaak’s lap. Groaning in agony, on her way out. Her subsequent demise chalked up to TB on her death certificate. Since she’d been put in a TB ward. Everyone knows that these HIV-positive blacks get TB. Except that she never had TB. Said four TB tests. When Vermaak put it to Botes that people on the trial like any other patients had a basic right to their own medical information, Botes answered brightly, “I’m not aware of that. I’m not a legal expert.”

Vermaak took the story to the MNet television programme Carte Blanche, a platform for spilling beans every Sunday night, prime time. The accused rang their lawyers. There was a set-to. How dare MNet tell such lies. Do you want us to sue you? MNet reacted by repudiating Vermaak’s investigation by way of a televised disclaimer, denouncing the exposé and apologising for all the hard feelings it caused. Vermaak, MNet suggested, was both incompetent and dishonest: Mamosodi had never been on the antiretroviral drug trial. Said Dr Botes. This was the principal falsehood for which Vermaak was publicly flayed. Yet Mamosodi insisted to Vermaak that she’d been on antiretroviral drugs, nevirapine included. And that it was when she was given the AIDS drugs that she started feeling really sick. No, no, Botes told Vermaak. Mamosodi had actually been on an antifungal drug trial. She’d been given an “innocent” drug that “couldn’t cause the side effects [that she’d] complained of.” Except that her signed Informed Consent form, finally produced, warned of some pretty dark ones for the “innocent” drug too, like hearing loss and kidney damage.

But it turns out that Vermaak was right about those antiretrovirals after all. Although Mamosodi booked in to volunteer her body to medicine, for the pittance it would earn her family, with no more than a sore throat, Botes, being a terribly kind person, admitted at the enquiry subsequently conducted by her university that she’d put her on antiretrovirals. Being a humanitarian, apparently. Didn’t write a prescription though. Didn’t see the need. Not even the legal one. And of course there was nothing in her file about such drugs. All very odd. But nothing odder than Botes’s reluctance for that medical file to see the light. First withheld on the basis of a lie, and then another, and then finally produced with important contents missing – nothing about Mamosodi being given an experimental combination of antiretroviral drugs, and of course nothing about her blindness that developed after she commenced taking them. Or the uncontrollable diarrhoea and myopathy that set in and continued even after she stopped. Until she died.

Vermaak also investigated the “rash” case that De Lille had encountered – a classic case of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis. A well documented ill effect of swallowing nevirapine. Big words for poisoning off skin cells in thick swathes. We’ll call the unlucky subject “Tsietsi Madimabi” since he’d prefer his real name not be told. He told Vermaak: “A rash broke out all over my body. I wanted to throw up all the time and had a fever.” Within days, Madimabi’s “rash” had developed into suppurating open sores, head to toe. He couldn’t walk. As the toxic reaction began to intensify, he desperately tried reaching Dr Botes, but her cellphone number just rang and rang. He’d forgotten that his copy of the Informed Consent form contained an emergency hotline number. But it wouldn’t have helped to phone it either. It was wired to a telefax machine in a small office at the hospital. So Vermaak found out when she tried it. Hardly a fitting medium for a discussion of your life-threatening toxic drug reaction. And not much use if you live in a shack and don’t own a fax machine. Who in Atteridgeville does? But it wouldn’t have been any use having such a hi-tech gizmo anyway. Because the fax machine was unmanned most of the time.  On a lucky day it would be staffed by volunteers. Off the street, knowing nothing about the management of drug toxicity emergencies. But you have to understand; we had to contain our costs. This is how capitalism works. And anyway they were only blacks.

Fearing that it was the treatment that had made him sick, Madimabi staggered into casualty at Kalafong hospital where he showed his pills to the quacks. They had the rare good sense to instruct him to quit the drugs immediately and to book him in, noting on his medical file: “Grade 4 skin rash due to nevirapine” – Stevens-Johnson syndrome in other words. Botes paid Madimabi a visit a few days later. Except her diagnosis was different: HIV was to blame, she said, not the tablets. Being an ‘AIDS expert’. But then, on 16 November 2000, she dumped him from the trial. A funny thing to do, considering: Aren’t the drugs supposed to rescue you from the march of AIDS?

Helped by social workers and de Lille, Madimabi and other trial subjects also seriously injured by the drugs filed handwritten complaints with Pretoria University’s Ethics Committee. We live in a constitutional democracy now. We’re not apartheid untermenschen any more. We have rights. We’ve been burned. We expect something should be done.

They were expecting too much. The gist of their complaints was that they didn’t understand the Informed Consent forms and that the drugs caused them to suffer unexpected serious adverse effects. But they got ripped up. You signed; haven’t you heard of the caveat subscriptor rule? The hospital filed an all-clear report with the MCC. It didn’t go down well. Particularly since only four of the eight complaints filed had been investigated. Do it properly, the MCC ordered. Eventually, after a year of boiling dissatisfaction and grassroots politicking in the township, a formal hearing was held into the deaths and injuries that occurred on the trial.

Madimabi complained at the enquiry that he never understood that taking the pills might have caused him to suffer such terrible injury. His grasp of English as a second language wasn’t great, but it wouldn’t have helped to have spoken the Queen’s best in any event. The Informed Consent form for the clinical trial, read out to him before he signed it, went: “Side effects that have been seen with nevirapine (Viramune) are rash, fever, nausea, headache, and abnormal liver function tests. These symptoms will be closely monitored.” They weren’t, as we know. But the mild ill effects so described are a far cry, you’ll agree, from the fate that befell Madimabi – consistent with the toxicity alert appearing on the nevirapine package insert for First World consumers, reflecting what had “been seen” more frankly: “Warning: Severe and life-threatening skin reaction (Stevens-Johnson syndrome, toxic epidermal necrolysis), including fatal cases, have occurred in patients treated with Viramune.”

There was something else about that Informed Consent form that bothered Madimabi. All recruits to the drug trial were in good health with CD4 cell counts within what ‘AIDS experts’ consider normal range, and all had low or undetectable ‘viral loads’. But the ‘AIDS experts’ had told Madimabi that he was infected by a deadly germ, and had ‘HIV-disease’. And that it would be just a matter of time before his health crashed, thanks to some or other ‘opportunistic infection’. Which surprised him since he felt as fit as a fiddle. As such news does to most people who light up these tests in good health. Told he was actually diseased – according to the tests – he was invited to take the trial medicines. He understood that the drugs would keep him well – quite reasonably, having regard to what the Informed Consent form stated: "It is expected that the suggested study treatment will lead to reduced severity and frequency of opportunistic infections (the common diseases that go along with HIV- infection)..." Who wouldn’t jump at the chance offered by the kind doctors? Gee, they even pay us to take the medicines. Unfortunately for Madimadi that they didn’t share with him the contrary information appearing in the package insert for the drug that nearly killed him:"Information for patients: Patients should be informed that Viramune is not a cure for HIV infection and that they may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections.  Treatment with Viramune has not been shown to reduce the incidence or frequency of such illnesses...." Because had Madimadi known that, he wouldn’t have been so keen to join the experiment. On him.

The enquiry delivered a Biko verdict: Everything was found hunky-dory.  Just like the old days. The mostly white AIDS activists, journalists and human rights campaigners in South Africa who clamour for AIDS drugs for blacks at every chance were strangely mute for a change. We didn’t see a single one of them with their tee shirts and placards and banners at the funerals. But most noteworthy was MRC President William Makgoba’s silence in the affair. The guy who’d presented a paper at the 13^th International AIDS Conference in Durban in July 2000, called Ethics of AIDS Research in a Developing Country – Balancing Power in Disguise. Making points like: “…temptations may remain to subordinate the welfare of the volunteers…and treat human beings as a means to an end. Research may also be motivated by financial gains where expediency obscures ethics to the detriment of volunteers and the integrity of science. … Informed Consent has become one of the major ethical transgressions of our time – particularly in developing countries. Informed Consent has four essential components: disclosure of all relevant information about the research; comprehension by the prospective participant of this information to make an informed decision… However codes and requirements alone do not guarantee protection… In South Africa…most of our subjects speak…a different language from the languages of the researchers and practitioners; secondly most subjects in our countries are poorly informed with substandard education. … The weak and the powerless in our society require a different form of approach…in order to fully understand the magnitude and implications of signing an informed consent form. …the tendency is for power to prevail over protection.”

Finely spoken, William. We all agree. So what did you have to say to your Masters in the drug industry when these people were dying poisoned, others badly injured? Apart from Yes Sir; No Sir; Three bags full, Sir. Except of course in this country you say Baa