The Virodene affair (I)
The involvement by the ANC of Mbeki in the promotion, protection, and development of Virodene - an ‘African solution' for the African HIV/AIDS epidemic - is one of the most important, but least understood episodes in recent South African history.
The story sprung to prominence in early 1997 after the South African cabinet announced that a possible cure for AIDS had been discovered. It subsequently dropped out of the public consciousness after the Medicines Control Council blocked trials of the drug in South Africa.
A great deal of new information has trickled out over the past few years about how the Virodene developers then went overseas to have the drug tested - first in the United Kingdom and then Tanzania - and who funded them.
In broad terms the ANC's involvement in the financing of the Tanzanian trials has been on the public record since mid-2002. However, over the weekend Fiona Forde reported in the Saturday Star that much of the money for these trials had been directly "sourced from the Presidency" between 2000 and 2001. The article added that "on numerous occasions, money was collected from ‘the Presidency, in the Union Buildings' in briefcases and ‘always in US dollars, and always $100 bills'."
Yesterday, the Treatment Action Campaign called for "a judicial investigation into the activities of the presidency around Virodene." There is as much chance of President Thabo Mbeki allowing this, as there is of him instigating an unfettered investigation into the arms deal.
Even now, with so much material in the public domain, the full significance of the whole Virodene affair seems to escape informed opinion. The main issue is not - as many seem to assume - that procedural short-cuts may have been taken in the testing of the drug in Tanzania. The key question is whether the emotional and financial investment in Virodene by top ANC leaders, contaminated the South African government's response to the HIV/AIDS epidemic.
Between October 1998 and March 2002 - the exact period in which Virodene was being tested - the ANC blocked the provision of anti-retrovirals through the public health care system in South Africa. This action resulted in tens of thousands of newborns unnecessarily contracting HIV from their mothers.
The Virodene affair then goes to the heart of whether Mbeki is fit to serve a third term in office; and why he has little choice but to try and hold onto power.
To understand each part of the story it is necessary to have some sense of the whole. The following series of articles will therefore try and trace the development of Virodene from to its conception in 1995 to 2002 when the definitive scientific verdict was issued on its efficacy.
In reading the following account one should bear in mind that throughout this period the promoters of Virodene remained true believers. The originators of the drug were able to draw into their enterprise the ANC leadership, the National Intelligence Agency (which sought to protect this "national asset"), and also various prominent Western scientists.
On October 8 1995 the Sunday Times reported on a discovery by South African scientists which it said, "arguably matches, or even surpasses, the first heart transplant performed by Professor Chris Barnard in 1967". Olga Visser, a cardio-vascular perfusionist at Pretoria's H F Verwoerd Hospital, working under the head of cardio-thoracic surgery, Professor Dirk du Plessis, had supposedly discovered a formula in which donated hearts could be saturated, before being frozen.
"While much testing lies ahead" the article stated, "indications are that the formula will allow for the freezing of a donor heart for years, after which it will be unfrozen, made to beat and save the life of a needy recipient." The article quoted Mrs Visser as stating: "Scientists have for years tried this and got nowhere and here I started and there were no huge setbacks." She added, "It is unbelievable, the concept is perfect. But we still have many months of research and hard work ahead of us before we can perfect it to such an extent that it can be used in human transplants."
In the same month Olga Visser also discovered what she thought were the anti-viral properties of her chemical solution. A later company document described her route to discovery:
"Whilst researching new methods for viable organ preservation...Olga Visser developed a novel cryo protectant solution containing N, N Dimethylformamide (DMF)...with which rat hearts could be treated, cooled to minus 196°C, thawed and returned to full function... During this research and following an extensive [DMF] literature search for cryo patent purposes, she discovered the clinical use of polar compounds, including DMF as possible antiviral agents."
In December that year Visser and her husband, Jacques Siegfried "Zigi" Visser, established a company Cryopreservation Technologies (CPT) to patent and develop these compounds. Nothing would directly come of the discovery of the cryo-protectant qualities of this solution, as other scientists were not able to successfully recreate her experiment.
The news of this discovery did lead to an introduction to the Minister of Health, Nkosazana Zuma. The Visser's brought the possible anti-viral properties of these polar compounds to her attention in early 1996, and in July of that year, they met again to present a proposal to conduct clinical trials on HIV/AIDS patients.
By this stage the research team was composed of Professor du Plessis; Dr. Carl Landauer, also of the University's medical faculty; and, Olga and Zigi Visser.
In their agenda for the meeting they reported that "unofficial clinical trials on informed, consenting patients" had already shown "extremely encouraging results". They suggested that after extensive background research the scene was now set for "official intensive in vivo testing" of the substances.
"Conclusive proof of effectiveness of treatment" could be available with three to six weeks of the commencement of such clinical trials. The document added that the minister's involvement and support was "vital for SA to win the race towards the cure for AIDS" and thereby ensure that "not only the scientific prestige, but also the original idea and patent remain South African".
In mid-January 1997 the researchers requested an urgent meeting with Minister Zuma, to bring her up to date with the results of these trials, to introduce her to some of their patients, and to inform her of their future plans. "The results far exceed what we anticipated" they wrote. Their treatment, they said, was "far superior and effective than any known treatment to date worldwide; It is effective at any stage of infection. (Terminal cases are and have been reversed); Patients have regained heath and picked up as much as 10 kg within one month; Results are fast (within one to two weeks) of starting treatment."
Nkosazana Zuma arranged for Deputy President Thabo Mbeki to present the researchers to cabinet. In their presentation, on January 22 1997, the Virodene researchers claimed that they had discovered a possible cure for HIV/AIDS, which they had named ‘Virodene P058'. They made various extravagant claims for the drug saying that: it had "destroyed the virus in a test tube"; when given to humans "appeared to reverse full blown AIDS to HIV positive"; fought "HIV in areas other drugs cannot reach it, such as in the lymph glands and the brain"; had "minimal side effects"; and their findings "could lead to a cure by the turn of the century".
Olga Visser claimed that her solution "destroyed" the virus. "This had never been done before with a chemical which could also be safely administered to people. Medicines developed previously only succeeded in temporarily reducing the virus count."
Two HIV/AIDS patients testified of their remarkable recovery under the treatment. As Mbeki commented in a press conference afterwards, "The AIDS victims described what had happened to them as a result of the treatment. They were in the cabinet room, walking about, perfectly all right. It was a worthy thing to see because the general assumption is that if you get to a particular point with AIDS it really is a matter of time before you die."
At the end of the presentation, the cabinet "stood up in spontaneous applause".
Mbeki said that the government would look favourably on the researchers request for R3.7 million to continue their studies. "It was like a church confessional", Jakes Gerwel, Director General of the Presidency would later comment "The patients said they were dying, they got this treatment, and then they were saved! The thing I will always remember is the pride in South African scientists." Cabinet resolved that government should assist the Virodene researchers in pursuing their research.
The financial attractions for the ANC government of this cure for HIV/AIDS were obvious. The researchers said that their drug would cost between R80 and R160 a month, compared to combination therapy using anti-retroviral drugs which (at the time) cost up to R4000 a month. And as a newspaper report noted, at the time, if the researchers were correct South Africa may have chanced on a cure "that will be worth billions to the country".
Equally importantly Virodene promised to psychologically validate the new ANC government. The day after Virodene was presented to cabinet Olga Visser described it as a "medicine developed in Africa for Africa". Salim Karim, director of HIV prevention and vaccine research for the Medical Research Council, told the Washington Post in 2000 that, "The cabinet...believed the discovery would validate South Africa's black majority in much the same way that Christiaan Barnard's first successful heart transplant in 1968 affirmed apartheid South Africa to the world."
Quarraisha Karim, the first director of South Africa's national AIDS program, was quoted in the same article as saying:
"There was this sense that this drug would be the thing that offset the perception . . . of Africans as substandard and less than capable. All eyes were upon [the ANC] and the expectations were very high and they were really trying to find their feet but they didn't want to exercise caution. This was driven by this need to show the world: 'Yes, Africans can do this. We can do this. Virodene became our redemption.' "
In April 1997 Mbeki proclaimed the dawn of the African renaissance: "Those who have eyes to see, let them see. The African Renaissance is upon us. As we peer through the looking glass darkly, this may not be obvious. But it is upon us."
The first Professor Peter Folb, the chairman of the Medicines Control Council (MCC), had heard of Virodene was when a reporter called him and told him about the presentation to cabinet and asked what he thought about this drug. He told the reporter that he knew nothing but would find out, and phoned the MCC secretariat and asked if they knew anything. They said that the research workers had come in one day in 1996 and said they were intending to do a study and they just wanted to let the MCC know. Someone had made a record and a piece of paper had been deposited stating that this was their intention.
In a 2004 interview Folb stated that this was not the normal way they needed to go about getting approval. "They did not get approval. They [later told the MCC that they] got approval from the Minister which was unheard of and illegal."
The MCC immediately called the researchers to a meeting in Pretoria on January 24 1997 at which it was decided that the provision of Virodene would be stopped and the trials suspended until the MCC could carry out a review. The researchers agreed to comply.
After the meeting Folb stated that "the drug will be discontinued and the patients will come off it, until we have reviewed the situation. We need to look at their results and safety, and have a proper review of the whole story". The inquiry would report no later than February 5. Callie Landauer said the suspension of the trial was just a technicality, "They're just going to make sure that all the technical measures that were taken to treat the patients are correct".
Despite the suspension of testing, and the first rumours that drug was in fact DMF - a toxic industrial solvent - the government remained enthusiastic about the potential of Virodene. One anonymous "cabinet insider" told the Mail & Guardian that it would be "better for government to ‘own' the drug so it could be used cheaply and quickly in state hospitals, rather than to allow pharmaceutical companies to develop it overseas for sale at a high price".
At a press conference on her return from a trip to Cuba on February 4, Minister Zuma stated that the researchers should receive government funding "after certain technicalities are dealt with". She explained that "the reason I took them to the cabinet ... was because their research has not only produced exciting results, but also had implications for manufacturing at an affordable price".
Asked whether she gave permission to the researchers to test Virodene on patients - as Zigi Visser had told the press - she said she had encouraged them to continue with their work. "If that qualifies as permission, then I gave it to them." She added that she did not have a duty to keep an eye on scientific procedures, "the researchers know the procedures and it is their duty to adhere to them".
The following day the MCC announced the results of their review and banned any further provision of the drug to patients. In a statement the MCC revealed that the "formula contains a highly toxic industrial solvent which may cause irreversible fatal liver damage".
No further testing of the drug on humans would be allowed until its safety and efficacy was proven. "The serious and unresolved safety issues in the use of Virodene must be sorted out before any further work can be considered and before patients who previously received Virodene may be further exposed to the drug."
A committee comprising officials from the University of Pretoria and the Gauteng health department investigated the conduct of the research and reported at the end of February. According to their report the researchers had proceeded with clinical trials without the requisite permission being obtained from either the Ethics or Research Protocol Committee (ERPC) of the University of Pretoria or the MCC.
The committee found that at the start of the trial the researchers had no specific evidence that would indicate that DMF was either a protease inhibitor or that it would inhibit HIV in a clinical trial. Pre-clinical experiments had been carried out at the end of 1995 at the National Institute of Virology. They had not yielded any results before they were terminated; because the researchers had found articles purportedly showing the anti-viral characteristics of DMF. No animal trials were conducted, and the researchers proceeded straight from there to testing the substance on human subjects.
According to the report the researchers quoted "at least eight literature references" to substantiate their claim that "DMF has proven efficacy as an anti-viral agent". Only one of these articles actually referred to DMF. This particular article found evidence that DMF, "at a concentration of about 9 grams / litre" - a dosage 100 times greater than that proposed in the clinical trial - would partially "inhibit the replication of" but would not kill, the human herpes virus (which is unrelated to HIV).
The report noted that the researchers' confusion about the "antiviral effect of DMF" was based on the mistaken assumption that the substance belongs to a group of HIV protease inhibitors. They appeared to have reached this conclusion on the basis that DMF was similar to "another polar component, dimethylsulfoxide (DMSO), which they claim is a ‘known' protease inhibitor."
In fact DMSO was commonly used as a solvent for protease inhibitors when they were screened for HIV protease activity. DMSO did not inhibit HIV protease activity even at relatively high concentrations (of 10 or 20 gram / litre). It was only at 80 gram/litre that such activity would be inhibited by about 50 percent.
"On the basis of this evidence" the report noted, "the researchers then come to the surprising conclusion that DMF also has anti-protease activity, and they subsequently used it in the clinical trial at a concentration of 0.1 gram / litre, which is still only 1% of the concentration at which DMSO is known NOT to inhibit the HIV protease."
The report noted that DMF was "an industrial solvent" which had been shown to cause liver damage. The toxicological reports cited by the researchers had described the toxicity of DMF "as low when given as a single oral dose". There were several unresolved issues of toxicity when it came to the clinical trial. These included the effect of DMF during long term exposure through a skin patch; and the possible difference in toxicological response in patients with weakened immune systems. The report noted that according to the "best guidelines for the limit of industrial DMF exposure" the occupational exposure limit should not exceed 15mg/m3 over an 8hr period or a total daily exposure of 150mg/day.
The report stated that the amount of DMF exposure considered safe by the research team, had been miscalculated at 100 mg /litre. Moreover, the researchers had not given patients a single dose, but had administered DMF through a skin patch containing approximately 14g of the substance, over a period of eight hours. Even though the DMF concentration in the blood "may never have exceeded 100 mg/ litre at any particular time" the report pointed out "it is obvious that the total accumulated exposure to DMF over an 8 hr period would have exceeded the prescribed 150mg/day occupational exposure safety limit, by far."
The report expressed concern at the lack of toxicological expertise in the research team. The researchers had made basic errors such as miscalculating the starting point for potential liver toxicity at a blood concentration of 500mg/litre when the actual exposure rate was 50mg/m3; and, they had referred to the units of environmental exposure as being the equivalent of mg/litre instead of mg/m3 (mg/1000 litre).
The report stated: "It is very difficult to imagine that experiments, involving such a high level of exposure to a toxic substance under such untested conditions, could ever be considered without the approval from an expert body". The report did note that there "was no obvious evidence of liver damage" in the patients who had enrolled in the trial.
The report was highly critical about the conduct of the Virodene pilot study itself. A valid clinical trial requires the existence of a proper, statistically relevant control group. In a double blind study neither the patients nor those conducting the trial know which patients are receiving the drug being tested, and which are receiving the placebo.
There were numerous problems with the conduct of the Virodene trial. Eleven patients had apparently enrolled, although four had subsequently dropped out. The report questioned the wisdom of Olga Visser providing "emotional support" to the patients "in view of the fact that she is the main stakeholder of the Virodene PO58 patent". There was no control group. Only the first participant had been a referral. Once the dramatic "success" of this first experiment "spread by word of mouth... other HIV-infected people became aware of this and some ‘begged' to receive treatment".
The report noted dryly, "The placebo effect can be expected to have played an important role in a study in which patients were selected in such a non-random manner." It did not however "attempt to analyze the outcome of the trial nor the significance that should or should not be attached to the results that were obtained. Experiments that have been carried out in a secret, non-transparent manner without the benefit of proper controls or peer review do not lend themselves to such analysis."
In a subsequent interview with the South African Medical Journal Professor du Plessis, the most senior member of the team, acknowledged that the Virodene researchers knew "sweet nothing" about medicine research. In July the University of Pretoria disciplinary committee found Du Plessis and Landauer guilty of misconduct for testing the drug on people without following correct procedures. Olga Visser was not subject to the committee as she was not a member of the University.
This damning report should probably have been the end of the whole affair. And it probably would have been, were it not for the fact that the Virodene researchers continued to enjoy high level political support.
To read the second installment click here ...