PRESIDENTIAL AIDS ADVISORY PANEL REPORT
THE TREATMENT OF AIDS AND THE USE OF ANTI-RETROVIRAL DRUGS
Issues pertaining to the use of anti-retroviral drugs dominated the debate on the treatment of AIDS. On the one hand, panellists who disputed the causal linkage between HIV and AIDS, the use of an anti-retroviral drug to treat a disease that was not caused by a retrovirus was deemed morally indefensible. On the other hand there were panellists who subscribe to the causal linkage between HIV and AIDS and who argued that sufficient and incontrovertible evidence existed in the scientific literature and from clinical experience which affirmed the value of anti-retroviral drugs in the treatment of HIV/AIDS.
The toxicity of anti-retroviral drugs was not in dispute from any of the panellists. It nevertheless generated two different sets of attitudes based on whether these drugs should be used or not. One group felt strongly that anti-retroviral drugs were toxic to the point of producing disease conditions in otherwise healthy people. Consequently the drugs should under no circumstances be used in the treatment of AIDS. The other group felt there was incontrovertible evidence from well-conducted randomised clinical trials that anti-retroviral drugs were of substantial clinical value when used in correct dosages and under carefully monitored conditions. The latter group presented varying opinions on which drugs to use, and how and when to use them.
5.2 Evidence in support of the use of anti-retroviral drugs
Proponents for the use of anti-retroviral drugs produced evidence that these drugs improve the quality of life of HIV-infected people. There was reference to clinical experience proving this effect.
Some of the panellists quoted examples from clinics in the USA, where previously people died of AIDS-related infections, whereas now no deaths are being recorded and people are living longer since the introduction of anti-retroviral medications.
There was evidence from a number of areas, for example, Prof Montagnier quoted a decline in death rates from 72 patient years lost per 100 patient to 2.92 patient years since 1990 following the use of three anti-retroviral drugs. His slide, however, also showed that patients not receiving any anti-retrovirals had also improved with a current mortality of 50 per 100 patient years, presumably due to the use of supportive therapies such as multivitamins, nutritional supplements and psychological support. It was also notable that improvements in mortality are never quoted as average increase in life expectancy per patient, but rather as cumulative ‘patient years saved’; and there are of course no control groups to measure such presumed increases in life expectancy against. Prof Montagnier also referred to hospitals in France that had closed down due to lack of patients. However, he conceded that these drugs are toxic and cannot be used without proper monitoring. Dr Sonnabend confirmed the efficacy of these drugs in his own experience of treating patients at his clinic.
Dr Vella, who explained that new techniques in drug development have led to the development of less toxic drugs, provided further evidence of efficacy. He also argued that the decline in AIDS-related deaths was certainly due to the drugs, because there was no decline in new infections.
Dr Lane highlighted the fact that there cannot be a blanket approach to the administration of these drugs, and that it was necessary to categorise the treatment groups according to the stage that the disease had reached. What may work for one group may, in fact, be toxic to another. With patients in the very early stages of the disease, who show no evidence of significant immunological compromise, giving them anti-retroviral drugs may, in fact, be the wrong thing to do.
Claims were made that there are no hard data to confirm that there are gains in terms of survival with the use of anti-retroviral drug therapy, because many other factors impact on outcome. Such factors include compliance, whether the choice of anti-retroviral drug therapy was correct in the first place, issues around the development of resistance, as well as prior use of anti-retroviral drugs.
In developing countries, where issues of costs are significant, the choice of drugs may be dictated by what is affordable. Strategies in this regard may include negotiating for price reductions, parallel importation, local manufacturing and the use of generics.
5.3 Evidence against the use of anti-retroviral drugs
Panellists opposed to the use of anti-retroviral drugs asserted that the evidence in favour of their use comprised only anecdotal claims of benefits, and no real scientific data. They requested that any recommendation to provide anti-retroviral drugs to South Africans must be accompanied by scientific evidence.
On the contrary, Dr Rasnick presented a case against the use of anti-retroviral drugs based on their toxicity and scientific references that questioned the merits of prescribing these drugs. Statements from published articles by, inter alia, Jay Levy, Phillips and Smith, and Abrams were presented which included the following:
- "These drugs can be toxic and can be directly detrimental to a natural immune response to HIV…This effective antiviral immune response is characteristic of long-term survivors who…have not been on any therapy. …[T]he current antiviral therapies…do not bring about the results achieved by a natural host anti-HIV response. This immune response, observed in long-term survivors, maintains control of HIV replication without the need for antiviral therapy."
- "I have a large population of people who have chosen not to take any anti-retrovirals…They’ve watched all their friends go on the antiviral bandwagon and die, so they chose to remain naïve [to therapy]. More and more, however, are now succumbing to pressure that protease inhibitors are 'it'…We are in the middle of the honeymoon period, and whether or not this is going to be an enduring marriage is unclear to me at this time…"
- "No randomised trials in asymptomatic patients have established that those treated early survive any longer than those for whom treatment is deferred. Extended follow-up of patients in one trial, the Concorde study, has shown a significantly increased risk of death among the patients treated early. The suggestion is that the situation is different for combination therapy. But where is the evidence…?"
- "There is no more hard evidence now of the benefits of early therapy than there was in 1990. We need new randomised trials to determine whether the notion that was probably not true in the era of [AZT] monotherapy – that early therapy prolongs survival as compared with deferred therapy – is now true."
The director of the National Institute of Allergy and Infectious Diseases (NIAID) Dr Anthony Fauci was quoted as saying: "There is an increasing percentage of people in whom, after a period of time, the virus breaks through, people do quite well for six months, eight months or a year, and after a while, in a significant proportion, the virus starts to come back."
It was also highlighted that the label on AZT bottle produced by Sigma reads: "Toxic. Toxic by inhalation, in contact with skin and if swallowed. Target organs, blood, and bone marrow. Wear suitable protective clothing."
Furthermore, it was mentioned that there was considerable evidence to support its toxic effects on other organs. Researchers have documented that persons on protease inhibitors develop abnormal fat accumulations called buffalo humps. As time passes, more and more metabolic and endocrine disturbances are described in such individuals, including hypertrophy of the breasts, increase in blood sugar, cholesterol and triglycerides, pancreatitis and angina. Protease inhibitors can also induce the development of AIDS-defining diseases, such as mycobacterium infections.
It was also argued that the drugs themselves caused AIDS, since they act on cells that are either metabolically active or in constant division. A characteristic feature of immune cells is that they have to divide during the immune response, making them much more vulnerable to the action of these drugs.
The well-documented Concorde study showed that AZT was unable to prevent progression to full-blown AIDS in asymptomatic HIV-positive patients; and that, instead, mortality was increased by 25% in the treatment group, compared to the controls. The possibility that AZT may actually contribute to the pathogenesis of AIDS is real. Dr Koehnlein also cited the Darby study that was published in Nature (1995) which showed a sudden ten-fold increase in mortality of HIV-positive haemophiliacs who had been given the then recommended dose of 1500 milligrams of AZT. Other studies were cited which showed that AZT users experienced more rapid depletion of CD4 cells.
The use of AZT for pregnant women has been shown to cause congenital malformations such as cavities in the chest, abnormal indentations at the base of the spine, heart defects, extra digits and many other abnormalities.
Dr Giraldo concluded by stating that enough data exist to demonstrate that it is not rational to treat or prevent AIDS with toxic anti-retroviral drugs. It is contrary to common sense to treat a highly toxic syndrome with even more toxicity.
5.4 Recommendations on treatment with anti-retroviral drug
5.4.1 Recommendations on the use of anti-retroviral drugs from the group opposed to their use
The recommendations on the treatment of AIDS from panellists who refute that HIV has a causal link to AIDS were informed by their observation that the definition of AIDS in western countries was different from that used in Africa. These definitions have changed over time to the point where a person diagnosed with AIDS in Africa would not be considered an AIDS patient in the USA, Europe and Australia. There was also the critical question of whether Africans clinically diagnosed with AIDS were in fact HIV-positive. These considerations led to the following assertions:
- AIDS is not contagious, although many of the opportunistic infections are
- AIDS is not sexually transmitted
- AIDS is not caused by HIV
- The admittedly toxic anti-HIV drugs are killing people
- The drug-induced toxic effects cause AIDS-defining conditions that cannot be distinguished from AIDS
These considerations led to the following recommendations on treatment of AIDS:
- The South African government should devote the bulk of national and international biomedical and other resources to the eradication of prominent AIDS defining diseases such as malaria, TB and enteric infections and also to the improvement of nutrition and the provision of improved sanitation and clean water.
- Anti-retroviral drugs and any other immune suppressive drugs should under no circumstances be used to treat AIDS patients or any other patients that are immune-compromised. These drugs inevitably require significant amounts of compensatory medications and are claimed to produce, at best, only short-term benefits in seriously sick patients.
5.4.2 Recommendations from the proponents of anti-retroviral drug use
Given the demonstrated benefits of anti-retroviral drugs in the treatment of HIV/AIDS, the usage of that accumulated knowledge to the benefit of South Africans living with HIV infection was critical. However, given the fact that there is relatively little relevance of the recommendations on the use of anti-retroviral drugs in the USA and Europe for a developing country like South Africa, there is a need for more locally derived evidence based on strategies that are based on locally relevant research. This research will enable the identification of manifestations of HIV infection and of cofactors as well as the definition of local standards for the diagnosis of the conditions and the description of the local epidemiology. There is also a need for South Africa to collaborate with other countries and international organisations that are addressing the issue of how anti-retroviral drugs use is or should be different in a South African type setting. The development of these strategies would need to address the following specific issues:
1. In whom should these drugs be used. Secondary to this question are the following issues:
- how should these drugs be used
- at what stage of infection should the drugs be used
- how should the use of these drugs be affected by the different recipient populations such as adults, children, pregnant women, etc
- how might the use of these drugs be influenced by the ongoing transmission that is likely in different populations
- issues related to use in post-exposure prophylaxis, whether in healthcare settings or after rape
2. The choice of the anti-retroviral drug or drugs that might be used, their dosing and the scheduling of the dosing as well as the cost and effectiveness
3. How might the effectiveness of the chosen drugs be affected by concomitant use of traditional medicines?
The issues listed above generated a number of considerations which informed the recommendations that were made on treatment. These considerations are as follows:
- Protocols need to be developed according to what is affordable and sustainable.
- Protocols will also be decided by the resistance profile in the community. This may necessitate expensive tests for resistance, which may not be cost-effective.
- Under the most ideal circumstances, a combination of drugs is best. This combination should comprise two protease inhibitors and a reverse transcriptase.
- Decisions on when to start anti-retroviral treatment may be difficult and must be based on the onset of symptoms. There is a move away from the early introduction of anti-retroviral medication.
- Starting treatment too early increases costs and may also undermine compliance. The development of resistance limits the number of combinations that may be effective.
- There is the possibility that patients may present late when they have opportunistic infections. The recommendation in this regard is to deal effectively with the opportunistic infections before instituting therapy with anti-retroviral drugs.
- Prior to commencing treatment, it is important to undertake a baseline assessment of CD4 and viral load.
- Finally, there seems to be a need to have guidelines on the use of anti-retroviral drugs, which must be updated regularly as new developments emerge.
1. A constantly evolving set of guidelines needs to be developed for the treatment, care and support of patients with HIV and AIDS. These guidelines need to address patients at all levels of care, including those in institutions and under community-based care, and include the following:
- Diagnosis, initial evaluation and long-term management
- Prophylaxis and management of opportunistic infections
- Psychological support and end-of-life care
- Anti-retroviral therapy
2. Infrastructure needs to be developed for the purpose of:
- Provision of medication, monitoring of usage of anti-retroviral drugs and of clinical outcomes, including drug toxicity
- Education and training of healthcare workers
- Counselling and support of patients
- Establishment of a panel for the development of guidelines and continuing review of new data, clinical outcomes and uses of medication. This panel should include local experts, health officials and persons with HIV and AIDS.
3. Ongoing programmes for the control of sexually transmitted diseases and tuberculosis should be linked to initiatives outlined above
4. There remains a series of unanswered questions of relevance to the treatment of HIV and AIDS in South Africa which must be addressed through direct clinical research
The Strategic Plan (2000–2005) developed by the South African government to combat HIV, AIDS and sexually transmitted diseases was considered a good start to addressing some of the recommendations made here.
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