Jessica Conway has spent her career studying patterns. Initially, she probed the patterns that form in vibrated fluid layers. But she quickly turned her attention and modeling skills to epidemiology and understanding the patterns seen in disease data, such as how the timing of vaccination influences the severity of a flu season. Conway and her group have now developed a model that predicts if and when the HIV virus will rebound if someone stops taking their medication. Speaking in early January at the Dynamic Days conference in Hartford, Connecticut, she said the model could help inform efforts to find a so-called functional cure, where the disease is kept below detectable levels without the need for continued drug intervention.

“Our aims are modest,” Conway says. “We don’t want to go to a clinician and say, ‘do this.’ Rather we want to generate hypotheses and make testable predictions as to what mechanisms might delay or control viral rebound.”

HIV is a disease of the immune system. The disease infects white blood cells, known as CD4 cells, and then uses the machinery of these cells to replicate and spread through the body. Antiretroviral therapies disrupt this cycle by stopping the virus from replicating. But the drugs are not a cure. Typically, when a person living with HIV stops taking their medication, the virus starts to replicate again, and the amount of HIV in the blood (the viral load) jumps back up. There is significant variability in the timing of this rebound, which can take from days to years. In fact, two studies, one in France and the other in the US, identified some HIV sufferers whose viral load never rebounded. Conway wanted to see if she could explain the variability in rebound times.

Conway’s model predicts an individual’s viral state at future times, given certain initial medical indicators. Her approach is based on a standard model of viral dynamics, which captures the infection and spreading of the virus via CD4 cells through a series of coupled differential equations. But Conway’s version has two important modifications. First, she added in the effects of so-called latently infected cells. These are infected cells that may lie dormant for days, months, or years and then suddenly wake up and start spreading the disease. If a person with HIV stops taking their drugs, these latently infected cells can cause the infection to rebound. She also included the impact of “killing” cells, which destroy infected cells and are meant to mimic the natural immune response. She then ran the model, varying parameters such as the efficacy of the killing cells and the number, or “reservoir size,” of latent cells in the body.

In 2015, Conway succeeded in predicting three medically observed outcomes from a single rebound model. She found that rebound occurs below a certain killing rate, while rebound is avoided when killing rates are high enough and latent reservoirs are sufficiently small. Finally, a certain combination of inputs led to a third state called elite control, where an infected individual keeps the disease at bay without ever needing medication.

More recently, Conway has also captured the variability in observed viral rebound times using a simplified version of the model, which predicts the distribution of rebound times for a group. The essential assumption is that the activation rate of the latent cells—when they wake up and start producing virus—decays exponentially in time. “An exponentially decaying rate does a great job at capturing the short and long delays,” Conway says. “It captures them a lot better than we anticipated.” But Conway notes that this behavior is still under investigation and the results have yet to be vetted by peer review.

Now that Conway has a model that can replicate a diversity of HIV rebound scenarios, she hopes the information could be used by doctors to better plan clinical trials that work toward a functional cure for HIV. For example, her model predicts that if rebound occurs, it should happen within 1 to 4 weeks for 90% of people with HIV. That information could help determine how soon a person should get tested after stopping therapy. The model could also be used to inform treatment strategies that aim to avoid rebound. For example, knowing that a small latent reservoir is key to stopping the virus from rebounding, clinicians might monitor biomarkers associated with an individual’s reservoir to determine how, when, or if the person should be taken off their drugs.

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La Jolla, California (January 18, 2020). A new study published in the Journal of Clinical Investigation enrolled people with HIV who also happened to have a terminal illness to study where HIV hides in the human body so doctors can better treat and maybe even cure HIV.

Selfless Terminally Ill Persons Join Doctors To Study HIV

Despite understanding that HIV exists throughout the human body, researchers working toward a cure of HIV do not understand how HIV populates deep tissues. “Unfortunately, we simply cannot know the answer until a person is deceased and subject to an autopsy. Delays between death and when tissues are collected means the virus degrades, obscuring where HIV really hides,” said Davey Smith, MD, the senior author and Chief of Infectious Diseases and Global Public Health at UC San Diego.

To fill this gap, the team turned to terminally ill persons who happened to have HIV, and with their consent, the team serially collected blood while the person was alive, and then performed a rapid autopsy at the time of their death. “This donation at the end of one’s life is the first of its kind in HIV research, and allowed us to discover all the places HIV hides, even during treatment where the virus is difficult to detect in standard blood tests.”

Terminally ill volunteers were eager to support this groundbreaking work. “Our participants have HIV but are dying of something else, like cancer. They are going through a lot, but they still want to leave a larger legacy behind and help find a cure for HIV,” said Sara Gianella, MD, assistant professor at UC San Diego Health and study coauthor. Study participants were either self-referred from hearing about the study or referred from their primary HIV providers. “Only one potential volunteer decided ultimately not to participate,” added Dr. Gianella.”It is an amazing gift from both the participants and their families.”

Where does HIV hide?

Study investigators found HIV in every one of the 30 organ sites they studied, even when the deceased participant was taking modern HIV therapy . When the virus was sequenced, some of the virus had genetic defects, which meant that it was nonfunctional or likely ‘dead’, but most of the virus seemed to be intact and able to grow.

“As expected, most of the HIV was in the blood, gut and lymph nodes,” said Antoine Chaillon, MD, PhD, assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego and the study’s lead author. “But, intact HIV was also found in the brain, liver, spleen, kidney, basically everywhere.”

It seems that having HIV in all these tissues can cause problems, even when someone is taking HIV therapy, and active HIV growth is ‘undetectable’ in blood. Being ‘undetectable’ in blood means that a person’s HIV therapy has basically stopped the growth of HIV in the blood. Although antiretroviral therapy can keep HIV from replicating, it does not stop all of the problems associated with HIV. Persons with HIV have more inflammation-related diseases, like heart attacks, stroke and cancer, than people who do not have HIV. “We do not fully know why,” Dr. Gianella said. “We think that when HIV tries to regrow in each of these tissues where it was lying dormant, it can cause an inflammatory response. Even though the antiretroviral therapy keeps it from fully replicating, it still causes local damage.”

“Yes,” Dr. Smith added. “For example, half of persons with HIV have neurocognitive impairment even when taking the very best HIV therapy. How HIV causes local inflammation in the brain, even during therapy, may explain this.”

“Further improving the health of people with HIV likely means we need to figure out how to clear HIV from its hiding places,” Dr. Chaillon said. “This means new therapies.”

How HIV moves in the body?

Two of the study’s participants had stopped taking their HIV therapy, leading to even more new insights. “Sometimes when people have a terminal illness they don’t want to keep taking their medicines anymore,” Dr. Gianella explained. “This gave us a unique opportunity to study how the virus replicated and moved in the body while the virus was untreated. We collected the participant’s blood before and after stopping their therapy, while they were alive, and then we collected all the tissues after they died. Since HIV evolves quickly within a person, we were able to identify the same viruses that restarted replicating in the blood after the person stopped their therapy in all their tissues after death.”

“We expected the replicating virus to seed blood cells and cells in the gut and lymph nodes,” added Dr. Chaillon, “but we were surprised at how quickly the virus was everywhere!” The team used new analytical methods, to find that the virus moved between tissues in the body. Cells in the blood and the gut seemed to be the source of most HIV in the rest of the body, and most HIV was trafficked through the body by the blood.

What does this mean for curing HIV?

Developing a way to keep HIV from replicating when therapy is stopped, often called ‘therapy free remission’, is a major goal for HIV researchers. Two people seem to have achieved this goal through treatments with special bone marrow transplants. “But even in these patients they still have intact virus throughout their body, even if it cannot get to the bloodstream,” said Dr. Smith. “Our study found that HIV was mainly trafficked through the body in the blood. This might explain why we saw therapy-free remission in the two persons with bone marrow transplants,” Dr. Smith explained. “After the transplants, their blood cells were protected and could no longer carry HIV. They still have intact virus throughout their body, but it can’t get to the bloodstream to start replicating.”

“But, HIV in these tissues still likely cause local inflammation and damage,” Dr. Chaillon added. “We need new ways to clear those places and extensions of our work can some day answer how.”

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A group of medical researchers in Maryland believe the answer for curing HIV/AIDS may be gene therapy.

American Gene Technologies (AGT), a Rockville-based medical research company, has submitted a Investigational New Drug (IND) application with the FDA to begin gene therapy trials that researchers believe could eliminate HIV in people already living with the virus.

The drug—an HIV treatment program called AGT103-T—is a single-dose, lentiviral vector-based gene therapy that AGT says could remove infected cells from the body and decrease or eliminate the need for lifelong antiretroviral treatment in HIV-positive patients.

If approved, the company hopes to begin a Phase 1 clinical trial that will examine the safety of AGT103-T in humans.

In a press statement, AGT chief science officer C. David Pauza, PhD, said the company’s objective is “to treat HIV disease with an innovative cell and gene therapy that reconstitutes immunity to HIV and will control virus growth in the absence of antiretroviral drugs.”

AGT’s approach differs from other medical researchers’ attempts to cure HIV. As NewNowNext reported earlier this year, researchers in Europe made headlines when two separate HIV-positive patients no longer had the virus after obtaining bone marrow transplants from donors with an HIV-resistant mutation to treat unrelated cancers.

Those patients marked the second and third time doctors were able to effectively “cure” patients living with HIV via bone marrow transplant in the history of modern medicine. However, HIV/AIDS activists and medical professionals were quick to raise concerns about the feasibility of curing HIV with bone marrow transplants on a more widespread basis.

Kenneth Freedberg, MD, a professor of medicine at Harvard Medical School and Massachusetts General Hospital, told NewNowNext in March that the method “is not a remotely plausible strategy for HIV treatment” for the vast majority of patients.

“A bone marrow transplant is an extraordinarily toxic and life-threatening intervention, which you do if someone has an illness that’s clearly going to be fatal,” Freedberg explained. “There must be no other treatment options available. It puts people at massive risk for infections and toxicity complications.”

As the fight against HIV/AIDS wages on, communities at risk of contracting the virus continue to take preventative measures against new infections—including daily use of Pre-exposure prophylaxis (PrEP), a potentially life-saving HIV prevention drug that is massively popular among gay, bisexual, and queer men.

In the United States, PrEP is pretty much exclusively available as Truvada, its brand-name version manufactured by Gilead Sciences with a very high retail markup. That may change soon, though: Earlier this week, the government filed a lawsuit against Gilead alleging patent infringement on PrEP, which was patented by public health researchers at the Department of Health and Human Services years ago.

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Telemedicine, which involves consultation of patients by doctors remotely, is being used in many parts of the country. A new study has shown that it can be used for treatment of HIV patients as well.

Anti-Retroviral treatment of HIV-affected children through telemedicineis better than conventional method in terms of average cost, treatment compliance, follow up visit and number of patients treated.

The Pediatric Centre for Excellence for HIV care at Sion Hospital, Mumbai with the collaboration of UNICEF and National Health Mission established the Pediatric HIV Telemedicine Initiative in 2013.

Some of the centres providing anti-retroviral therapy (ART) treatment were connected to the Mumbai centre through video links. This enabled expert opinion and services, nutritional counselling, care and treatment adherence motivation to HIV-infected children and adolescents easily.

For mid-term evaluation of the initiative, researchers selected three out of 35 telemedicine-based ART centres functioning in Maharashtra, and another three that were not linked with Mumbai via telemedicine link.

At the end of the two-year study period, the team reported that the per-visit cost in telemedicine linked centre was about Rs 1,803, while it was Rs 3,412 for conventional centres.

The most critical part of ART treatment is timeliness of the visit. Usually patients are required to revisit ART centres within 32 days of their first visit for subsequent checkup and prescriptions.

The study, published in the PlosOne journal, showed that that the timeliness of visit was better in the telemedicine-based treatment.

Overall, the success of ART centres can be computed based on the decrease in the loss to follow-up. Any person failing to access the ART services for three consecutive months after the first visit are accounted as loss to follow-up. There was 5 per cent decrease in the loss to follow-up cases in the telemedicine-linked centres.

“In remote areas, doctors in ART centres are getting exposed to expert advice through telemedicine initiative. As it is done on a regular basis, it gives an opportunity to discuss the clinical significance of cases in depth.This has a large scope to improve access to advanced care for the rural population with less cost,” pointed out Sarit Kumar Rout, a member of the research team, while speaking to India Science Wire.

“Our findings will help policymakers to scale up these initiatives as it reduces the cost per visit. As a proof of concept, telemedicine linkage leads to improves compliance and reduces loss to follow up,” he said.

There are other cost studies undertaken in Indian condition but they did not provide a complete picture due to certain lacunae. For instance, a study in 2009 reported that average cost per patients for ART services was Rs 1,287.

It computed the cost of ART services without accounting for capital cost. Thus the findings of the new study provide evidence needed for the expansion of telemedicine services in India, the researchers said.

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