Influenza AH1N1, Venezuela and the Tamiflu Controversy

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The flu season started in Latin America this year and has hit a number of countries with epidemic numbers. The majority of them are responding to this epidemic course with logic and responsibility, regardless of the limitations that each of their respective health sectors may have. As far as we are concerned, the sad exception is Venezuela, where the Ministerio del Poder Popular para la Salud (MPPS – Ministry of Health) has not only responded so clumsy but also, in my opinion, irresponsible.

To start, the Venezuelan ministry denied the existence of an epidemic and termed it as a normal situation. Of course that depends on the definition of “normal,” while it is true that the cycles of inter-pandemic influenza (seasonal flu) can be very variable in numbers of cases from one year to another, it is no less true that the number of cases of influenza H1N1 currently seen or calculated in Venezuela indicates an epidemic level, even within the limitations of information provided by the ministry. There is nothing to be gained by denying that the numbers are higher, and that there are cases that ended in death. It does not have to generate anguish to provide such information to the population and discuss plan of action. Al these have been openly demonstrated by all other countries in Latin America that are doing so without any complex.

Secondly: once it is determined the magnitude of the problem (in this case the epidemic) the obligation is to act, but unfortunately the response should not be to hide hide the information or minimize the gravity of the situation (probably made worse by not having done the work of promotion and prevention usually recommended), and much less to take the irresponsible decisions to remove from the plan of treatment, the only medication that has shown some activity against influenza. I am referring to oseltamivir (Tamiflu).

Why the Venezuelan government takes this decision? As we have been accustomed, the Venezuelan government makes decisions without many explanations of why but I think that the reasons are the following:

1. The government does not have the medication and when one says the government does not have it, we mean the country does not have it, because in an economy where the dollar strictly controlled by the government, as it has been the case of Venezuela for years, what you can achieve in terms of product offering passes by what the government allows. To make the matters worse, the MPPS has decided to restrict the prescription of these antiviral drugs at their discretion (presumably to avoid the inappropriate use of the same and avoid the generation of resistant strains of the virus; a response similar to the way we deal with the treatment of malaria in the country but with the problem that we’re talking about two completely different diseases (specially in a country where most of the malaria cases are due to Plasmodium vivax) except that both may result in death. In the case of influenza, it is particularly important to initiate treatment early, in the first 24 or 48 hours of the onset of symptoms, to get the clearest benefits of the drug. Obviously, if the medication cannot be freely prescribed by doctors in Venezuela this difficult to achieve this goal.

2. The minister of health and his advisers believe that the medications are not necessary because they are not effective, even though they are recommended by experts consensus, and Venezuelan, Latin America and worldwide guidelines, as well as by the World Health Organization (WHO) and the Pan American Health Organization (PAHO). Since the 2009 influenza pandemic, it has been attempted to dismiss the importance of these antiviral medications noting that the same are not effective and rather wanting to make people see that their use correspond to interests of the international pharmaceutical companies to sell junk, that is to say by following only an economic interest (in fact it is argued that the pandemic of 2009, was not such pandemic, but a media product headed by the same economic interests). Newly TeleSur issued the following interview with the Spanish journalist Miguel Jara indicating the above and you can read more about this and other related topics in his blog. You can also see the statements of the Venezuelan Minister that points toward the same direction.

To start with, let’s say that I do not believe in conspiracy theories, where there are some sinister personalities (in this case, the pharmaceutical companies, international agencies such as the WHO and agents of various governments) that manipulate a large population of innocent people (all of us) and then few sincere individuals who are only interested in the truth (such as the journalist Miguel Jara and others) are trying to defend us. For these theorists there are no honest mistakes or wrong decisions, but baleful manipulations, implying in addition as members of the plot a huge payroll of employees (in the case of the “false pandemic” of the 2009 we would have to include the WHO, CDC, and many independent researchers). So for now not disputing this point further but I understand that the Venezuelan government likes greatly this type of theory.

More interesting and complicated however is to discuss the potential merits and benefits, or damages and false claims of the use of antiviral drugs (specifically oseltamivir, the known Tamiflu) to treat or prevent influenza infection. WHO, and the majority of the specialized medical organizations in the area of infectious disease, pulmonary medicine and critical care, suggest the use of oseltamivir for the treatment or prophylaxis of infection with the influenza virus. It is true that the data in which these recommendations are made are not perfect (as it is not for the vast majority of the diseases especially when we try to extrapolate to the individual level), and perhaps are weak, but this is not due to a conspiratorial plan, but due to the inherently complexity of carrying out and analyze medical studies. The dispute with the use of oseltamivir has to do with the meta-analysis by Kaiser (2003), which concludes that the use of oseltamivir in patients with influenza reduces the risk of respiratory complications, hospitalization and the use of antibiotics in healthy adult and high-risk patients. This meta-analysis included 10 studies, all sponsored by the pharmaceutical industry (in this case Roche), and 8 of these studies had not been previously published. This study was essential to promote the use of oseltamivir during the 2009 influenza pandemic. Other meta-analyzes published later came to similar conclusions. In 2009 Jefferson published a meta-analysis, excluding the studies used by Kaiser -and with this 2/3 of the patients- which concluded that oseltamivir indeed was effective in reducing the symptoms of influenza in healthy patients and in the treatment and prophylaxis of patients exposed to confirmed cases of influenza but not to reduce the risk of complications, including death. Due to the persistent controversy generated on this topic Roche requested Hernán and Lipstish (recognized researchers and epidemiologists at the University of Harvard) to reassess the data independently. The result was published in 2011. What was the conclusion? That the use of oseltamivir does reduce the risk of respiratory complications requiring antibiotic treatment in patients with confirmed influenza infection. In spite of this, the controversy continues. Why? In 2010, Jefferson and his collaborators of Cochrane decided to update the meta-analyzes previously conducted by them in 2006 but this time, and based on previous results of similar analyzes about other medications, they decided to use the clinical reports of clinical trials (in possession of the drug company) and not the published reports (which represent only a fraction end, product of the analysis of the first). In spite of extensive communication with Roche in the course of the past 4 years, Cochrane researchers argue that they have received only partial information from Roche. His new meta-analysis concludes that in adults and children with illness compatible with influenza the use of oseltamivir reduces the symptoms of the disease in about 21 hours when the treatment is started early, but could not reach any conclusion with regard to reduction of complications and prevention of viral transmission. In April 2013, Roche said that it will make delivery of all information required for the evaluation. This controversy has been so serious that the reputed British Journal of Medicine is currently campaigning in the United Kingdom for the medication to be withdrawn from the British market. In fact, it is very interesting to read the  pro and cons version of the two sides involved in this diatribe.

The question is: does the above demonstrate that oseltamivir It is not effective in the treatment of influenza to the point to decide to remove it from the Venezuelan government’s treatment plan? My answer is no. Even though the dispute move us to a deep reflection on how we generate, analyze and have access to scientific research, which should generate changes in the procedures of how to make it more transparent and reliable, the data so far is not (at least for now) sufficient to discard the use of the medication. Even more, although the analysis of randomized studies are important, the final result (once you have obtained all the data for the analysis) may not provide all the information you need to reach a final conclusion. To site an example, high-risk patients are usually not included in these randomized trials (in the case of the studies of influenza: pregnant women, patients with lung disease or chronic cardiovascular, etc. that are those who usually have a high mortality risk when they become infected with the influenza virus). In addition, the evaluation of Cohcrane, does not include non-randomized studies (case-control studies, observational, etc.), which although may have disadvantages in terms of methodologies and can introduce bias to the conclusions, can however provide very instructive information on the use of these antiviral drugs, in particular in the case of those groups not included in the randomized studies. The reality is that there are a number of non-randomized studies publish since and about the H1N1 2009 influenza pandemic that suggest that in fact oseltamivir is useful to avoid complications and probably to decrease transmission(Vernon et al. NEJM 2010Janice et al. CID 2012,Delgado-Rodriguez et al. JAC 2012). Seen this way and assuming that the real reason the MPPS to eliminate the neuraminidase inhibitors of the schema for treatment of influenza is this controversy that I have just noted, I do not find it sensible to take this type of decision and worse in way little informative toward the medical community as it was carried out.

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