Better anti-AIDS drugs in the doctor’s eyes could stop HIV from being inserted into the human genome.

Before today’s article begins, let’s take a look at a photo. The guy in the photo is Raif Derrazi from Los Angeles. What words would you use to describe him? Sunshine, handsome, warm people… Indeed, Rifford is a bodybuilder, but he is also an HIV-infected person! I can’t imagine, he looks healthier than the average person.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Raif Derrazi and his little niece

Seven years ago, Rifford was diagnosed with HIV on his 27th birthday. At first he was depressed, but under the support of his family and under the guidance of doctors, he began to actively treat, take medication on time, and took good control of his condition.

Three years ago, Rifford made the bold decision to make a video of his experience, post it on social networking sites, share the real experience of treating HIV infection, knowledge about AIDS, has been broadcast on YouTube more than a million times, and tens of thousands of followers on Instagram, becoming a “one”. Internet celebrities.”

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

In July 2018, Rifford’s attending physician recommended the best anti-AIDS drug available, the Pitutovi, which can effectively suppress the virus by simply taking a pill the size of a nail cap daily.

Under the treatment of Bidtovi, the HIV in Rifford’s blood is now undetectable, which means that it is largely uninfectious, i.e. u-U(Unabledetect- Unintransmittable).

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Comparison of the size of the same type of anti-AIDS drug

So what’s the story behind this anti-AIDS drug? It starts with HIV.

Sniper “Pretender”

We know that HIV is the cause of AIDS. The virus, which is only about 100 nanometers in diameter (about one thousandth of the diameter of hair), is actually a heart-heavy “pretender”.

HIV needs to use human cells to reproduce (replicate), and its genome is different from normal organisms, two RNAs. Therefore, the proliferation of viruses actually requires the transmission of genetic information from RNA reverse currents to DNA, and then from DNA to RNA.

In this process, HIV completes the process of identity conversion (reverse transcription), dive into command (integration), and expand the team to strike again (mature) with the help of the three magic methods of reverse transcriptase, integration enzyme and protease. Therefore, inhibiting these three key enzymes can inhibit the reproduction of HIV, reducing the harm of HIV to the human body.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

HIV replication cycle schematic

Since 1981, when the CDC officially named AIDS in the United States, humanity has been in a long war against HIV.

In 1987, zidoovin, a drug against transcribes, was approved by the FDA, becoming the first anti-AIDS drug to be marketed. Since then, a variety of anti-transcriptase inhibitors and protease inhibitors have been listed.

In the 1990s, The “cocktail therapy” proposed by Chinese-American He Dayi, through the use of several antiviral drugs, effectively inhibited THE replication of HIV, reduced the risk of drug resistance, so that the mortality rate of AIDS patients dropped sharply.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Picture source . . . pixabay

In 2006, AIDS treatment ushered in the era of mono-tablet regimens (STR). The combination of several drugs into a single drug STR, in optimizing the drug ratio, to ensure the safety and tolerability of long-term drug use on the basis of making it easier to take the drug. AIDS has gradually become a preventable and controllable chronic disease.

However, the high one foot of the magic, for HIV such a “smart” virus, the emerging problem of drug resistance so that most of the existing drugs greatly reduced the effectiveness of human ityes are in urgent need of a new target of antiviral drugs. At this point, years of study of integrated enzyme inhibitors were put back on the agenda.

As mentioned earlier, the integration enzyme is responsible for the process of diving into the command during HIV replication, i.e. the reverse-transcribed viral DNA (cDNA) is inserted and integrated into the dna of the host cell.

This process is actually very sophisticated, not only need to integrate enzymes but also cell cofactors, metal ions, etc. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The two main steps are 3′ processing, which occurs in cytoplasm and chain transfer.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

3′ Machining and Chain Transfer Schematic

The so-called 3′ processing is a cut at a specific point at the cDNA 3′ end, exposing the highly conservative CA end, which is like a key, while chain transfer is the integration enzyme to cut the host DNA can be paired with the CA end of the incision, so that cDNA can be integrated with the host DNA, successfully sneaked into the command.

Since the integration process is so cumbersome, then in theory, we have the opportunity to block the integration of HIV in different links, such as interference with integration enzymes and cofactor binding, blocking 3′ processing, blocking chain transfer.

In fact, in the 1990s, scientists did find a number of substances that inhibited DNA integration in biochemical experiments, such as chrysanthemum acid, coffee acid ethyl, oligonucleotides, and so on.

However, they can not block the integration of HIV in cell experiments, nor can they inhibit the replication of the virus in cells. Helplessly, scientists had to put the research on integrated enzyme inhibitors stranded.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Photo source: pexels

The turnaround came in 2000, when a paper published in the journal Science brought the development of integrated enzyme inhibitors to Sugon.

U.S. scientist Daria Hazuda led the team to discover a range of substances that contain diketon acid groups and inhibit HIV replication, and that their target is the integration enzyme.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Daria Hazuda

Photo source: nature.com

Specifically, these substances can specifically block the key step of integrating enzyme catalysis, the chain transfer reaction, so that the DNA of the virus is degraded or formed a ring structure, thereby irreversibly blocking the HIV infection process.

Inspired by this, three integrated enzyme inhibitors (INSTI) have been introduced: raltegravir, elvitegravir and dolutegravir.

These drugs are also combined with drugs for reverse transcriptase that form a compound monotablet for HIV treatment. Although they show good antiviral effects, each of the three drugs has its own drawbacks.

For example, latiravir needs to be taken orally twice a day to reduce the patient’s compliance, and Avirevir needs an enhancer to increase its drug exposure concentration, and there is cross-resistance with latilau. Some people living with HIV who take dotrivir will stop taking medication for insomnia, anxiety, depression, gastrointestinal discomfort, etc.

All this is calling for a simpler, more effective and safer INSTI drug, which has been achieved by the efforts of Gilead’s scientific research and development team.

Simple and extraordinary little pills.

Since 2011, researchers have been working on new INSTI drugs.

They first analyzed and compared the structure of the existing INSTI and integrated enzyme contact interface, then modified and synthesized different substances, carried out plasma half-life, solubility, effective inhibition concentration of HIV wild strains and clinically isolated mutant strains, and finally a substance code-named GS-9883 came to the fore. It was later bictegravir.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Biktirawe Chemical Structure

In preclinical studies, Biktiravir not only can effectively inhibit the transfer of integrated enzyme chain, and viral integration enzyme/DNA complex solution half-life of up to 38 hours, can long-lasting inhibit the activity of the integrated enzyme, and is still effective for some of the existing INSTI-resistant strains. In addition, its plasma half-life is about 18 hours, which means it can be taken once a day.

The study also found synergies between Biktilave and nucleoside anti-retrovirus inhibitor enbutan/propofol innitorynove (FTC/TAF) to enhance anti-HIV effects.

Be aware that the FTC/TAF is an effective HIV backbone drug, and TAF is a precursor drug that can be given in low doses and improve sliver and bone safety to meet the long-term treatment needs of people living with HIV.

As a result, the three-drug compound mono-disc preparation Bitovy (Biktarvy, Biken propien tablet) was born, it is currently based on the integrated enzyme inhibitors of the smallest combination of combination single-chip preparation.

A nail cap-sized bidtovi (15mm x 8mm) with 50mg bikitilave, 200mg of entrotabin (FTC) and 25mg propofol tenofovir (TAF).

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Photo source: pexels

So, what is the effect of the treatment of HIV by the bitovi? This requires clinical studies to prove it.

In 2015, four clinical Phase III studies on bidtovi were formally launched, comparing the combination of bitovi and the combination of dotrilave, the first-line treatment recommended in many of the guidelines at the time.

Of these, 1489 and 1490 clinical studies were conducted in adults with first-time treatment of HIV-1 infection, and 1844 and 1878 clinical studies were conducted in adults with a treatment of HIV-1 infection with virological inhibition.

The results of 48 weeks showed that the pitovy treatment group reached the primary virological endpoint index of non-disadvantage. No subjects developed therapeuticly induced virological resistance in the Pretovesive treatment group, and none of the subjects were discontinued due to adverse events in the kidneys, bones, or liver.

It should be noted that there is a risk of hypersensitivity to the joint treatment regimen (dotirave/abaclaw/ramifdine), which requires HLA-B-5701 genetic testing prior to use and the need to determine whether the patient is co-enticing hepatitis B infection.

In contrast, Itutovi has great simplicity: there is no need for genetic testing, and no need to distinguish whether patients are co-infected with hepatitis B (propofol tinofovweben is the recommended first-line medicine for chronic hepatitis B in Europe and the United States). As a result, treatment can be initiated quickly after clinical lying of HIV infection.

Better anti-AIDS drugs in the doctor's eyes could stop HIV from being inserted into the human genome.

Photo source: pexels

After that, Bidovi reported it.

In February 2018, the FDA was the first to approve the listing of Bidov, and four months later, Ituve was approved by the European Commission.

In the same year, bidovi was also listed as the preferred option for antiretroviral treatment for first-time HIV infections by the United States chapter of the International Antiviral Association (IAS-USA).

In August 2019, just 18 months after the FDA approved the listing, Bidovi obtained approval from the Chinese Drug Administration for the treatment of HIV-1 infection sinomas as a complete program, and that patients have no evidence of viral resistance to integrated enzyme inhibitors, entofaorbins, or noofforvirs.

At the recent 17th European AIDS Conference, Bidovi had good news.

The latest results of clinical studies of 1489 and 1490 showed that the non-disadvantage of the treatment of bitovi continued to be similar to that of the virological inhibition in the control group at the 144th week of treatment.

In terms of safety, no patient with treatment resistance and good tolerance were in no patient within 144 weeks of the treatment, and the rate of discontinuation due to adverse events and drug-related adverse events were lower than in the control group.

This result adds strong data support to the long-term efficacy and safety of the bidov. In addition, the 48-week clinical study of bitovi for the treatment of adolescents and children and women living with HIV also showed that bitovi therapy maintains virological inhibition and is drug-resistant.

On January 11, 2020, “Return to Normal freedom rebirth” Biduwei China listing ceremony was held in Beijing, which marked the official welcome of China’s HIV-infected people.

As of October 2019, 985,000 people reported surviving HIV in China, and 131,000 new cases were reported in January-October 2019.

Facing the serious challenge of AIDS prevention and control in our country, I believe that only one piece of oral medicine every day, no food with the same service restrictions, strong and safe must-have, will bring a new treatment experience to people living with HIV, to maximize the return to normal life.

Resources:

https://www.youtube.com/watch?v?ApXvIUPe24s

https://www.ema.europa.eu/en/documents/product-information/biktarvy-epar-product-information_en.pdf

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Post F A, Yazdanpanah Y, Schembri G, et al. Feacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disopyil furoxa (FTC/TDF) as ressed adults: subgroup analysis by third third agent of agent of randomized, double-blind, active-controlled phase 3 trial.j. HIV clinical trials, 2017, 18 (3): 135-140.

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[16]https://www.gilead.com/news-and-press/press-room/press-releases/2019/8/china-national-medical-products-administration-approves-biktarvy-bictegravir-emtricitabine-and-tenofovir-alafenamide-for-treatment-of-hiv1-infect

https://www.gilead.com/news-and-press-room/press-releases/2019/11/gilead-led-tarvy-high-efficacy-with-no-biks-of-treatment-in-phase-3-clinical-trials

http://www.nhc.gov.cn/jkj/s3586/201911/c2388ce70bdd404ea6dfcd8886591784d.shtml

The author of this article . . . WXY707