The Russian scientist, part of Rospotrebnadzor, announced the high effectiveness of the vaccine he created against the human immunodeficiency virus - HIV.
Thus, in our country, for the first time in the world, the problem of developing an effective vaccine against the “plague of the twentieth century,” which has been unsuccessfully pursued for more than thirty years, has been solved. In this, domestic scientists were helped by their own knowledge, a new approach to creating the active element of the vaccine, and several modern technologies that became available quite recently.
Read about Russia's latest success in biotechnology in FAN's .
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“Killer” lymphocytes and “VDNKh” on the cell
“HIV-specific antibodies and cytotoxic T-lymphocytes after double vaccination were recorded in 100% of volunteers,” the press release said.
What does this phrase mean, translated from the language of technical terms into our everyday language?
HIV is a very dangerous enemy of our immune system. One of its features is that it belongs to the type of so-called retroviruses. Unlike ordinary viruses, which use only their RNA genome for reproduction, retroviruses are much more dangerous: their genetic code is integrated into our cells in a special way, “cutting” human DNA and integrating into chromosomes.
In this form, classical antibody proteins are useless against the virus, since its harmful genome is hidden deep inside our own cell. Because of this, some skeptics among microbiologists even came to the pessimistic conclusion that it is impossible to resist HIV itself - you can only try to delay its total infection of humanity with the help of various quarantine measures for those already infected.
In fact, as it turned out, the body also learned to fight such viruses and other intracellular parasites, creating a second immune system. For such a case, we have special immune cells, the so-called killer T-lymphocytes, the same “cytotoxic T-lymphocytes” from the Vector press release.
The mechanism of action of T-killers is somewhat different from classical antibody proteins, which simply block viral particles using the “key-and-lock” principle, literally clinging to them on all sides and thus deactivating foreign viral particles. Instead, killer T cells constantly "inspect" our body's cells, checking what proteins they assemble inside themselves, in their cellular protein factories.
To do this, any of our cells has on its outer surface an entire “exhibition of national economic achievements”, in which there are samples of all the main proteins that it is currently producing. If a cell is infected with HIV, which has secretly integrated into its DNA, then the viral proteins will also end up on such a cell “VDNKh”.
If the killer T cell is tuned to important HIV proteins and begins to recognize them as harmful, then it will be able to issue a special command for the so-called apoptosis (self-destruction) of the infected cell. This is an unconditional order “Die!”, which any of our cells must fulfill. Therefore, apoptosis must be adjusted very precisely so that killer T cells kill exactly the infected cells, and not all those “that come their way” in the production of unknown proteins.
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How it will turn out
In his review of this situation, Harvard immunologist Bruce Walker calls it "a cause for hope" - and, perhaps, at this stage, it does not yet claim to be more than that. After all, experiments on monkeys do not guarantee success in humans, and simian cytomegalovirus and immunodeficiency virus are not identical to human ones.
So far we have only one work at our disposal, during which researchers in vitro
partially replicated the success of this vaccine in human cells. They collected T cells from the blood of healthy donors and found among them those that are able to bind to MHC-E on the cells - and kill them if they are infected with HIV. Thus, it was possible to confirm that human T-lymphocytes are, in principle, capable of working in the same way as macaque T-lymphocytes, but to what extent this will work in reality is still completely unclear. The clinical trial that should clarify this is still recruiting volunteers - healthy people who will be given the experimental vaccine and tested to see if they develop a T-cell response to HIV.
At the same time, even if the first phase is successful, the vaccine's creators will have to figure out exactly how it works. So far, strictly speaking, it is not entirely clear why HIV proteins presented in the MHC-E “crust” cause a more successful immune response than if they are shown to lymphocytes as part of MHC-I. There is a suspicion that the issue here is in the structure of the passports: the “cover” of MHC-I and MHC-E contains different fragments of viral proteins. Since cells typically present them to the immune system as part of MHC-I, it is these regions of proteins that quickly evolve and become diverse—and elusive to a vaccine. And MHC-E may bind to other fragments that are more similar among different HIV variants - and if this is so, then the vaccine may turn out to be universal.
But even if this hope does not come true, the developers have one more in stock. Those features of cytomegalovirus that were revealed during these studies actually make it possible to switch the immune response. That is, the creator of the vaccine, by manipulating the genes of the cytomegalovirus vector, can now choose through which of the MHC passports the cell will show its contents to the immune system. And perhaps other vaccines will appear - viral, bacterial or tumor - for which it will be important in what “cover” unfamiliar proteins are presented to the immune system.
Polina Loseva
HIV is changing - that's why it's taking so long
Why, then, did it take so long to make a vaccine that would form antibodies against free particles of HIV and its “hiding” harmful DNA?
The fact is that to date, about 200 different strains have been discovered in the human immunodeficiency virus, which are conditionally combined into four large groups, divided into 14 subgroups. By comparison, a virus as dangerous and prone to mutation as regular influenza A has only 14 major variations.
This unusual situation is associated with an interesting feature of HIV: the enzymes encoded by its genetic sequence are quite “inaccurate” and cannot track frequent errors during virus replication, which, in addition, create new mutations in the virus genome.
By the way, many antiretroviral drugs are based on this property - they introduce errors into the process of replication of our DNA, which human enzymes easily recognize and eliminate, but viral enzymes cannot. As a result, although the antiretroviral drug does not destroy HIV and does not remove its code from DNA, it very reliably blocks its reproduction in the body - the virus cannot assemble its proteins into a new viral particle.
However, a working vaccine must not only block the virus; its task is precisely to destroy all its copies, obvious and hidden. And for this it was necessary to find the so-called “conservative” proteins, which are the same in all more than two hundred strains of the virus that causes AIDS.
Relatively speaking, if you found a protein that “makes HIV HIV” and forced antibodies and T-killers to react specifically to this protein, then you have practically created the vaccine itself.
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Academician of the Russian Academy of Sciences told when a drug that completely destroys HIV will be ready
“Everyone understood that our country was at risk”
— Why did you decide to devote yourself to this particular disease in the 80s?
— By this time, I had already spent 21 years studying, graduated from medical school, was involved in the development of vaccine drugs, defended my dissertation in immunology, and then also studied epidemiology. I was a fairly well-educated specialist in the field of infectious diseases. And at this time, a new disease appeared, which at first was considered as purely immunological - it was called acquired immunodeficiency syndrome.
It was only around the end of 1983 that it became obvious to specialists that this was an infectious disease. And according to my education, I was just the most suitable.
The task was to find out: is there HIV/AIDS in Russia? How much of a threat does he pose to the country? The institutes of immunology, virology and our epidemiology - we all took up this problem. Immunologists looked for people with immunodeficiency, virologists tried to isolate the virus.
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Head of the AIDS Center Vadim Pokrovsky during a press conference, February 26, 1997
TASS
- Was there an opportunity to exchange scientific developments with Western scientists?
— At that time there were no electronic means, so everything was distributed by mail, in magazines. It was possible to find all the journals only in the Medical and Lenin libraries. There, too, we had to do some serious work.
We started working at the end of 1984. They examined 200 thousand suspicious patients with immunodeficiency for immunity, found several children who seemed to have AIDS, but they did not have HIV. The Gamaleya Institute had a very large archive of sera - they began to test them for antibodies, did 200-300 thousand tests, and did not find the presence of the virus anywhere. Therefore, there was an amazing situation that it seems like there is HIV all over the world, but in Russia there is no HIV yet.
Then came statements that AIDS was a disease of American homosexuals. And since homosexuality is criminalized and prohibited in our country, this disease does not threaten us, as some have said.
Here, unexpectedly, as always happens, material from a sick African was suddenly brought to a neighboring laboratory - and it turned out that he had an immunodeficiency virus and an AIDS clinic. It was the end of 1985.
He came from South Africa to study at the Trade Union School. Such a healthy guy - he fought in South Africa against the whites. He had a lot of sexual contacts in different countries. But he was in no way suitable for a homosexual. After that, our group examined all foreign students in Moscow - we found about 50 more people from different countries infected with HIV, but not with AIDS.
And only at the end of 1987, when I was giving a lecture at a medical institution, one very young resident suddenly decided that a patient from her clinic just fit my description of the patients. Although the authorities laughed, she still managed to convince her to show this patient to our specialists. It turned out that he was really sick with HIV infection; he had Kaposi's sarcoma - one of the manifestations of AIDS. He is considered our first patient. He was homosexual and also found himself connected to Africa.
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Senior researcher at the laboratory, Candidate of Medical Sciences Vadim Pokrovsky and junior researcher Alexey Pletsitny answer anonymous calls to the Central Research Institute of Epidemiology, June 1, 1987
Roman Poderni/TASS
Five years ago he had symptoms of acute respiratory infections and rubella - this was the acute stage of HIV infection . It goes away after a few months or even a few days. But the virus does not go away - immunodeficiency develops over many years.
During this time he had about 25-27 sexual partners. I then had to look for them all in Russia.
Of these, five turned out to be infected, one was a donor, blood was transfused from him to five people - they also became infected. One of the infected women's husband became infected. One child became infected from one child due to violations of the anti-epidemic regime in the hospital. Then this child, infected in the hospital, grew up and infected three girls. In general, a whole chain has formed.
We showed it to the authorities - everyone understood that our country was at risk. Moreover, not only homosexual but also heterosexual couples were included in the chain, and even nosocomial cases of HIV transmission were recorded.
After this, truly massive work to combat HIV began in the country. We started checking all donated blood.
At the end of 1988, we identified a female donor in Elista, Kalmykia. What was very surprising was that she did not have any acts of risk. The husband was not infected. The only thing: she was in the hospital with her child, and he recently died of some kind of septic disease.
And then they identified a child who was also lying in this hospital in the same room with the deceased child of this donor woman. Here I was again unwinding everything, conducting an epidemiological investigation. It's almost like a detective action. But since the routes of transmission are limited, it is unlikely that a child could become infected through sexual contact. The blood of almost all donors in Kalmykia was examined - no one was infected.
Means what? Probably a hospital. I requested materials from all the children who were hospitalized at the same time as these two, and to horror it turned out that out of 13 sera, 4 were positive - it became clear that this was a nosocomial source of transmission. That is, we urgently need to go to Elista, get documents, identify all the children who have been in this hospital for a year, examine them all, establish who was in the same ward with whom. About 70 people who visited this hospital were infected.
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Health workers go to the residents of the city, whose children could have come into contact with HIV-infected people within the hospital walls, Elista, February 4, 1989
Konstantin Tarusov/TASS
Later it turned out that in May 1988 a child there also died of AIDS, his father and mother were infected. That is, the virus was transmitted from the father to the mother, and the mother passed it on to the child. This man himself served in the navy back in 1981, and they were stationed in the Congo port for several months. The country was poor, women could only earn money through prostitution. And the cost of sexual services was very low, so our soldiers could afford it. That's how they got infected.
It turned out that not only foreigners, but also our citizens who worked abroad brought the virus to the USSR.
But we can't say that this man was patient zero - apparently there were several.
— And what was the management’s reaction to all this?
“We reported everything to the authorities.” And then the head of the Ministry of Health, Yevgeny Chazov, announced the creation of a system of centers to combat AIDS. Now it was certainly clear that not only American homosexuals could get sick, but everyone.
The population was terribly worried. I was invited to a local television studio along with the Minister of Health. We tried to explain the situation there. I was very careful to say that this was most likely due to nosocomial transmission. The minister was grunting something there. And then in the evening, when I had already arrived in Moscow, I turned on “Vremya” at 21:00 and saw a report from Elista.
Of course, there was a very strong reaction. Everyone began to fight AIDS. In the summer of 1989, I was invited to the popular channel “Before and After Midnight.”
And there, for the first time on our television, I said that a condom protects against infection with the immunodeficiency virus. It was a terrible sensation. On Soviet television, saying the word “condom” was unthinkable.
Brief feeling of success
— From the moment the information campaign began, how quickly did the epidemic develop in Russia?
— We had a feeling of success. Until the mid-90s, no more than a thousand patients were registered, although 20 million people were examined per year. This was a very positive result. But then something happened that was no longer in our control.
Until 1993, there was not a single infected drug user, but in the mid-90s the number of drug addicts increased sharply. There was a slogan: “Get rich!”, and the easiest way to get rich is to distribute drugs. Opium, and then it was replaced by heroin.
There was a terrible wave of drug addiction. They told me in one area: “We have this sign: as soon as a drug dealer appears in the village, the district police officer begins to build a new house.” Every spring, when cleaning the area, I always found a dozen used syringes in front of the dacha.
If in 1989 there were 30 thousand drug users in Russia, then by the mid-90s they were already talking about 2-4 million users. And then the virus hit this group. And if they use one syringe, then the blood remaining in the syringe is enough to infect the next person who uses that syringe. The same thing happened in Elista, only on a smaller scale: sisters sometimes used one syringe to get the job done faster.
— But then people already understood that the virus is transmitted through blood?
- Yes, but not drug addicts. As soon as the virus entered their environment, it began to spread instantly. And somewhere in 2001 there was a peak - 87 thousand cases per year. A terrible epidemic has begun.
And after all, if a person becomes infected with HIV, he will remain infected all his life. Coronavirus - someone recovered, someone died, but the disease goes away, the virus disappears. But there is no HIV. A person can feel well until the age of 20 or more, but still be infected and infect their partners.
People are irresponsible, they have a lot of sexual partners, so somewhere in the mid-2010s, sexual transmission began to predominate in our country: not homosexual, but heterosexual.
And according to the latest data, about 60% of new cases are sexual transmission from man to woman, from woman to man. Drug addicts - 35%-40%, but male same-sex sex - approximately 1-2% of new cases.
— But society still maintains the idea that this is still a disease of gays and drug addicts?
- Unfortunately yes. At the same time, the danger for everyone has increased significantly. Moreover, we have other misconceptions: for example, that HIV is transmitted through casual sexual contact.
It turned out that it is not transmitted so often in principle, so it happens that one contact is not enough. But if people live together for a year or two, it is in such cases that the virus is transmitted.
It seems that people do not cheat on each other for a year, live with only one sexual partner, then quarrel, live for 3-4 years with another. This is now one of the main cases of transmission - in science it is called “serial monogamy.”
When will a drug appear that completely destroys the virus?
— How has therapy developed since the 80s: how were people treated then and how are they now?
“We treated the first patient with a domestically produced antiviral drug, azidothymidine. It showed quite pronounced effectiveness. Our patient was the first with AIDS to live another 5-6 years after diagnosis - this is quite a long time.
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Department of HIV-infected people in a Moscow maternity hospital, January 1, 1990
Valery Khristoforov/TASS
- What else was treated?
- Mainly, with various antiviral drugs, because very soon it became clear that all these vaunted immunostimulants and immunomodulators do not have any effect on the condition of AIDS patients. They even often make things worse.
It turned out that only antiviral drugs are effective. They first suppress the virus, it stops affecting the immune system, and even it is restored. Even people with AIDS are regaining their ability to work.
But this was only achieved in the late 90s, when they decided to treat not with one antiviral drug, but with three or four. And now this is the main method of therapy. Because if you take one drug, it has an effect for a couple of months, but then the virus develops resistance. And if you give three or four drugs - now, however, sometimes two are enough - then they completely suppress the replication of the virus.
It does not reproduce, so resistant forms do not form. And a person can live to a ripe old age.
We have one patient, a very famous artist, who became infected in the late 80s, and in 1997 he developed AIDS. We started treating him as one of the first with this method, as we called it, highly active therapy. He lived another 20 years and died not from AIDS, but from a heart attack. And this is now a completely common thing.
— Are they treated now with domestic drugs?
— Most of the drugs were developed abroad, but copies of these drugs, generics, are also produced in Russia. But I must say that this is no longer a very promising path, because these drugs block the enzymes of the virus, but do not kill it.
Now a completely different group of drugs is on the way - gene therapy. Why can't HIV infection be cured? Because the virus inserts itself into the genome of a human cell. The drugs do not allow it to come out. But as soon as they are canceled, the virus again begins to produce new particles of its own, they again attack immune cells, and the development of immunodeficiency begins. Therefore, the main thing now is to find a way to complete recovery. Kill the virus that is inside the cell genome.
— Are scientists close to this?
— Yes, there are a lot of developments - they are tested on animals.
Some drugs from this group are already being tested on patients, but, of course, it will still take 5-10 years before they are available to all patients around the world. But not before, unfortunately.
“The Ministry of Health does not use the word “condom” at all”
— How did the HIV epidemic develop in Russia during the year of the coronavirus pandemic?
- Much fewer people came for examinations - laboratories that usually carried out tests for AIDS were working for coronavirus. Doctors were also relieved of duty to fight the coronavirus. Last year, only 60 thousand new cases were detected, a year earlier - 80 thousand, and two years ago it even reached 100 thousand new cases. Therefore, I do not rule out that there may be a slight rise next year. Those who were not identified in 2021, 2021 will be identified.
But be that as it may, the numbers are very large - in Germany there are only 1.5 thousand cases per year, and we have 60 thousand.
I think the problem is that we don't have a proactive campaign to prevent new cases. Yes, 99.3% of the budget - and we spend about 65 billion a year on fighting AIDS - is spent on diagnosis and treatment. While the cost of preventing new cases is literally pennies, several hundred million for Russia. And most of it is spent on prevention - calls to get tested. That is, it turns out to be a vicious circle: we do not prevent new cases of HIV, but only diagnose and treat them.
Moreover, some specialists from the Ministry of Health are making aggressive statements: for example, that condoms do not help. The Ministry of Health does not use the word “condom” at all: neither “condom” nor “condom”. Although, according to the UN, they saved 120 million people from HIV infection.
About five years ago the rhetoric was so aggressive that television even refused to advertise condoms because it was afraid of public condemnation. Now advertising has already appeared in the evening, we managed to turn the situation around a little. That’s why we have to fight even for such simple things.
— Besides protected sex, what other issues should you be vigilant about?
- Under the same medical procedures. It is clear that the patient cannot always keep track of what tools the healthcare workers use. Make sure that disposable consumables are opened in front of you. The same applies to all cosmetic and dental procedures.
All these organizations are commercial; in order to reduce costs, they may not carry out disinfection and reuse the same needle.
On the one hand, a person should not be passive, and on the other, everything should be under the strict control of the sanitary and epidemiological service. There are also certain problems here, because now the sanitary and epidemiological station cannot just come. She must send a message in advance that we will come on such and such a date and will check you. As they say, you can prepare. Therefore, people themselves must report violations of the regime - then there will be an effect.
Particle decoy
The problem of identifying conserved proteins that are the same for all types and subtypes of HIV was solved in the early 2010s. The first experiments with a vaccine based on such proteins took place back in 2011, and permission for clinical trials of the vaccine, called CombiHIVvac, was received by Vector in 2013. Moreover, specific antibodies and the reaction of T-killers were registered almost immediately. However, the vaccine then entered a lengthy process of clinical testing and development.
Note that the task of fine-tuning the effect of the vaccine, as already mentioned, is a much more responsible process than simply identifying the desired viral protein. The vaccine must ensure the destruction of infected cells and block free HIV particles - but at the same time have minimal or no effect on the immunity itself. After all, as we know, HIV “loves” our immune cells, parasitizing them and destroying them from the inside.
Simply put, it was necessary to learn how to kill infected “zombie cells”, but in no case destroying healthy ones and, especially, without accidentally infecting them with a vaccine built on the same dangerous viral proteins.
Due to this approach, the option of using dead and weakened HIV was initially eliminated - it created the risk of accidental infection with the vaccine. Instead, Vector synthesized an artificial virus-like particle, on the surface of which two conservative proteins from HIV were placed in large quantities. An ordinary HIV viral particle “hides” these proteins, and killer T cells have difficulty forming a response to their presence in infected cells. And the virus-like particle created by Vector, on the contrary, put them on display, and even in huge quantities, which easily formed an immune response.
As a result, CombiHIVvac became not only a preventive, but also a therapeutic and therapeutic vaccine. It creates an immune response that destroys not only free viral particles, but also those cells of our immune system that are infected with HIV.
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What is the result?
Many media outlets today released news items with headlines stating that “the Russian HIV vaccine is effective,” or even “100% effective.”
But the only thing we know today about the performance of CombiHIVvac is the results of the first phase of its trials, published in 2021 in the journal Bioorganic Chemistry.
The first thing that is tested during clinical trials of a vaccine is safety. In their article, the organizers of the experiment report that they did not notice any pathological changes or even local reactions in the volunteers.
The second thing to measure is immunogenicity, that is, the ability to trigger an immune response directed against the desired virus. According to the authors of the work, all volunteers had antibodies to at least one of the standard set of HIV proteins. In addition, 100 percent of the participants had HIV-specific T lymphocytes, which, when encountering the virus, began to produce the antiviral protein interferon gamma.
Many also found neutralizing antibodies - that is, those that not only stick to the surface of the viral particle (this does not stop the virus), but also prevent it from penetrating inside the cell, preventing infection. Therefore, we can assume that the majority of subjects had an immune system that responded to the vaccine.
There is only one “but”. Antibodies from the blood of volunteers neutralized different subtypes of the virus with varying effectiveness. Six months after vaccination, the A/392 variant could “neutralize” the antibodies in 71 percent of the participants, and the B/PV04 variant could only neutralize the antibodies in 29 percent. And a year after the injections, none of the subjects had these antibodies left in their blood.
Shield vs Sword
We will remember 2020 not only for the COVID-19 pandemic, but also for the extremely short time frame for creating effective vaccines against the new coronavirus. Humanity today not only faces the challenge of new dangerous viral infections, but also already has in its hands an effective weapon against them - these are vaccines that can tune our own immunity to fight viruses.
Overall, the “sword and shield competition” is just beginning. It will use naturally mutated or artificially created viruses as a sword, and vaccines as a shield. Experts are still not sure how COVID-19 entered our world: was it a random mutation of a natural virus or, what looks very alarming, an artificial, human “development”? Therefore, now we live in a world of constant, albeit irrational, fear: what if, in the unknown future, an infection worse than the new coronavirus will come to us, and even one that is tuned to maximum hostility towards us?
But Russia has clearly demonstrated to the whole world that it is capable of creating an effective shield against any, even the most dangerous infection. After all, in fact, our country has just defeated HIV - following the already defeated smallpox, plague and cholera.
What vaccines are recommended for people living with HIV?
- Against Hepatitis B.
- Against Flu.
- Pneumococcal (against pneumonia).
- Against tetanus, diphtheria and whooping cough (DPT) - administered once, in childhood. It is recommended to repeat the tetanus and diphtheria vaccine (TDV) every 10 years.
- Against human papillomavirus (HPV) (people under 26 years of age).
Other vaccines may be recommended for an HIV-positive person depending on age, previous vaccinations, risk factors for a particular disease, or characteristics associated with HIV. Talk to your doctor about which vaccines are recommended for you.
"This is a huge disappointment"
At the beginning of 2021, the third phase of clinical trials of another HIV vaccine in South Africa was stopped. “There is absolutely no evidence of effectiveness. Years of work went into this. This is a huge disappointment,” said South African Medical Research Council chief executive Glenda Gray.
More than 5,400 men and women aged 18 to 35 took part in the trials. Among those who received the vaccine, 129 people became infected with HIV, and among those who received the placebo, 123 people became infected, the scientific journal Science reports.
In a trial in Thailand in 2009, the same vaccine was found to be 30% effective. That is, 51 people who received the vaccine and 74 people who received the placebo became infected with HIV.
It turned out that the vaccine leads to the formation of antibodies in the body that bind to the causative agent of the disease, but do not neutralize it completely.
Experts agreed that this was not a sufficient level of protection to bring the vaccine to market, but trials continued. “We jumped at the slightest positive effect,” explained Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), at the time.
Mosaico is currently undergoing clinical trials in North America and Europe. They involve about 3,800 transgender people and men who practice same-sex relationships. The vaccine was developed by Janssen Vaccines (owned by Johnson & Johnson, USA). The vaccination is done in two stages. The drug for the first injection is based on a “mosaic” of genes of different types of HIV, built into an adenoviral vector.
The second injection consists of HIV surface protein and an adjuvant. Tests should be completed in 2023.
At the same time, “sister” trials of Imbokodo are taking place in sub-Saharan African countries, which should be completed at the end of 2021. The same vaccine is being studied, but with more than 2,600 women.
Travel and vaccines
If you are planning a trip, you may need vaccinations against a number of diseases: yellow fever, rabies, tick-borne encephalitis or typhoid fever.
If you have HIV, talk to your doctor about vaccines you can get before traveling.
Keep in mind:
- If immunization is required and only a live attenuated vaccine is available, find out how high the potential risks are and whether they outweigh the potential protection.
- If you start treatment but your CD4+ cell count is less than 200, your doctor may recommend postponing travel until ART works and your immune system has recovered.
Lenacapavir: capsid inhibitor
Lenacapavir (GS-6207) is the first member of a new class of antiretroviral capsid inhibitors that inhibits HIV replication by stabilizing and subsequently preventing functional dissection of its capsid in infected cells. The capsid (the shell around the viral genome), required for the successful completion of virtually every step of infection, involves a series of interactions between its proteins and a variety of host cell factors. For example, lenacapavir interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6, which mediate viral nuclear import and direct integration into gene-rich regions of chromatin.
The capsid inhibitor lenacapavir has activity against HIV-1 of all subtypes and HIV-2, interacts synergistically (supplementing and enhancing) with the main classes of HAART drugs, and does not have cross-resistance to other antiretroviral drugs, including maturation inhibitors.
Gilead is actively studying lenacapavir, which is given by subcutaneous injection once every six months. Thus, the phase II/III clinical trial CAPELLA (NCT04150068) was successfully completed, involving HIV-positive patients with multidrug resistance and confirming the justification of adding lenacapavir to a HAART regimen that had stopped working. Sending the registration dossier to the regulator is scheduled for the second half of this year 2021.
The Phase II clinical trial CALIBRATE (NCT04143594), which will test the addition of lenacapavir to various HAART regimens among previously untreated HIV patients, will begin in the second half of the year.
This year, lenacapavir will begin clinical testing of its applicability in the task of pre-exposure prophylaxis (PrEP) for HIV infection. The experimental drug will be tested among cisgender men, transgender women, transgender men and non-binary people who are at high risk of HIV infection and have sex with men, as well as among adolescent girls and young women engaging in heterosexual relationships.
HAART: simple and convenient
A dramatic change in the HAART paradigm began to occur when Gilead introduced the once-daily oral single-tablet Biktarvy (bictegravir + emtricitabine + tenofovir alafenamide [BIC/FTC/TAF]). The new product instantly became a bestseller: 1.18; $4.74 and $7.26 billion in sales in 2021, 2021 and 2021. respectively.
HAART then received a powerful boost from ViiV Healthcare, three-quarters of which is owned by GlaxoSmithKline, and Janssen, owned by Johnson & Johnson: they were the first to The pharmaceutical industry has offered HIV patients incredibly convenient treatment with a long-acting drug.
Cabenuva (cabotegravir + rilpivirine), which is approved in the United States, Canada and the European Union and is given by injection intramuscularly, can be given either once a month or once every two months. In other words, people are finally free from tedious courses of daily HIV pill therapy.
Gilead and Merck & Co., impressed by Cabenuva's ideas, decided to do something similar, but in an oral formulation. At this stage, given the due expertise of the partners, there is no doubt that everything will work out in the best possible way.
The volunteer will be treated as HIV positive
Volunteers will have to undergo regular PCR testing for HIV RNA.
Photo from mv.ecuo.org Russian developers have already encountered difficulties when trying to recruit volunteers. “In St. Petersburg at one time they wanted to create a group of volunteers from sex workers. But they don't really go well. To recruit several thousand participants, you need to work on this for two or three years, no less,” noted Sergei Netesov.
According to him, there is one important reason for refusing to participate in the tests. “After a person is vaccinated, he or she develops antibodies to HIV infection. They will be detected by conventional test systems.
If volunteers do not have some official document that has not yet been invented, they will be perceived by medical institutions around the world as HIV-infected.
They will have to regularly undergo PCR testing for HIV RNA, and more than once, because the disease is too serious,” the expert said.
Another challenge that arises during phase three trials is communication. For ethical reasons, participants are professionally explained how HIV infection spreads and how the risk of infection can be reduced.
“This means that the volunteer will take such precautions as to prevent infection. The control group will be instructed in the same way, and in this group the risk of infection will also be greatly reduced,” explained Sergei Netesov.
So, also for this reason, it will take a very long time before researchers can compare the number of infected people in the main and control groups and summarize their work, he added.
Typically, 6-9 years pass between the start of the first phase of clinical trials and the results of the third phase, according to an article on the WHO website.
