Why are potential HIV treatments never "here and now"?

SSpecialists have cured HIV in mice. They say that a human cure could be next. "

– BON MagazineJuly 13, 2019

"The hope of a cure for AIDS after bone marrow transplant rids the man of HIV"

– The GuardianMarch 5, 2019

"A new breakthrough could cure HIV"

– Fox BusinessMarch 4, 2017

"Scientists are developing a drug that" could cure HIV and AIDS "

– L & # 39; IndependentNovember 3, 2016

These are all exciting titles on the Internet that announce a "cure" for a terrible disease that has been lacking for a long time. These words fuel the expectations and hopes of some 37 million people living with HIV in the world. The best option these people have now is to manage the symptoms of their complex disease as effectively as possible with a multitude of expensive drugs. More and more curative treatments based on genetic manipulation are reported. The most publicized recent example is the March 2019 report in Nature of the second case of long-term remission of HIV-1 in a human patient following a CCR5Δ32 / Δ32 hematopoietic stem cell transplant. Another example is the July 2019 report in Nature Communications of the first-ever elimination of HIV-1 DNA "competent for the replication" of live animal genomes.

However, patient frustration can be excused as the practical application of the much touted research on HIV / AIDS treatments always seems to take years – never in the here and now. This article examines these leading genetics-based research, focusing on the challenging practical challenges that impede research results from being applied to patients in a clinical setting.

Treatment versus cure

The main treatment for HIV-positive people is currently using a combination of antiretroviral drugs, known as antiretroviral therapy (ART), on a daily basis. These drugs can reduce the amount of HIV in the blood to very low levels, which can become undetectable in some patients' dosages. The typical antiretroviral regimen consists of three different drugs belonging to at least two of the seven clbades. These medications must be taken every day for the rest of the patient's life in order to continue to suppress the viral load – a requirement that many patients have difficulty complying with. Many patients also struggle to afford drugs, with average wholesale prices per drug and per month ranging from hundreds of dollars to over $ 4,000. In addition, antiretroviral drugs have many potential side effects, ranging from relatively minor nausea, fatigue, and muscle aches to life-threatening conditions badociated with swelling of the throat, eyes, and face.

These issues underscore the need for "functional cure" for HIV / AIDS patients, which would permanently maintain viral load at undetectable levels without the need for continued medication. It is the goal of research based on genetics.

"Remedies" based on genetics

Although there are several tracks of genetic research on HIV / AIDS treatments, the area that has received the most attention from the media – due to two "treatments" over a period of more than 10 years – Involves hematopoietic stem cells CCR5Δ32 / Δ32 transplantation (HSCT).

In March 2019 in NatureA team of researchers led by Ravinda K. Gupta of University College London and Eduardo Olavarria of Imperial College London reported the second case of long-term remission of HIV-1 after HSCT. The only previous case of this type was reported by Hutter et al. in Berlin, Germany, in 2009. This famous "Berlin patient" was Timothy Ray Brown, who was treated in 2007 and continues, as of 2019, to show no signs of HIV infection – 12 years after discontinuing antiretroviral drugs. The Berlin patient has been widely regarded as the only case of cure for HIV / AIDS. The unidentified "London patient" has proposed a second case of cure – although it is "HIV-free" without using antiretroviral drugs for only 18 months at the time of the case report.

The Berlin patient had undergone two transplant procedures involving the use of hematopoietic stem cells taken from the bone marrow of a donor with a rare homozygous mutation in the CCR5 HIV co-receptor gene. This gene normally encodes a receptor protein on immune cells to which HIV binds during the infection process. The mutation is known as CCR5Δ32 (or simply Δ32). When the mutation occurs on both copies of the CCR5 gene, it confers HIV resistance by blocking gene expression and, therefore, removing functional receptor proteins on the surface of immune cells. HIV can not infect immune cells lacking the receptor protein.

For the Berlin patient, HSCT procedures were performed to treat human-badociated acute myeloid leukemia badociated with HIV, a type of cancer of the immune system. At each stem cell intervention, the Berlin patient received aggressive total body irradiation. He also received intensive chemotherapy. The result was a long-term remission of the patient's HIV infection, with the disappearance of HIV in his blood and the restoration of healthy immune cell populations. The vast majority of her new immune cells came from the donor stem cells and had the same type of HIV resistance as the donor cells.

For the London patient, the researchers used a single HSCT procedure with bone marrow stem cells from a donor carrying the homozygous CCR5Δ32 / Δ32 mutation. The treatment, designed to treat his Hodgkin lymphoma, also included chemotherapy. Unlike the Berlin patient, he received no radiation. The patient developed mild symptoms of graft-versus-host disease while his HIV infection went into remission. Sixteen months after HSCT, the treatment was stopped. Eighteen months after stopping antiretroviral therapy, the HIV infection remained in remission, with no trace of the virus in her blood other than the intermittent detection of residual levels of RNA and HIV DNA.

Challenges in clinical application

While the word reported in the HSCT case reports that caught the attention of mainstream media was "cure," many field experts cautioned that multiplying positive reports results in clinically effective treatment options and safe for the wider population with HIV / AIDS. AIDS remains in many years or it may not be possible at all. This warning was, of course, absent from the headlines, although the more carefully written news mentioned it in their description of the research. Among the many complexities and other problematic considerations that have not been sufficiently emphasized or explained in many reports on genetic research, we can cite the following:

The mechanisms underlying the HSCT results are not fully understood. What specific role did radiotherapy and chemotherapy play in relation to HSCT? What exactly were the stem cells of the donor in relation to the patient's immune cells? What was the importance of graft versus host attack on immune cells to rid the body of HIV-infected cells? Without a clear understanding of the mechanisms, it is impossible to develop a clinically applicable cure. The lack of understanding also suggests that it is possible that the virus is reactivated at some point. Thus, the "cure" may not be permanent. London researchers have recognized that there is a "far-off" risk that residual levels of the virus could eventually lead to a relapse in their patient.

It is relevant that it took 12 years to replicate the Berlin results with the patient from London. Patients in Berlin and London had some similarities that many other HIV / AIDS patients do not share. Both people had immune cell cancers and HIV strains that used only CCR5 and CD4 receptor proteins to infect immune cells. These characteristics allowed these two patients to become familiar with the HSCT technique involving the transplantation of stem cells from donors carrying the Δ32 mutation in both copies of the CCR5 gene. In addition, the Berlin patient might have benefited from a clean Δ32 mutation on a copy of his CCR5 gene.

There are many such details that complicate the process of HIV infection, HIV genetics, and the patient's immune genetics, which make each individual case different from other cases. This means that treatments that might work for some patients will not work for other patients. Because of the many variables, each stem cell technique should be carefully tailored to each patient, which would require levels of knowledge and understanding that are beyond our comprehension.

The HSCT procedure used in the case reports is extremely complex, risky and costly. Brown nearly died as a result of the harsh treatment he was given and he remained with neurological wounds and other physiological problems. The immune system of both patients was essentially "gutted" by the drastic approaches adopted. Are such radical and dangerous methods necessary? Considering the efficacy of current antiretroviral treatment regimens as a long-term treatment, no health professional would consider it wise or practical to replace these regimens with curative, novel and poorly understood stem cell therapy. could lead to further complications or even death. Genetic-based therapies have no cost advantage. Most of the US Food and Drug Administration approved gene therapies for other conditions cost more than $ 2 million due to various technical complexities.

Other research

Other genetics-based research on HIV / AIDS treatments include techniques for modifying genes in the patient's own cells that facilitate HIV infection or replication, as well as insertion. protective genes, making genes that enhance the immunity and manipulation of HIV genes. disable certain functions or activate them. Some gene editing methods involve "cutting" HIV DNA from infected cells, thus eliminating the body's virus. The CRISPR gene modification technique, badociated with long-acting slow-release antiretroviral therapy (LASER), is behind the July 2019 report published by researchers from Temple University and the Center. University of Nebraska that they had, for the first time, eliminated HIV. -1 DNA from the genome of live animals (mice). This research had yet to be duplicated with non-human primates before it could be switched to human clinical trials.

Such research summarizes the hopes of millions of people living with HIV / AIDS, but none of this research will produce clinical applications close to the often cited artificial delay in finding a curative treatment by 2020. Unrealistic delays are cited by People who should know better, false hope is engendered.

In the expectation of a treatment that could possibly be available in the future, patients should be sure to read the reports with the utmost care. As always, it is wise to remember that media reports about new medical discoveries should, if they are honest, include words and qualifying phrases, such as to suggest than to heal may to be possible One day in certain patients after further research resolves remaining problems. "At a minimum, these types of qualifiers should be used in reporting if journalists are not able to explain the detailed complexities of the research.

With such qualifiers in mind, we can still hope, but our hope will be based on reality.

UN J. Smuskiewicz is an independent editor and publisher specializing in science, medicine, world events and cultural issues. It can be found on his website