Reducing HIV Mortality: A New Paradox for Practitioners Working in Countries with Socialised Health-care Systems

Summary

It has been only 10 years since we experienced an event that not even the most optimistic amongst us would have predicted before 1997. If the HIV infection is no longer synonymous with a death sentence it is due almost solely to those that were considered as the unscrupulous “merchants of health”. The dialectic analysis should be read as a prophylactic a posteriori auto critic, never pointing out faithlessness, but inefficiency and misguidance and the presentation of questions for sustaining the future of good intentions and adroit decisions is salutary. The paradox analyzed occurred since 1997 should teach us on how without ruining good intentions, not to shape the appropriate strategies to face future emergent health crisis, keeping in mind the crying need to push research policies forward because cancer is still killing massively.

Pablo Goldschmidt

CHNO des Quinze Vingts

75012 Paris France

The milestones marking substantial changes in the lives or in the survival of humans deserve to be remembered: it has been only 11 years since we experienced an event that not even the most optimistic amongst us would have predicted before 1997.

To place the facts in time, at the beginning of the 80s we were embroiled in a distressing reality by which more than three quarters of all children, men and women in the most creative facet of their existence were condemned to death if antibodies directed against a new infectious agent named human immune deficient virus (HIV) were detected in their body fluids. The mere reactivity of the serum of a human being against a virus characterized in 1983 (antibodies) handed an almost inevitable sentence of death.

At that time the evolution of this viral infection was assessed by the quantification of a sub type of white cells, the auxiliary lymphocytes or CD4. This count was the principal evidence for most of the predictions on how a person might survive without degradation and the value of such cells was the abacus which marked the time forecast for an individual to develop irreversible blindness or predicted respiratory failure or the time before weakness will appear after devastating diarrhea, etc. We shall recall that the CD4 cell count was even used as the predictor of the initiation of cognitive shrinkage, forecasting dementia as well as the signs that would take hold of personality as a consequence of infections or neoplastic transformations in the encephalitic mass.

The predictions

From the early 80s to 1997, undertaken HIV patients’ assistance has been perceived as futile and the health care establishments worked by the absorption of pain amidst quasi resignation, receiving lab results in which the CD4 figures (surrogate markers) alleviated the nurses, auxiliaries, students and doctors by helping them to hide their despair behind a protective fence built with objective cell numbers.

Before 1997 the sensation of powerlessness was gripping, given that in addition to offering the people with HIV the possibility to be included in research protocols to evaluate the primary or secondary prevention of opportunistic infections (pneumonia, encephalitis, retinitis, diarrhea), little could be done to limit the devastation that had been triggered by the viral infection: the physician’s work was limited to the description and assessment of technical events referred to prognostication (CD4 count, levels of beta two micro-globulin or the intensity on the band of the protein P25 in the Western Blot test). Between 1985 and 1997 the surrogate marker results from the laboratories generated postures that in the intimate forums of physicians could have been related to those fond of sport bets or prophecies and the circulating lymphocyte figures entitled the clinical staffs to “predict” death in 8 months or less in some, or in less than 2 years in others.

At that time it was permanent the distress while trying to articulate the answer to the question of how, in the HIV infected patient’s life, the decrease of CD4 cells would create a propitious area for life threatening infections, for the growth of certain tumor masses or cancers of the immune system, adding supplementary physical and moral wasting signs and lethal risks to the suffering already triggered by this particular viral infection. The predictions were expressed in a context of anguish of both, the patient and the physician; the last had to put on words the eventuality of the imminent patients’ irreversible degradation.

When patients raised the question: “And now what can I do for me?”, I do recall having frequently to listen to colleagues -who were hostages of their own fears and phobias-, answers loaded with syntactic constructions in the style of: “arrange your papers”, or “make ready your will”, or “seek advice with a lawyer”, or “call your family and order your business”.

Before 1997 the health workers facing people infected with HIV were overwhelmed with constantly sustained frustration about the appropriateness of prescribing and verifying the best lab test conceived to foretell physical degradation. In fact, once the auguries were established by this bunch of scientific forecasts, no efficient therapeutics with long term efficacy could be proposed and if certain treatments failed to protect the HIV infected individual from pneumocistosis, cytomegalovirus, toxoplasmosis or mycobacterium infections, the little that could be made to confront the immune collapse was to encourage the people without any certainty to fight empirically for life. At that time, in a humanistic framework of affection and understanding it appeared even “helpful” to put in words the evocation of the imminent arrival of the end of life.

From the position of the infected persons, the surrogate markers results were gobbled down with resignation and fear, probably because the specific peculiarities of the transmission of this virus mixed the suffering with guilt, and this enhanced a space for anguish and inexpressible expectations. Because confidentiality had to be guaranteed, many patients transformed their suffering into inscrutability and silence, and this was palpable while apprehending the beds of the hospitals with lonely human beings coming to the end of their lives in conditions of affective and physical abandonment.

Treatments before 1997: State of the Art

Approaching 1997, neither the alternative medicine, nor the macrobiotic diets, nor the organic food, nor the varied nutritive complements or supplements overloaded in vitamins and minerals, nor any kind of gym or sport, nor the sea water, nor the thermal stations, nor the essential oils, nor the western or the oriental massages, nor the consumption of oligoelements, nor the antioxidants, nor the reorganization and harmonization of the circulating energy of the body with that of the universe, nor the yoga, nor the tae-kwon-do, nor the good vibes of the associative groups, nor the witchcrafts, nor the transcendental meditation, nor the alkaloids of Cannabis sativa in any preparation and in any route of administration, nor the products obtained from Latin American cactus or of other fungi or exotic vegetables from any continent, nor the systemic or the ex-vivo administration of cytokines, nor the interferons, nor the growth hormones, nor the steroidal anabolic agents, nor the heavy-metal associated organic molecules, nor the preparations obtained following the formulae of the extreme east or the western countries pharmacopoeias, nor the passive immune therapeutics with hyper immune gamma globulin preparations, nor the treatments with antigens of the virus, nor the auto vaccines, nor the derivatives of human placenta, nor the first antiretroviral strategies, proved beneficial effects either on the immune regeneration or on the quality of life of the infected persons, less even on the survival of the persons who had "declared" the AIDS.

Efficacious therapeutics

Optimism rose in 1997 when it was proven worldwide that new antiviral strategies associating two or three synthetic antiviral compounds were able to reduce the mortality due to AIDS. In the United States the mortality decreased from 93 % in 1981 to 6% at the end of 1997, and the follow up of patients in Norway showed that the level of mortality between 1986 and 1990 (47%) was dramatically decreased after 2006.

Several other trials did confirm these results worldwide and in Brazil it has been reported that the global number of VIH infected people who had been treated with antiretrovirals needing hospitalization and the number of deaths was significantly reduced after 1997 (the Brazilian population started to benefit from free antiretroviral therapeutics in 1996). However, the number of persons who got infected increases, indicating that the access to free treatments requires consistent additional efforts to educate the population on the best way to avoid being contaminated by this virus.

In Barcelona a constant increase of HIV related mortality was observed until 1995, but the curve of mortality showed an inflection, with a significant decrease in almost the whole population from 1997. However, in this city, it should be underlined that the treatments associating antiretrovirals have not shown equivalent efficacy after stratifying the population according to the economic resources of the different groups of patients: the reduction in mortality was significantly lower in the layers of the population with the lowest resources and in persons who routinely intravenously inject psychoactive agents. Because in Spain the antiretroviral treatments are free of charge, the free treatment appears as an element that although necessary to fight AIDS is not sufficient to explain the discrepancies on the results obtained on mortality. Hence, to improve the quality of life and to prolong life expectancy, the intrinsic capacity of the antivirals to act on the specific molecular targets of the viral enzymes and the appropriate oral bioavailability of the pharmaceutical preparations should not be dissociated from other factors that determine clinical efficacy: from the patients side, people should actively adhere to the treatment and respect all the hourly indications ("compliance"), and from the side of the health workers, first, they should construct with the patient relationships which develop respect and affection with bonds of confidence, and second, they should educate the infected ones and the not infected ones, especially the populations with a low level of education.

In adjunction to the encouraging results, there is no doubt since 1997 (when the therapeutic strategy known as post-exposition prophylaxis of the newborn baby was validated) that antiretroviral treatments have limited the transmission of HIV from mothers to their babies due to a prominent reduction of the viral load in the blood of the progenitors. Moreover, the first large studies realized with pregnant women in 16 countries confirmed the efficacy to limit the transmission of the virus from the mothers if appropriate treatments were administered according to specific dosage and schedules. Currently, the levels of transmission of HIV from mother to child are ranged at levels between 1 and 2 % in highly industrialized countries and the benefits of antiretrovirals have been demonstrated in the cases in which the toddlers had the maternal milk as their only nutritional option.

The awakening of delusions

The catastrophe triggered by AIDS became noticeable in western countries in the early 80s, allowing certain individuals to undertake simultaneously the function of judges, juries, referees and contenders. The newborn connoisseurs of AIDS overran the whole scientific and medical scene, and from this new arena they ruled the work positions and they qualified the relevance and the value of the investigations: the ex-nihilo structures played as unarguable commanders in duty who did decide on the pertinence of the tasks to be conducted and on the kind of enlightment that deserved to be spread to the society.

During the first year of the emergent epidemic, the rapid development of scientific leaders and state machines could be seen retrospectively today as beneficial if this emanation was followed by decisions leading to the improvement of people’s health. However, according to what was produced during those years it appears a sketch in which AIDS only created –in countries with highly public concerns on health and socialized medicine- concentrates of power in which some flocked to the state network, rapidly flourishing their own careers and who broadcast their views as if they had received supreme revelations and dogmas on the infections and their evolution. This extensive occupancy of the AIDS environments of both, the basic research and the medical apparatus was propitious for quick and unexplained fame as well as the appointment of a bunch of new medical professors. Those who in other geographical contexts could have been labeled as “apparatchiks” drove indisputable decisions regarding the appropriateness of who, why, where and how should be conducted all the work related to AIDS research.

On this matter, during the first epidemic years the investigation concerns were largely occupied by imposed visions, and today, it deserves to be re signified the extent of human and financial resources allowed to show among others, the repeated issues imposing the mycoplasma as the essential cofactors that determined the progress of a viral infection towards AIDS (today this processes are only limited by the association of antivirals).

Moreover, it deserves to be recall and analyzed the clinical relevance after administration of organic heavy metal salts complexes, or the treatment with cortisone to limit the HIV evolution, or the benefits of palsmapheresis, or the implications of the supreme determination of the last identified lymphocyte or macrophage membrane associated protein or receptor and the overriding implications of other infectious agents different from HIV in the clinical degradation of people with HIV…It is amazing to ascertain that at that time, many of those holding the presupposed "knowledge on AIDS” validated their work by their mere appearance in the mass media, and it happened frequently that many of these revealed-truths were denied a posteriori.

As a paradigm of what was happening during the first years of the AIDS epidemic in France around the scientific and medical areas, generous donations granted for research to governmental and non governmental institutions as the result of the gifts flooded of people with AIDS, most dead as consequence of ineffective therapeutics. In addition, the cash influx to certain institutions increased between the mid 80s and the mid 90s thanks to a significant real estate patrimony that had been donated from those who were dying from AIDS or from persons in the advanced phase of their infection who kept the hope that the bequeathed goods would contribute to the remedy of AIDS and would help to finance the development of a vaccine. The citizens organized public performances, spectacles, concerts, fairs, and highly covered media events to raise funds for the research against AIDS, and it was in the 80s and 90s when there were found in some French public notary waiting rooms pre printed leaflets to be filled, dated and signed by the future deceased so that his/her goods could be automatically transferred to organizations promoting AIDS research.

However, it seems from the results obtained by the recipients of these sums that the expected labor was not accomplished and those of us who were in permanent contact with the people with AIDS ask ourselves if the decisions regarding the assets bequeathed to the ideal nobleman of scientific progress of humanity have been effectively utilized. Let’s remember that thanks to such generosity important sums were raised and used to build facilities that did not fulfill the intentions of the legatee and pay for buildings where the AIDS authorities and their groups of followers might have expanded their ambitions of big spaces. Our intention here is not the criticize the quality of the results, but the retrospective assessment of scientists' activities, shows that the research has not always been conceived to approach the objectives desired by the legatees, but to give chance to work in scientific areas which the researchers considered personally as interesting or entertaining.

Simultaneously, but in the public hospitals, funding collected from the generous donators but also from the national budget for public health, were spent for a so called “machine to produce papers”: in public infrastructures a relevant portion of the work carried out in those years by the staffs (whose salaries came from the taxpayers) was equivalent to what is offered for registration purposes by the private clinical research organizations to pharmaceutical corporations for phase II and phase III clinical trials. These CRO-like activities conducted by the medical staff increased the chances of civil servants or residents getting better positions, and at the bottom line, the health system build by the believers in socialized medicine was articulated as a public machine to feed resumes. Hence, this was also far from what the donors expected. However, because neither policy nor procedure taught at that time -(when illness, suffering, donators, altruism, generosity were mixed with good will)- how to manage the funds, it seems senseless to accuse anyone a posteriori of inefficiency. Nevertheless, this peculiar situation reveals that the towers of fallacy and delusion which were built while struggling to reduce AIDS suffering should be burned into the future to avoid precipitated decisions and new virtual creatio ex-nihilo establishments: the birth and rapid grow of the HIV centers created an unfortunate picture that should be retained as a pattern so as to predefine what should never be done again.

Efficiency and optimism and raise of a paradox

In this old world AIDS generated a new unexpected ideological paradox that was inconceivable before 1997. In fact, a series of results show that the HIV infection is no longer synonymous with an announced death and persons who endured the consequences of bacterial, viral or parasitic infections in what was known as “declared AIDS” may recover their immune functionalities as well as their corporal mass and their aptitudes to work, to love and to create. In the countries with health systems offering the benefits of free access to the appropriate treatments, the lethal HIV infections have been transformed into a chronic controllable affliction, but none of these achievements were the result of appropriate public research policies, either of the product obtained from the avant-garde investigators who proved while working in public institutions to be eager to face the pertinent issues for the cure of AIDS, nor from acts of altruism!

If the life of the persons living with HIV improved, this was the result of the accurate, creative and systematically labors of the chemists, biologists and clinicians who were pushing research forward from inside the pharmaceutical corporations and these statement requires to be placed in the perspective of our primitive cultural perception of the original actors fighting against this infection: it appears today that not all was pristine because generated by honest civil servants in their respective positions or was the consequence of public research policies.

The HIV paradox deserves to be pointed because if since 1997 this viral infection is no longer synonymous with a death sentence it is due almost solely to those that were considered as the unscrupulous “merchants of health”.

The pharmaceutical industry carrying out therapeutic developments were stigmatized and labeled as deprived of any kind of engagement in the public health and only interested in medicines able to produce quick and high turn over and profits by targeting pathologies affecting larger populations in rich countries. In congresses, meetings, scientific and extra scientific publications released during the first years of the AIDS pandemic it was repeatedly enounced that because AIDS affected much smaller number of people that other pathologies and since in most of the HIV infected people the levels of revenues were low, the pharmaceutical corporations would be of little help. However, the survival, quality of life and reduction in physical and moral suffering was possible thanks to those from whom less was expected (and the big delusion came from whom much was expected!).

Finally, the purpose of presenting the concatenation of the events which changed the life expectancies for HIV infected people has the intention neither to be trapped by indulgent and easy diatribes nor to put forth ideological pamphlet arguments that could have been drafted in the absence of proven evidences. Because the fight against AIDS shows a positive corollary, the assignment of blames to any particular establishment or individual may apparently have no impact. However, on the above it appears that the presentation of questions for sustaining the future of good intentions and adroit decisions is salutary and the dialectic analysis should be read as a prophylactic a posteriori auto critic, never pointing out faithlessness, but inefficiency, prejudices, disorientation and misguidance. Therefore, the events occurred between 1985 and 1997 should teach on how not to shape the appropriate strategies to face future emergent health crisis without ruining good intentions, keeping in mind the crying need to push research policies forward because cancer is still killing massively, and politicians, media managers and fund raisers become agitated with the potential relevant returns of human distress.

In a regulated framework which respects universal ethical standards and free access to health care, a paradox was created by a “revolutionary” change operating in the management of HIV infection as a consequence of the speedy and efficient contribution from the private pharmaceutical sector. Because the antiviral therapeutics have largely proven to reduce the fatal prognosis due to HIV, it still remains an urgent duty to share the success of the pharmacological strategies with our peers in countries with limited resources and with fellows living in industrialized countries, which, whether due to their socio-cultural, affective or educational situation require additional caring and dedicated efforts for education.

Dr Pablo Goldschmidt, Paris, France- In Press.

Contribution to the understanding of bird flu

January 2006 (still valid in 2008)


Contribution to the understanding of bird flu


History of a future “virtual” pandemic

In December 2003 the largest outbreak of highly pathogenic avian influenza H5N1 virus occurred among poultry in eight countries. In order to control this infection two hundred million poultry birds across Asia were destroyed and at the same time the H5N1 (avian variant) was isolated from a young girl who died after visiting her family in China.

Clinical cases have occurred in otherwise healthy young individuals (mortality rates approaching 70%), which were considered by specialists in epidemiology predictions as reminiscent of the 1918 Spanish influenza pandemic. No data were reported indicating if the victims of this infection were previously vaccinated one or several times against influenza, or regarding the time elapsed between the probable contact with an infected animal and the clinical signs, or the delay between the first signs evoking influenza and the admission at the hospital.

The populations exposed to influenza viruses or vaccinated recently bear antibodies recognizing the viral strains circulating in a certain territory and during a certain time and in people immunological “naïve” to new viral variants (absence of antibodies) the pathogenic power of these new viruses is objectively unpredictable. However, no data obtained from animal models or from theoretical predictions are able to predict the morbidity and mortality that may or may be not induce the new variant H5N1 in people vaccinated in 2004 and 2005.

The avian influenza A viruses are the result of the combination of twenty-four different proteins on their surface (15 Hemagglutinins and 9 Neuraminidases) and can be spread by healthy or sick migratory birds and waterfowl, carrying them in their intestines.

Before the event reported in 2003, the subtypes of influenza A virus mostly found in humans were H1 and H3 (H refers to the type of Hemagglutinin and N to the type of Neuraminidase, that are proteins expressed independently by the influenza viruses). The H and N are protein spices anchored on the viral surface at a ratio of about 8 to 1 and are capable of stimulating protective immune responses against infection (neo-synthesis of antibodies).

The influenza viruses continue to experience what is called “antigenic drift” by expressing modifications in the proteins expressed on their surface. These modifications allow them to escape partially or totally to the neutralization of antibodies induced by other surface proteins like those used as antigens for vaccines or those present in the virus that may have provoked previous infections. The continual viral modifications are not inducible by changes in the ecosystem or by any kind of “viral intelligence” or “viral intentionality” perpetrated to perpetuate information but are the consequence of the natural activity of all the enzymes replicating genes in biologic systems. Therefore, the biological machineries should be understood as bioreactors and not as photocopiers and the viral variability is a continuous natural process due to a lack of effective proofreading of the genes by the RNA polymerase, which result in the amino acid substitutions in surface antigens. The variations expressed on the viral surface may attain a threshold of differentiation with other viral-quasi-species. If this difference is located in the antibody-binding sites, the new viral generations may evade (at unpredictable degrees) immunity and re-infect immunised individuals.

The genes coding the information for influenza viruses are not structured as a continuum quantum of linear information but in segments physically separated. Because genetic information is segmented, when two different influenza viruses simultaneously infect cells, reassortments may occur and generate different hybrids that may not be properly neutralized by antibodies directed to the parents. The result of the mixture of different viral information called “antigenic shift” generates the new variants and its detection is the ground for the warning of the new pandemic.

Before 1997 the direct transmission of avian Influenza viruses to the human was considered practically impossible and it was thought that bird viruses did not bind directly to human receptors. A “virology dogma” established that intermediate hosts like the pigs (which carry both receptors) were necessary to allow the “mixing and reassortment” of viral genes to generate new strains capable to infect humans. However, the recent outbreak in poultry has spread a highly pathogenic virus from chicken to humans and has changed the understanding of the genesis of this yet “virtual” pandemic. It is now accepted that birds can shed reassorted pathogenic viruses to pigs, tigers, cats and humans.

The geographical expansion of the new H5N1 variant across Asia in an unprecedented event of transmission of viruses to humans and proof that a new avian-human reassortment did emerge and has been transmitted. The emergent virus is a necessary but not sufficient condition to predict sickness and death in humans. Figures predicted by Experts need a comprehensive revision, and diluted into realistic relativism: in the previous influenza pandemic, the coverage of the populations with influenza vaccines was much lower than at present. Moreover, during the pandemic occurred at the beginning of the 20th century and in the late 50s, the choice of agents to treat efficaciously bronco bacterial infections was limited and the management of inflammation, oedema, pyrexia, artificial ventilation and blood clotting were far from what is currently available today.

Today, in January 2006, because the pharmacologic management of bacterial (co)-infections, the development of protective devices, the improvement in intensive care techniques, the development of corticosteroids and active antibiotics, the antibody levels against various influenza strains in the global population and the communication channels to aware and teach populations on the health risks did dramatically evolve in the last 30 years, the drafting of pandemic forecasts and the prediction of global sanitary catastrophes (including the forecast of numbers of potential casualties) by mathematic models combining data obtained from the history of epidemiology with viral gene reassortments should be considered as a maximalist panic-triggering non-sense.



The approaches to protect populations

Active protection with vaccines

Influenza vaccines (viral antigens) contain whole viral preparations obtained from allantoic fluids harvested from infected egg cultures, inactivated by formalin or lactones, mixed with adjuvant and administered by parenteral route. Vaccines induce humoral responses (humoral= immunoglobulins or antibodies), which protects from sickness and death.

Even if arguments for the use of vaccines are advocated for poultry on the basis of economic and social consequences of influenza outbreaks, it was shown that chickens immunised against highly pathogenic viruses might carry and excrete virulent variants following challenge with live virus. Because the incomplete prevention of virus excretion and the immune pressure can generate variants, the vaccines produced with low and high pathogenic H5 andH7 viruses had been prohibited in the USA between the 80’s and 1995 (the distinction between vaccinated from infected animals could mask the presence of high pathogenic viruses and allow its transmission).

If the next influenza pandemic were to begin the inactivated vaccines would offer a rapid means for mass human protection, but the production of this vaccine (obtained by viral expansion in embryonated chicken eggs) is time consuming and dependent on a steady supply of biological material since at least six months may be necessary to organize sufficient fertilized eggs for manufacturing a vaccine. Additional problems to be solved while producing vaccines refer to the high pathogenicity of the H5 strains that cannot be easily grown in large quantities because they are lethal to chicken embryos.

To complicate this picture it has to be also understood that because vaccines may induce adverse reactions in a non negligible number of recipients, the product liability and the unavailability of reasonable cost liability insurances in industrialized countries discourage manufacturers of vaccines for what’s called universal use. It was indicated that no new vaccine approach seems to trigger the interest of manufacturers for universal use unless the health authorities implement new mechanisms that limit liability for human adverse effects.

Antivirals

The H5N1 strains responsible for what is called “bird flu” are susceptible in-vitro to Neuraminidase inhibitors and in this family, two pharmacological agents, Oseltamivir (150 mg, two daily for 5 day) or Zanamivir (two inhalations in the morning and in the night for five days for 12 years or older).

For the anti-influenza compounds a “furor curandis optimism” was perceived when the information regarding these agents was released, but the fact of the matter is that up to this date no controlled clinical trials did prove the real levels of efficacy of any of the antivirals in humans exposed to or clinically affected with the H5N1 influenza virus. The therapeutic conclusions were built on pharmacological amalgams, empirical approximations and “good wishes” from data obtained in-vitro and on animal models known to have a certain predictive value for the clinical efficacy of antivirals in humans. It has to be emphasized that the recommended anti-influenza compounds, whose potential benefits are massively diffused by the media (and for the first time in the history of antiviral pharmacology using brand names!) "may be" active in human settings against the virus responsible for bird flu and that these drugs “may be” useful in protecting health workers and other exposed individuals.


The passive therapeutic approach

The experiences of colleagues who had to face previous outbreaks of viral diseases should inspire the design of strategies for treatments against the bird flu. On this matter it has to be pointed out that Junin's virus (Arenavirus) was responsible for several years in Latin America (Argentina) for a hemorrhagic fatal fever with high levels of mortality. This virus infects humans by aerosols (like Influenzaviruses) but from a reservoir in rodents, and without treatment the mortality reaches levels equivalent to that reported for the bird flu Influenza H5N1.

In 1975 several investigators reported that animals treated with hyper immune sera in appropriate doses (passive immunotherapy) showed significantly lower mortality rates than those treated with sera from animals with no antibodies (the reduction in mortality did dramatically diminish from 100% to 25%). The hyper immune sera were obtained from survivor animals during the phase of convalescence (animals that were sick but able to survive thanks to their ability to synthesise high levels of neutralizing antibodies). It was then shown that the administration of hyper immune sera in the phase of incubation or in the acute phase did improve the prognosis. It was also shown that the antibodies present in the mothers’ milk from mice previously immunized were able to reduce the out spring morbidity and mortality of animals challenged.

Clinical trials carried out with passive antiviral therapeutics, that could be today considered an “old fashion” approach, showed in 1994 in humans with Junin’s haemorrhagic fever, that the mortality rates ranged between 15 % and 30% in non treated subjects but was reduced to levels close to zero in patients receiving hyper immune sera obtained and purified from convalescents. In addition to the benefits observed while treating Arenavirosis, a group of veterinarians in Ohio showed differences in mortality between the offspring of mothers previously hyper immunized and not hyper immunized (14% and 86% respectively) in piglets experimentally infected by the oro-nasal route with Coronaviruses responsible for gastroenteritis and fatal pneumonia (to this family of viruses belongs the agent responsible for SARS). In 2004 it was shown in Japan that the passive immunotherapeutic approach was able to protect animals from myocarditis caused by Influenza A virus, significantly reducing morbidity and increasing the survival rate. The passive immunotherapy with specific immunoglobulins also reduces significantly the morbidity and mortality in children with respiratory sincytial-virus (RSV) bronchiolitis. The different issues discussed above are strong enough to support the rational for studying the potential clinical benefits of the treatments with high-titres of specific immunoglobulin preparations on severe virus infections transmitted by aerosols.

To produce pharmaceuticals containing specific immunoglobulins the ex-vivo large scale-up approach can be applied, and here the purification of proteins produced in bioreactors after the incubation of genetic engineered cell-clones producing each one a specific neutralizing immunoglobulin directed to a N or H epitope has to envisaged (monoclonal cocktail), but the narrow activity of each monoclonal antibody and the risk of immune escape may limit their clinical interest. The approaches based on proteins extracted from cells need a comprehensive screening and may take several years before the population could be granted with the benefits of these “bio-tech” ex-vivo produced antibody mixtures.

An alternative (and inexpensive approach) can be drafted if in different countries we decide to cooperate and harmonise health policies. Here, inspired by the experience while struggling in the 70’s against Junin’s haemorrhagic fever, the survivors’ solidarity should be solicited in order to obtain their formal consent and to proceed to a scheduled collecting of sera (and/or lymphocytes). This appears as a simple and inexpensive alternative, but here, additional non-scientific “limitations” have to be verbalised. First, passive immunotherapy is not patentable and in the international context of the pharmaceutical and biotechnological industries the levels of profitability of plasmatic human derivatives do not tempt the ones deciding for new therapeutic developments. Second, the manufacturing of hyper immune sera and/or plasmatic proteins (obtained from convalescents) requires technologies that are in the public domain (added value is minimum) without royalties to be charged or paid. The preparation of these products requires minimal investments in equipment and most of the activities have to be carried-out in order to keep the records updated of the sick subjects who would be requested to donate plasma (and/or lymphocytes). The centres in the areas where the outbreaks are detected with new viral variants could then provide the plasma, the sera or circulating cells producing the antibodies.
Because flu peaks as a consequence of seasonal variations, the production of hyper immune sera could be forecast. The international and inter-seasonal cooperation should make possible to elaborate an efficient answer to the needs of countries at risk where new strains may be isolated. This issue could limit the expenses kept as provision for the stockpiling of expensive antivirals.


Conclusion

Presently, there is an urgent priority to verify the impact of the cross-reactivity induced by the available influenza-A vaccines on the morbidity and mortality that may provoke the new viral strains, because little is known if the antibodies directed to the viral preparations used previously for vaccination have a positive impact on the transmission or on the morbidity of the new variants.

Facing the risk of an eventual pandemic, all the approaches must be considered as complementary and non-excluding. However, a critical analysis suggests that clinical proofs for hypothetical efficacy of antivirals against bird flu in humans have to be placed at the same level that those found for preparations with specific hyper-immune gamma globulins. The extrapolation of results obtained for other pathogens in pneumology and in animal models with Influenzaviruses is a solid argument justifying the interest for developing affordable treatments based on preparations with high titres of specific antibodies (with safety requirements warranted). In the event of an avian flu epidemic in humans, the health workers should implement rapidly the best public health responses, and the rational measures (isolation, efficient mechanical barriers for biologic fluids, quarantine, availability of clinically active and affordable antivirals, production of vaccines and safe preparations containing high titres of human neutralizing antibodies) are part of the tools to bring future outbreaks under control.





Dr Pablo Goldschmidt
Laboratoire du Centre National d´Ophtalmologie des Quinze Vingts
28 rue de Charenton, Paris-France











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