Archive for October, 2022

Over the past year, news of two new people cured of HIV grabbed headlines, stirring hopeful talk of what these scientific wonders might portend for the four-decade fight against the virus.

To researchers working in the HIV cure arena, these cases are inspiring because they prove it is in fact possible to eradicate this extraordinarily complex virus from the body.

That said, such cures are the result of treatments too toxic to attempt on all but a select few. So while they provide a scientific roadmap toward success, they do not necessarily make researchers job any easier as they work to develop alternatives: safe, effective and, crucially, scalable therapies to cure HIV.

HIV has been a tough nut to track, says Marshall Glesby, an infectious disease specialist at Weill Cornell Medicine in New York City and a coauthor of one of the recent HIV cure case studies. But there is incremental progress being made in terms of our understanding of where the virus hides within the body and potential ways to purge it from those sites.

The HIV cure research field is yet quite young. And it likely never would have ballooned as it has in recent years were it not for the very first successful cureone that served as a catalyst and guiding light for scientists.

During the late 1990s and early 2000s, the HIV research establishment focused the lions share of its energy and resources on treatment and prevention of the virus. Actually curing HIV was generally regarded as a distant dream, with only a small set of researchers pursuing such a goal.

Then, in 2008, German scientists announced the first case of what would ultimately be deemed a successful cure of the virus. This proof of concept ignited the field and sent financial investment soaringto $337 million in nonpharmaceutical industry funding in 2020, according to the HIV nonprofit AVAC.

Clinicians were able to cure HIV in an American man living in Berlin named Timothy Ray Brown, by exploiting the fact that he had also been diagnosed with acute myeloid leukemia, or AML. This made Brown a candidate for a stem cell (bone marrow) transplant to treat his blood cancer.

Browns treatment team relied on the existence of a rare genetic abnormality found among people with northern European ancestry. Known as the CCR5-delta32 mutation, it gives rise to immune cells lacking a certain coreceptor called CCR5 on their surface. This is a hook to which HIV typically latches to begin the process of infecting an immune cell and hijacking its machinery to manufacture new copies of the virus.

The clinicians found a stem cell donor who was not only a good genetic match for Brown, but who also had the CCR5-delta32 mutation. First they destroyed Browns immune system with full-dose chemotherapy and full-body radiation. Then they effectively gave him the donors immune system through the stem cell transplant. This cured his HIV by ensuring that any remaining virus in his body was incapable of infecting his new immune cells.

Variations of this method have yielded cures, or likely cures, in four other people during the years since. These cases provide researchers with increasing certainty that it is possible to achieve the ultimate goal: a sterilizing cure, in which the body has been rid of every last copy of virus capable of producing viable new copies of itself.

It was not a given that if you completely replace the immune system, even with a purportedly non-susceptible immune system, that you would cure infection, says Louis Picker, associate director of the Vaccine and Gene Therapy Institute at the Oregon Health & Science University. It was possible that HIV could be hiding in non-immune cells, like endothelial cells, and still find targets to infect.

But the small cohort of people who have been cured or likely cured to date, Picker says, show thats not the case.

Nevertheless, these successes have not opened the door to a cure for HIV available to much more than a few of the estimated 38 million people living with the virus worldwide. Critically, it is unethical to provide such a dangerous and toxic treatment to anyone who does not already qualify for a stem cell transplant to treat blood cancer or another health condition.

Brown, for one, nearly died from his treatment. And a number of efforts to repeat his case have failed.

Highly effective treatment for HIV hit the market in 1996, transforming what was once a death sentence into a manageable health condition. Today, the therapy, a combination of drugs called antiretrovirals, is so safe, tolerable and effective, that it has extended recipients life expectancy to near normal. But despite the fact that these medications can inhibit viral replication to such a degree that its undetectable by standard tests, they cannot eradicate HIV from the body.

Standing in the way is whats known as the HIV reservoir.

This viral reservoir is composed in large part of long-lived immune cells that enter a resting, or latent, state. Antiretrovirals only target cells that are actively producing new copies of the virus. So when HIV has infected a cell that is in a non-replicating state, the virus remains under the radar of these medications. Stop the treatment, and at any moment, any of these cells, which clone themselves, can restart their engines and repopulate the body with HIV.

This phenomenon is why people with HIV typically experience a viral rebound within a few weeks of stopping their antiretrovirals. And it is the reason why, given the harm such viral replication causes the body, those living with HIV must remain on treatment for the virus indefinitely to mitigate the deleterious impacts of the infection.

A key new advance is the finding that those cells which harbor the virus seem resistant to dying, a problem with cancer cells, HIV cure researcher Steven Deeks, a professor of medicine at University of California, San Francisco, says of the viral reservoir. We will be leveraging new cancer therapies aimed at targeting these resilient, hard-to-kill cells.

Brown stood alone on his pedestal for over a decade.

Then, at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, researchers announced two new case studies of men with blood cancer and HIV who had received treatments similar to Browns. The men, known as the Dsseldorf and London patients, were treated for Hodgkin lymphoma and AML, respectively. By the time of the conference, both had spent extended periods off of antiretroviral treatment without a viral rebound.

To this day, neither man has experienced a viral reboundleading the authors of the London and Dsseldorf case studies recently to assert that they are definitely and almost definitely cured, respectively.

In February 2022, a team of researchers reported at CROI, held virtually, the first possible case of an HIV cure in a woman. The treatment she received for her leukemia represented an important scientific advance.

Called a haplo-cord transplant, this cutting-edge approach to treating blood cancer was developed to compensate for the difficulty of finding a close genetic match in the stem cell donorwhich is traditionally needed to provide the best chance that the stem cell transplant will work properly. Such an effort is made even more challenging when attempting to cure HIV, because the CCR5-delta32 mutation is so rare.

The American woman received a transplant of umbilical cord blood from a baby, who had the genetic mutation, followed by a transplant of stem cells from an adult, who did not. While each donor was only a partial match, the combination of the two transplants was meant to compensate for this less-than-ideal scenario. The result was the successful blooming of a new, HIV-resistant immune system.

The authors of the womans case study, including Weill Cornells Marshall Glesby, estimate that this new method could expand the number of candidates for HIV cure treatment to about 50 per year.

A variety of antiretroviral drugs used to treat HIV infection. Image Credit: NIAID, Flickr

In July, at the International AIDS Conference in Montreal, researchers announced the case of a fifth person possibly cured of HIV. Diagnosed with the virus in 1988 and 63 years old at the time of his stem cell transplant three years ago, the American man is the oldest to have achieved potential success with such a treatment and the one living with the virus for the longest. Because of his age, he received reduced intensity chemotherapy to treat his AML. Promisingly, he still beat both the cancer and the virus.

The lead author of this mans case study, Jana K. Dickter, an associate clinical professor of infectious disease at City of Hope in Duarte, California, says that such cases provide a guide for researchers. If we are able to successfully modify the CCR5 receptors from T cells for people living with HIV, she says, then there is a possibility we can cure a person from their HIV infection.

Scientists also know of two women whose own immune systems, in an extraordinary feat, appear to have cured them of HIV. Both are among the approximately 1 in 200 people with HIV, known as elite controllers, whose immune systems are able to suppress replication of the virus to low levels without antiretroviral treatment.

Researchers believe that these womens immune systems managed to preferentially eliminate immune cells infected with viral DNA capable of producing viable new virus, ultimately succeeding in eradicating every last such copy.

As they seek safer and more broadly applicable therapeutic options than the stem cell transplant approach, HIV cure researchers are pursuing a variety of avenues.

Some investigators are developing genetic treatments in which, for example, they attempt to edit an individuals own immune cells to make them lack the CCR5 coreceptor.

The science that I am particularly excited about and that we and others are working on is to make this treatment as an in vivo deliverable therapy that would not rely on transplant centers and could ultimately be given in an outpatient setting, says Hans-Peter Kiem, director of the stem cell and gene therapy program at the Fred Hutchinson Cancer Center in Seattle.

Then there is whats known as the shock and kill method, in which drugs are used to flush the virus from the reservoir and other treatments are then used to kill off the infected cells. Conversely, block and lock attempts to freeze the reservoir cells in a latent state for good. Researchers are also developing therapeutic vaccines that would augment the immune response to the virus.

Progress will be incremental and slow, Picker predicts, unless there is a discovery from left fieldan unpredictable advance that revolutionizes the field. I do think it will happen. My personal goal is to be a very good left fielder.

This reporting was supported by the Global Health Reporting Center.

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How a select few people have been cured of HIV - PBS

Diagnosis, Treatment, and Prevention of Blood Cancer By Dr Gaurav Kharya

Written by Tavishi Dogra | Updated : October 4, 2022 9:56 PM IST

In India, the increase in cancer cases over the past ten years has become a significant public health problem for the country. These cases have a long latent period, are primarily lifestyle-related and require specialised infrastructure and human resources to be treated. Cancer's physical, psychological and financial toll on people, families, communities and health systems keeps rising. The prevalence of cancer varies across India's regions, making prevention and management extremely difficult. Due to cancer not being a notifiable disease, the national burden assessment is still a task for which many developing nations, including India, rely on statistical models. The estimated number of cancer-related Disability-adjusted life years (DALYs) (AMI) in India in 2021 was 26.7 million, and that number was predicted to rise to 29.8 million in 2025.

Each year, 1.24 million new instances of blood cancer are reported worldwide, making up about 6% of all cancer cases. Blood cancer develops in the bone marrow, tissues that create blood and compromise the immune system. According to incidence rates, there are primarily three different forms of blood cancers: lymphoma/leukaemia, multiple myeloma, myelodysplastic syndromes (MDS)/myeloproliferative neoplasms (MPN). In addition, blood cancer may arise when the body produces abnormal White Blood Cells (WBCs). It typically starts in the bone marrow, which produces blood in our body. This malignancy impairs the normal development, growth and functioning of blood cells that fight infection and produce healthy blood cells.

White blood cells produced by the body during leukaemia are incapable of battling infections. Depending on the type of blood cell involved and whether it is fast-growing or slow-growing (acute or chronic), leukaemia is divided into distinct forms (myeloid or lymphoid). Consequently, it can be broadly divided into four subtypes: acute lymphocytic leukaemia (ALL), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Apart from these are some rare blood cancers such as Juvenile myelomonocytic leukaemia (JMML).

Diagnosis, Treatment, and Prevention of Blood Cancer By Dr Gaurav Kharya, Clinical Lead Apollo Center & Indraprastha Apollo Hospital

Various diagnostic techniques are used to identify blood cancer, including clinical examination, blood testing, bone marrow tests, cytogenetic/karyotyping, molecular analyses, and flow cytometry. Most pediatric patients diagnosed with ALL or AML can be treated by chemotherapy. However, a smaller percentage of patients who don't respond well to chemotherapy are candidates for Bone marrow transplant to offer a long-term cure to these patients. In contrast, almost half of adult patients need BMT as consolidation to provide long-term treatment. If required, BMT can safely be done now using half HLA identical donors in case HLA matching donors are unavailable in experienced centres.

In most cases, the doctor will make a treatment recommendation based on research on the most effective treatments and national recommendations developed by experts. They will assess the type of blood cancer, the outcomes of any tests the patient has had, the state of the overall health, the available therapies, their effectiveness, and any potential risks or side effects.

There is a range of different treatments for blood cancer. But the most common ones include:

The cost of blood cancer therapy in India has several significant advantages. First, the most outstanding hospitals in India, equipped with the most cutting-edge equipment and a staff of oncologists and doctors with years of experience, are accessible to offer blood cancer patients comprehensive care.

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An operation that has its roots, conceptually, in the earliest history of mankind (it was first spoken about by Chinese doctors), it is nevertheless a very recent therapeutic solution: the knowledge that made it possible (immunology, study of antigens) was only acquired at the beginning of the 20th century.

From 1950 onwards, transplantation became an established choice in the treatment of those pathologies that lead to the irreparable destruction of the organ and, therefore, to the death of the patient.

But transplantation is not only the last prospect for those whose lives are in danger: this operation also makes it possible to improve the quality of life for those patients suffering from chronic disabling diseases (e.g. kidney transplantation for dialysed patients).

The future of transplantation is still to be sketched out, but is very clear in the minds of scientists and doctors engaged in research: implantation of artificial organs or organs taken from genetically modified animals (xenotransplantation), cloning and implantation of stem cells are just some of the directions in which the worlds scientific landscape is moving.

The word transplant often indicates, in a reductive way, the operation of replacing a diseased organ with a healthy one.

In reality, there is a whole organisation and preparation behind this operation that involves extreme precision and synchronisation of people and instruments.

The practice of the operation differs depending on the donor: if the organ removal is from a living person, in fact, it is possible to plan the operation; which is obviously not feasible if the organs come from a cadaveric donor, who died of accidental and unforeseeable causes.

Once the medical committee has obtained the familys consent and declares the potential donors brain death to have occurred, the evaluation of his data begins: compatibility with potential recipients on the waiting lists, medical history, immune characteristics, blood group, etc.

PHASE 1

A person with injuries that could be a donor (for example, a very serious head injury) is admitted to intensive care.

A doctor speaks to the family about the possibility of donating his or her organs; if they are available, the coordination centre is immediately alerted, which is responsible for reporting the potential donor and identifying the potential recipient.

Meanwhile, the donor patients data are assessed: compatibility with potential recipients on the list, medical history, immune characteristics. The 6-hour observation period begins, which is mandatory before the certification of brain death.

PHASE 2

The explantation team is activated and must be available in a very short time.

The doctors usually reach the facility by helicopter. Meanwhile, at the hospital where the transplant will be performed, the recipient is called in to undergo various examinations and to assess his or her state of health.

Numerous checks are also carried out on the organs to be donated to prevent the transmission of infectious diseases or tumours from donor to recipient.

PHASE 3

At the end of the observation period, if all indications point to a diagnosis of irreversible brain death, explantation can begin (approximately 2 hours).

The recipient enters the operating theatre and is prepared for the operation. The administration of immunosuppressive drugs starts now to prevent the lymphocytes from recognising the organ as foreign and causing rejection.

PHASE 4

The organ finally arrives, immersed in a special solution to protect its cells and transported in a special container filled with ice to slow down its cellular activity.

One team of doctors prepares the recipient, the other takes care of cleaning the organ to be transplanted.

PHASE 5

The transplant can now begin: the blood vessels are connected, the bleeding is controlled.

STEP 6

The patient comes out of the operating theatre, but is still under anaesthesia, which will be prolonged for at least another 6 to 8 hours to allow the new organ to get used to the temperature difference between the container with the ice and the body and, of course, to the organ itself.

The patient remains connected to the machine to breathe.

STEP 7

The patient wakes up in the intensive care unit; if his general condition is good, he is taken off the artificial respirator.

After about 4 days, he starts walking again and eating.

After about 10 days, he will be able to leave the hospital and live with his new organ.

Initially, he will have to return to the hospital every day for immunological checks; after a year, he will be able to return once every two months.

Once brain death has been ascertained and the familys consent obtained (in the case of a lack of explicit donor wishes), the potential donor is no longer assisted by the mechanical respirator and the organs can be harvested for transplantation in the same hospital that established suitability.

The previously alerted team enters the operating theatre for the removal operation.

Opposing the removal never means helping the patient to have better care; care, in fact, ends the moment brain death is established; opposing it would therefore only mean depriving someone else of a better life thanks to a new organ.

Today, another type of transplant is also gaining ground, that from living people.

Indeed, it is now possible to take a kidney, liver or lung lobe for transplantation in particularly at-risk people who would not survive on the waiting list.

These are usually children, both because of the shortage of paediatric transplant organs and because of the small size, which also means that the donor does not face too high a risk.

Once taken, organs require special procedures to preserve them for transplantation.

There is, for each organ, a maximum preservation time, beyond which the tissues, no longer receiving blood, and therefore oxygen, go into necrosis, i.e. their cells die, and are therefore unusable.

These times vary from organ to organ: heart (4-6 hours), lung (4-6 hours), liver (12-18 hours), kidney 48-72 hours, pancreas (12-24 hours).

Rejection is the reaction that the recipient organism has towards the transplanted organ or tissue.

In fact, the recipients immune system recognises the organ as foreign and attacks it as if it were a pathogen.

There are four types of rejection

Experiencing rejection of the transplanted organ does not necessarily mean inevitably losing it; on the contrary, rejection is successfully treated if action is taken within a reasonable time frame through the use of immunosuppressive drugs.

The immunosuppressants that the doctor prescribes after the transplant will help the transplanted organ not to risk rejection and to remain healthy.

Since the cells of the immune system are different, the drugs prescribed for immunosuppression will also be different.

The largest and most immediate indication for transplantation is irreversible failure of vital organs such as kidneys, liver, lungs, pancreas, but also corneas, bone marrow, intestines.

Indeed, in these cases, transplantation is the only effective treatment to ensure survival.

Therefore, any pathological condition that prevents the organ from functioning in such a way as to threaten the patients survival is to be considered an indication for transplantation.

After transplantation, recipients are admitted for the first few days to a ward equipped for intensive care, where immunosuppressive therapy is started.

The immunosuppressed patient requires isolation in sterile rooms, specially created to avoid contamination of any kind from the outside environment.

The box in which the recipient is admitted after the transplant operation is completely isolated from the rest of the resuscitation unit used for conventional surgery.

The condition of strict isolation persists for as long as it takes for the patient to overcome the critical post-surgical phase (usually 5-6 days), or in cases where anti-rejection therapy is required.

In the immediate post-surgical period, visits to close relatives are permitted as long as they are appropriately dressed (according to the clean room entry procedures).

Each person is admitted to the filter zone one at a time and, of course, persons with suspicion and/or evidence of infectious diseases may not be admitted.

The most serious issues in transplant medicine are, on the one hand, the rejection of the transplanted organ and, on the other, the insufficiency of donated organs compared to those needed.

In both directions, research is experimenting with various solutions to overcome these problems.

With regard to rejection, attempts are being made to create solutions that manage to trick the immune system, thus reducing the immunosuppressive therapy currently in use, or that protect the transplanted organ from attack by T lymphocytes, which are responsible for eliminating agents outside the body.

On the other front, that of organ shortage, artificial organs, tissue engineering or xenotransplantation are being experimented with that can replace human organs.

Through gene therapy, it is possible to go to the source of the problem and eliminate genetic defects directly in the affected cells, tissues or organs.

The healthy gene is introduced directly into the affected spot, where it begins to produce those substances that the diseased body cannot produce on its own.

However, gene therapy is still far from being used. In order to be able to transport foreign DNA into the cell nucleus, special vectors are needed viruses that have lost their infectious characteristics, but are still able to attack cells and transmit their genetic heritage to them.

To avoid rejection, the organ to be transplanted would have to be treated in the laboratory, transferring genes into it that would make it capable of defending itself against the recipients immune system.

Now the genes are known, but they are not yet handled with the necessary precision. The next step will be to search for the perfect combination of genes that prevents the action of all the recipients immunological mechanisms.

The aim of this type of therapy is to find an alternative to human organs.

Already now, researchers are able to produce tissues such as blood vessels, heart valves, cartilage and skin in the laboratory.

It has been possible to overcome this new frontier thanks to the fact that cells tend to aggregate to form organs and tissues.

Stem cells are the undifferentiated cells found in human embryos one week after fertilisation.

They are also the starting cells from which the tissues and organs of the child to be born will develop.

Their function is to regulate the turnover of blood cells (red blood cells, white blood cells and platelets) and those of the immune system (lymphocytes).

Today, computerised machines, separators, are used to collect these cells, allowing the selection of the necessary cells. The recipients of the cells are patients suffering from skin diseases, blood diseases or solid tumours.

In addition to the fact that stem cells are still largely unknown, there is also an ethical problem: harvesting embryonic stem cells implies the death of the embryo.

That is why the way to harvest stem cells from adults is being perfected.

The cloning technique would make it possible to circumvent the problem of organ rejection altogether.

It would involve introducing the patients cell nucleus, with all its genetic heritage, into the stem cell of a human embryo or oocyte that previously had no nucleus of its own.

Cultivated in vitro in the laboratory, these modified cells would be genetically identical to those of the patients immune system, which would not recognise them as foreign.

This technique is not a viable option at present because both cloning, stem cell harvesting and the indiscriminate use of oocytes are prohibited by law.

Xenotransplantation, i.e. the transplantation of animal cells, tissues and organs into humans, seems to be the future solution to the shortage of organs for transplantation.

Experiments in this field are numerous and face ethical, psychological and, last but not least, immune problems.

The few attempts that have been made, in fact (a pig liver and a baboon heart transplanted into two different human beings) have not yielded the desired results.

The rejection crisis, in fact, was particularly violent and impossible to control.

Yet this technique could really be the solution to the organ shortage.

In fact, what is most feared is the development of typically animal infections, transferred to humans via pathogens present in the organ to be transplanted, which could prove disastrous.

A possible alternative to this handicap could be genetic modifications on donor animals; in practice, the animals would be bred in a sterile environment and genetically modified to make their organs more compatible with the recipients organism.

For the time being, however, some milestones have been achieved; these are cell xenotransplants and not organ xenotransplants, such as pig embryo cells for the treatment of Parkinsons disease, baboon marrow cells transplanted into terminally ill AIDS patients in an attempt to recover the patients immune system, or pancreas insulae still from pigs in the stimulation of insulin production as a therapy against diabetes.

Another solution to organ failure such as rejection is artificial organs.

The main problem is biological compatibility; these are, after all, mechanical organs that have to adapt to a biological organism.

Biocompatibility must cover all morphological, physical, chemical and functional characteristics that are able to provide for the organs functionality and, at the same time, its survival without the risk of rejection.

It is all these implications that make the production of artificial organs capable of completely and perfectly replacing natural organs in their functions complex.

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As the world observed World Chronic Myeloid Leukemia Day recently, leading medical experts emphasized the need of creating awareness aboutthe condition, a relatively uncommon type of bone marrow and blood cancer.

Chronic Myeloid Leukemia (CML) occurs with an incidence rate of 0.4 to 3.9 per 100,000 patients, which increases with age and has a slight male preponderance. It is a chronic disease in which patients must take lifelong treatment and hence, experts stress its appropriate management and adherence to treatment.

CML occurs due to spontaneous chromosome mutation which causes diseased white blood cells to build up in huge numbers, crowding out healthy blood cells and damaging the bone marrow.

Dr. Ankit Jitani - Hematologist, Hemato-Oncologist, and BMT Physician, Ahmedabad says, CML is caused by secondary passenger mutations in the stem cells. The most common way that patients present symptoms of CML is leukocytosis or have respiratory discomfort and hence go to a cardiologist, or have gastric discomfort, and then visit a gastroenterologist who then refers the patients to us. However, post COVID-19 awareness of CML has increased amongst all patients, they are now actively doing blood tests and measuring CBC.

He further stated that For CML, regular monitoring and adherence to treatment are essential. We are actively working more toward treatment-free-remission. Regular monitoring and adherence to treatment if done actively, only then the patient is a suitable candidate for treatment-free-remission. A lack of adherence to treatment protocols can make the condition severe.

Therefore, it is recommended that patients continue to take medication as prescribed by their healthcare professional. CML management and treatment require a lot of patience and discipline. It is a great thing that cancer gets cured with a drug, hence regular check-ups, and sticking to your schedule with your doctor is important.

Dr. Abhishek Dudhatra, Haematology Consultant & BMT Specialist, HCG Oncology, Ahmedabad mentions, Tyrosine kinase inhibitors (TKIs) are the initial treatment of choice for CML, and more than two-thirds of patients achieve long-term control of the disease with this.

Regular monitoring of the condition is equally critical as it enables the physician to prescribe the appropriate dose and hence, keep the condition under control. Monitoring is done through a blood test, primarily to check the quantification of BCR-ABL transcript in the blood. When the condition is initially diagnosed, monitoring is recommended to be done every 3 months and later, the frequency can be 6 months. While these are the recommended periods, the frequency of monitoring also depends on individual cases. One should adhere to what is suggested by the physician.

While CML is caused by a genetic mutation in the stem cells, its exact cause is not known. The condition is not hereditary and cannot be passed on to future generations.

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Experts emphasize appropriate management and adherence to treatment for Chronic Myeloid Leukemia - First India