Evolution of therapies in 25 years

Lakar Iraizoz, Oihane

Elhuyar Zientzia

This year marks 25 years since the development of the first AIDS drugs. The seriousness of the disease and the pressure of society led from the beginning to accelerate the progress of research. In fact, four years after the onset of the first clinically diagnosed case of AIDS, these first drugs came out. Ten years later the severity of the disease changed dramatically.
Evolution of therapies in 25 years
01/12/2010 | Lakar Iraizoz, Oihane | Elhuyar Zientzia Komunikazioa
It was approved in 1987 as an anti-AIDS treatment. The drug was created in 1964 for use against cancer. Ed. : Jim Minor/NIH Pharmacy.

Samuel Broder is one of the researchers who laid the foundation stone in the fight against AIDS. During these twenty-five years he published in July in the journal Science Translational Medicine an article that explains the trajectory of anti-AIDS research. He has interspersed in the article his experiences and the convictions and feelings of society, with details about drugs. He was one of the specialists who treated some of the older patients affected by AIDS.

"Doctors know they now have several medications to administer to their patients, but many don't remember what the situation was at the time," said Broader. Nor was it clear whether there were pathogenic retroviruses for man.

However, "the fact that there was a retrovirus behind AIDS did not solve much: retrovirologists generally considered it more important to look for an antivirus vaccine than to develop antiretroviral therapies. Antiretroviral therapies were considered useless and patients, doctors and researchers were dissatisfied."

Although this conviction slowed research on antiretrovirals, some researchers decided to follow this path. Among others, Broader. Working at the National Cancer Institute in the United States, for the first time they were able to demonstrate that a particular drug partially inhibited HIV replication. They were the first results of a joint work by various private pharmaceutical companies and academic centers.

The results were released on 28 June 1985. It was not two years since this presentation until it was accepted as a treatment by the U.S. Food and Drug Administration (FDA). The pharmacy was named TR. In fact, it was a drug created in 1964 and confined in a laboratory. It was used in some cancer tests and subsequently ruled out for its toxicity. As for the treatment of AIDS, the benefits were greater than the damages.

This good result encouraged researchers to continue on the open path. Society also encouraged researchers and administrations to seek healing from this disease. "It was especially the groups of American gays who pressured, since they first detected the disease and many died," explains Daniel Zulaika, coordinator of the Osakidetza AIDS Plan. "This social pressure greatly accelerated the usual steps in clinical trials. The path that a drug travels for two or three years was the result --dio-- of antiretrovirals that were carried out for several weeks or months, which allowed the success of these therapies." Zulaika took up the work of coordinator of the AIDS Plan in 1987, and currently continues.

Repentisation

They took advantage of the rapid development of treatments and, as Broder wrote, "by 1990 we were quite clear that AIDS would cease to be a deadly disease and could be treatable."

But the real revolution came in 1996. Zulaika recalls: "At a Vancouver congress the results of an investigation were given: A group of dying patients weighing 33 kilos were resurrected upon receiving the treatment being investigated. As is normal, immediately, that same year and in 1997, patients began receiving this therapy in almost all health systems. At CAPV, for example, we had 2,200 patients taking this therapy by the end of 1997."

This sudden advance was due to two reasons: the development of a new type of medicine that combined with other drugs already developed. Thus, treatments became much more efficient.

Antiretroviral drugs act in the different stages of the infectious process of the virus: some (S) prevent the penetration of the virus into the cell, others (AT) interfere in the activity of the reverse transcriptase enzyme; a third group (I) prevents the integration of the DNA copy of the virus into the host cell genome and prevents the creation of the latest functional antiretroviral protein (P). Ed. : Russell Kightley.

The key to combined therapy is to attack the virus at more than a moment in the infectious process. For infection to occur, viruses enter the cell first. Then begins the process of introducing your genes into the host cell genome. By having the information stored in an RNA chain, they make a copy of it and make it a double DNA chain. This copy is generated by the enzyme called reverse transcriptase of the virus.

The next step is to introduce the DNA chain copied into the host cell genome and, finally, when the cell generates protein chains from the information of these genes, they are cut to produce functional proteins. In fact, several proteins are synthesized from the united genes. These last two steps are performed by two other HIV enzymes, integrase and protease, respectively. From there, viruses only have to correctly join the components of the new viruses and remove them from the cell to complete the cycle.

Every medicine, a task

Each antiretroviral drug aims to interrupt a specific step in the infectious process and there are already six drug families. The first ones that developed, such as AZTI, affect the reverse transcriptase enzyme. In short, using the RNA chain as a model, this enzyme forms the DNA chain, adding nucleotides. Well, these drugs have a nucleotide-like structure and replace the real nucleotides in the DNA chain. Thus, they block the chain and break the synthesis of DNA. There are analogues of the four nucleotides that form DNA chains and more than one for each nucleotide.

Medications from another family also have the function of interrupting reverse transcriptase, but they act differently: they are associated with the enzyme and distort its three-dimensional structure. This makes the enzyme not working properly.

This revolution in the anti-AIDS treatment occurred when protein drugs were developed. By not being able to generate functional proteins, it is impossible to complete the cycle to viruses. In December 1995, the FDA approved the first anti-protein drug, Saquinavir. Since then other drugs have been developed with the same effect, as well as enhancers that allow these inhibitors to stay longer in the blood.

Recently (since 2006) medicines with other effects have begun to appear. Two drug families have the function of preventing the virus from entering the host cell and another of converting integrase into an unusable enzyme. Each of these families has a drug marketed and there are many studies underway to advance these pathways.

For Zulaika, "it has been very important not to have stopped researching and to remain cutting-edge and dynamic research." Twenty-four antiretroviral drugs already exist on the market and, as has already been said, combine different effects to attack the virus with greater hardness.

From research centers to users

Drugs marketed by research centers, pharmaceutical companies or others have proven effective at the time of launch. From there, professionals who have worked with these medicines transmit their experiences in scientific societies, congresses, etc. "defining the best combination of drugs in terms of cost and effectiveness," explains Zulaika.

Since its inception in 1987, physician Daniel Zulaika has been the coordinator of the Osakidetza AIDS Plan. Ed. : Daniel Zulaika.

From these experiences, clinical guidelines are published. In them it is recommended to combine this type of medication, avoid its administration once and for all, even aiming to take into account depending on the clinical status of patients, etc. Each country has its own guides. There is a European guide and scientific societies use their guides...

The European AIDS Clinical Association (EADS), for example, has on its website a guide for the treatment of adult patients infected with HIV. The guide offers different patient treatment options. In general, it recommends using two-nucleotide analogs along with another reverse transcriptase or enhanced protease inhibitor.

Since there is more than one drug per type, it offers different possible combinations and determines in which cases each of them should be used or avoided. The clinical situation of patients is taken into account, that is, if they are pregnant, have cardiovascular risk, have developed another disease, etc.

"However, it can be said that all guides are equivalent," explains Zulaikak--. If the guidelines are equivalent, I would say that all developed countries use more or less equal therapies." Nor has he noticed significant differences in the process of introducing medicines into health systems: "Sometimes the United States has been a little more advanced than the rest of the countries, but sometimes not."

The fight against AIDS has also developed in administrations. Proof of this development is "spending on antiretroviral treatments," says Zulaika: In 1997, 9 million euros were invested in the ACBC and 36.9 million in 2009. This amount accounts for 1% of the total expenditure of the health department. "It is terrible," says Zulaikak--. Note that the health department spends one-third of the overall ACBC budgets. All that money is invested in 4,600 patients."

Annual expenditure per patient has doubled practically in this period: It goes from 4,100 euros to 8,015 euros. "There are more and more patients and treatments are increasingly expensive. They are more expensive as they are more efficient."

This expenditure has improved the survival and quality of life of patients, to the extent that 25 years ago it could not be imagined. It should be noted that "at first it was thought that treatments would be of little use," says Zulaika. Thanks to them, AIDS is now a chronic disease. It is true that the virus has not been eliminated from the infected body. However, keeping the amount of virus controlled, the immune system of patients is not reduced, so there are no other diseases that ended up causing the death of patients.

Better prevention in the absence of vaccines
Since AIDS was first described, researchers are trying to create an HIV vaccine. If they did, and if they did, it would be impossible for the virus to develop the infection, since our immune system would go against it.
However, they have been working on the development of the vaccine for more than 25 years and have not yet achieved it. Unlike other infectious diseases, there is a protective mechanism that can have the same function as the vaccine: prevention. That is, having safe sex and not sharing syringes when taking injected drugs.
Daniel Zulaika, coordinator of the Osakidetza AIDS Plan, said in a digital meeting organized by Diario M dico.com on prevention: "The 1990s was a decade of safe sex, as society saw AIDS killing millions for failing to take preventive measures. Death was the engine of change. Now, however, AIDS is a chronic disease that I believe has led to the disappearance of fear and the disregard of safe sex. As a phrase commonly used in the field of health says, 'for every step in treatment two steps are taken back in prevention'. It has been an unexpected consequence."
HIV infections by their way
More and more patients are taking antiretroviral therapies. This is good news as it indicates that patients survive longer and longer. However, antiretroviral treatments have not prevented HIV from infecting a new part of the population every year. That is the negative reading that there are more and more patients.
In the Basque Country, pollution rates by Autonomous Community or Region vary since 2003. The highest rates are recorded in the ACBC, with 6.9 and 9.4 citizens per 100,000 inhabitants, each year, in the period 2003-2008, as reported by the Carlos III Institute. In Navarre, for its part, the rates range from 4.7 to 6.4 per cent thousand inhabitants in this period (information from the same source) and between 5.2 and 6.9 in Aquitaine (source: InVS, Orsa). In 2008, 199 people were infected with ACBC and 29 in Navarra. In Aquitaine, for its part, 164 have been contaminated in 2007, the most recent data.
However, the amounts of pollutants that are contaminated each year were much higher a few years ago. In Navarre, for example, the pollution rate reached 32.3 pollutants per 100,000 inhabitants in 1987. Then nothing was known about HIV, AIDS and transmission routes.
(Source: National Centre for Epidemiology, Department of Health and Consumer Affairs of the Basque Government E InVS-Explotation: Orsa.)
As for the routes of contagion, in those early years AIDS was considered a disease that was contagious between drug addicts and homosexuals. In fact, most of the pollutants were observed in these population groups. Today, however, the situation is completely different. More than half of the reported cases of pollution occur through heterosexual sex and injected drug infections do not reach 15% in most cases.
The infectious pathways and proportions recorded in men and women are different. Gay sex infections, for example, are considered only in men. Thus, although it can be said that between 75% and 85% of the annual infected in the whole of Euskal Herria are sexually infected, in men approximately half of that percentage is attributed to heterosexual relations and the other half to homosexuals. Women, for their part, claim that all sexual transmission occurs through heterosexual relationships.
On the other hand, in Iparralde and Hego Euskal Herria the proportions of injectable drugs are different. Aquitaine is the municipality where more people are contaminated and more women (15.9% and 20.8% respectively) than men. In Hego Euskal Herria, on the contrary, they do not reach these proportions and it is more men (between 11 and 12%) than women (between 3.5 and 6%) who are contaminated by injectable drugs.
Lakar Iraizoz, Oihane
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