How HIV develops resistance to key drugs discovered

The mechanism behind how HIV can develop resistance to a widely-prescribed group of drugs has been uncovered by new research from the Crick and Dana-Farber Cancer Institute, with the findings opening the door to the development of more effective treatments.

Today, a number of drugs are available which help to control HIV infection, including a group called integrase strand transfer inhibitors. There are four drugs within this family of medication: raltegravir, elvitegravir, dolutegravir and bictegravir. They all work by binding with one of HIV’s key enzymes, called integrase, to stop it from inserting the virus’ genetic information into DNA of human cells. While initially highly effective, over time HIV can develop resistance to these drugs.
The study, published on-line in Science 30 January 2020, discovered the mechanism HIV uses to develop resistance to this group of drugs. Although the drugs are normally very effective at binding and blocking integrase, over time, the virus can weaken this bond and thus enable its key enzyme to work again.
The researchers at the Francis Crick Institute in London uncovered this by exploring the structure of integrase from a virus that is highly similar to the ancestor of HIV, using cryo-electron microscopy. This technique uses a powerful microscope which fires electrons at a frozen sample of the drug-enzyme complex. By recording how the electrons interact with the samples, the researchers created detailed images, at a nearly atom-by-atom level.
“The unusual property of these drugs is that they interact with metal ions, which normally allows them to make very strong bonds to the viral enzyme’s active site. We found that HIV can subtly alter the chemical environment of the metals, and as if using a remote control, reduce the strength of drug binding. This is an unexpected chink in the armour of strand transfer inhibitors,” says Peter Cherepanov, co-lead author and group leader in the Chromatin and Mobile DNA Laboratory at the Crick and Professor of Molecular Virology at Imperial College London.
“The good news is that we have finally visualised the precise structure of the viral enzyme’s active site, right where the drugs bind. These blueprints will inform the design of more effective integrase inhibitors that could improve the lives of the many millions of people living with HIV,” says Alan Engelman, co-lead author from the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School in Boston, USA.
“The weakening of drug binding occurs due to a combined effect of mutations and a loss of key water molecules in the active site. Understanding this mechanism will help improve this class of drugs in the future,” comments Edina Rosta, co-author from the Crick and Reader of Computational Chemistry at Kings College London, whose team conducted complex computations on the integrase structures.
Daniel Kuritzkes, Chief of Infectious Diseases at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School, who was not directly involved in the study, adds: “The work by the Cherepanov and Engelman laboratories importantly informs the mechanism of resistance to a class of drugs that are now recommended first-line treatment for HIV worldwide.”
“This research is an outstanding example of how we can use cryo-electron microscopy to reveal the intricate relationships between drugs and their targets, providing results that could lead to clinical benefit,” explains Peter Rosenthal, the head of the Structural Biology of Cells and Viruses laboratory at the Francis Crick Institute.

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Imaging study of key viral structure shows how HIV drugs work at atomic level

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More information: “Structural basis of second-generation HIV integrase inhibitor action and viral resistance” Science (2020). science.sciencemag.org/lookup/ … 1126/science.aay4919

https://medicalxpress.com/news/2020-01-hiv-resistance-key-drugs.html

Heart failure: Researchers make headway against diastolic dysfunction

Heart failure is a major public health concern, a disease that affects tens of millions of people around the world—forcing many into a vicious cycle of hospitalizations, discharges and frequent readmissions.

The disorder is so rampant globally that some heart specialists refer to it as a pandemic. It is a disease that causes increasing disability not only because of poor cardiac function, but because other organs can become compromised by the condition. An estimated 26 million people worldwide are affected by heart failure—a figure that is expected to rise in the coming decades as the population inexorably ages.
An international team of heart researchers led by medical investigators at Temple University in Philadelphia is tackling issues surrounding the form of the disease known as heart failure with preserved ejection fraction.
This type of the disorder affects the left side of the heart—its pumping side—and accounts for about 50 percent of all cases.
All told, there are four types of heart failure. The other three are right-sided heart failure (the heart’s right side is tasked with pumping blood into the lungs to be enriched with oxygen); diastolic heart failure and systolic heart failure. Regardless the form, symptoms can include swelling in the feet and ankles, shortness of breath unrelated to exercise, and trouble breathing while lying flat.
In heart failure with preserved ejection fraction, patients have normal cardiac pumping function as measured by the ejection fraction, the percentage of blood leaving the heart each time it contracts. Yet, the overall quality of the heart is poor. The prevalence of this form of the disease has been growing by 10 percent per decade, Dr. Steven R. Houser, Markus Wallner and collaborators, reported in the journal Science Translational Medicine.
In an effort to better understand the disorder and to treat patients encumbered by it, the research team launched a study to assess the effects of blunting the activity of a specific enzyme. Basically, this was done by using a medication called an HDAC, which causes histone deacetylase inhibition.
Houser and the team wanted to know if providing HDAC treatment produced a benefit on cardiopulmonary structure, function and metabolism. To test their hypothesis, they turned to an unusual animal model, male short-haired cats.
The studies arrive as doctors worldwide underscore the urgent need to find solutions for the form of heart failure that affects the heart’s left side. Not only are more people developing the condition, the prognosis is generally poor because the survival rate is low.
“Furthermore, the hospitalization rate is high, and quality of life for patients is substantially compromised. There currently are no U.S. Food and Drug Administration-approved therapies for this condition,” wrote Steven R. Houser of the Cardiovascular Research Center at Temple University’s Lewis Katz School of Medicine.
Houser and a team of cardiovascular scientists in Europe and elsewhere in the United States explored the role of histone deacetylase inhibition as a potential way to improve the heart. Histone deacetylases are a class of enzymes.
In a group of cats, scientists simulated the features of heart failure with preserved ejection fraction by performing a minor procedure on them. In so doing, medical investigators were able to mimic the diastolic dysfunction common to human heart failure with preserved ejection fraction.
Two months after the procedure, the animals were treated daily with suberoylanilide hydroxamic acid, or SAHA, an FDA-approved HDAC inhibitor. At a molecular level, HDAC medications affect gene transcription, influence the cell cycle and possess the capability to induce apoptosis, or programmed cell death.
Echocardiography at four months revealed the cats had significantly reduced left ventricular hypertrophy. Left ventricular hypertrophy is an enlargement and thickening of the walls in the heart’s main pumping chamber, the left ventricle. The word hypertrophy means thickening.
Left ventricular hypertrophy can develop as a consequence of high blood pressure, or any heart malady that results in the left ventricle working harder.
Researchers also found that diastolic pressure and mean pulmonary arterial pressure were significantly reduced as a result of SAHA treatment. The drug also increased myofibril relaxation, the relaxation of cardiac muscle fibers.
Houser and his collaborators additionally found that SAHA treatment preserved lung structure and improved blood oxygenation. SAHA, the team wrote in Science Translational Medicine, also altered lysine acetylation of mitochondrial metabolic enzymes. Lysine is an amino acid.
“These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients,” Houser and colleagues wrote.

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Common form of heart failure could be treated with already approved anticancer drug

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More information: Markus Wallner et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction, Science Translational Medicine (2020). DOI: 10.1126/scitranslmed.aay7205

https://medicalxpress.com/news/2020-01-heart-failure-headway-diastolic-dysfunction.html

Texas Medical Assn: 25% of patients say insurers denied physician orders

About a quarter of registered voters in Texas have faced insurance denials for treatment that a physician ordered for them, according to a survey published by the Texas Medical Association.
The survey, commissioned by TMA, asked 800 voters questions about insurance denials. Nearly 26 percent of survey respondents said that in the past year, an insurance company “refused to cover a medicine, procedure, test, or scan that a doctor ordered” for either them or a family member.
For the people who saw their orders denied, 30 percent said they paid for the medicine, procedure, test or scan out of pocket. Fourteen percent said they appealed and the insurer changed its decision. Ten percent said they or a family member had their symptoms worsen or diagnosis delayed.
https://www.beckershospitalreview.com/finance/texas-medical-association-25-of-patients-say-insurers-denied-physician-orders.html

Diuretic a Promising Treatment for Autism

The loop diuretic bumetanide appears to improve some of the core behavioral symptoms of autism by decreasing levels of the neurotransmitters gamma-aminobutyric acid (GABA), new research suggests.
Investigators found young children with autism spectrum disorder (ASD) treated with the diuretic for 3 months scored better on a behavior scale that measures emotional response as well as verbal and nonverbal communication compared with children taking a placebo.
“This study is important and exciting because it means that there is a drug that can improve social learning and reduce ASD symptoms during the time when the brains of these children are still developing,” study investigator Barbara Sahakian, DSc, FMedSci, professor of clinical neuropsychology, University of Cambridge, United Kingdom, said in a news release.
The study was published online January 27 in Translational Psychiatry.

Mechanism Revealed

As reported by Medscape Medical News back in 2017, bumetanide has been shown in earlier research to improve ASD symptoms. However, the new study sheds light on the mechanism of the drug, which alters the ratio of GABA to glutamate in the brain.
“This is the first demonstration that bumetanide improves brain function and reduces symptoms by reducing the amount of the brain chemical GABA. Understanding this mechanism is a major step toward developing new and more effective drug treatments,” study coinvestigator Ching-Po Lin, PhD, of National Yang-Ming University, Taipei, Taiwan, said in the release.
The study included 83 children aged 3 to 6 years with moderate to severe autism; 42 were treated with 0.5 mg of bumetanide twice a day for 3 months and 41 in the control group received no treatment. At baseline, both groups had similar scores on the Childhood Autism Rating Scale (CARS).
Compared with the control group, the bumetanide group showed significant reduction in symptom severity, as indicated by both total CARS score and number of items assigned a score of 3 or higher. The improvement in clinical symptoms was confirmed by the overall impression of a physician who was blinded to the study group.
Particularly noteworthy were decreases in repetitive behavior and decreased interest in objects in children taking bumetanide.
Fei Li, PhD, clinical lead on the study from Jiao Tong University School of Medicine in Shanghai, China, shared one interaction with a parent.
“The mother of a 4-year-old boy living in a rural area outside Shanghai who received the treatment told me that he was now better at making eye contact with family members and relatives and was able to participate more in activities,” said Li in the news release. “In the future, we hope to be able to ensure all families, regardless of where they are living, can receive treatment for their child.”

Neuroimaging studies showed that 3 months of treatment with bumetanide was associated with a decrease in the ratio of GABA to glutamate in two key brain regions: the insular cortex, which plays a role empathy and self-awareness, and the visual cortex, which is responsible for integrating and processing visual information. This decreased GABA/glutamate ratio was associated with a reduction in symptom severity.

“Not a Cure-All”

“Because social interaction and communication starts so early in life, it is best to use bumetanide as soon as possible after diagnosis,” Sahakian told Medscape Medical News. “This gives the best possible chance for children with ASD to develop eye contact, smiling, and other forms of social communication, and to have a good quality of life and well-being,” she added.
However, she noted that further studies are needed. If results of a large-scale, double-blind, placebo-controlled clinical trial “replicate the results of our study and find that bumetanide is safe and effective in reducing symptoms in children with moderate and severe ASD, then it will provide a treatment,” but that is “probably 3 to 5 years away,” she said.

Commenting on the findings for Medscape Medical News, Randi Hagerman, MD, medical director of the UC Davis MIND Institute in Sacramento, California, is not surprised by the positive results, having seen the benefits first-hand.
Hagerman, who was not involved in the research, said she tried bumetanide in a nonverbal patient with ASD who did “marvellously well” and was subsequently able to talk.
“I think it could be very helpful for individuals with autism. I don’t think it’s a cure-all, but I think this is one of the few medications that will show efficacy and make a difference. Because it’s a diuretic, potassium levels must be followed closely,” said Hagerman.
Hagerman added that her group at the MIND Institute will soon be starting a study of bumetanide in young children.
The study was supported by the Shanghai Municipal Commission of Health and Family Planning, Shanghai Shenkang Hospital Development Center, Shanghai Municipal Education Commission, National Natural Science Foundation of China, Shanghai Committee of Science and Technology, Xinhua Hospital of Shanghai Jiao Tong University School of Medicine, National Human Genetic Resources Sharing Service Platform, the National Key Research and Development Program of China, 111 Project, the Shanghai Municipal Science and Technology Major Project, Guangdong Key Project, and ZJ Lab. The authors and Hagerman have no relevant disclosures.
Transl Psychiatry. Published online January 27, 2020. Full text
https://www.medscape.com/viewarticle/924574#vp_1

China tells firms to resume production of medical goods for virus control

China’s cabinet on Thursday told firms to resume production of key medical goods for virus controls, amid widespread shortages.
Local governments are responsible for ensuring that local enterprises maintain the supply of protective clothing, face masks, goggles, ambulances and drugs, the State Council said in a statement.
The cabinet said it will be responsible for unified allocation of medical goods and local governments cannot intercept or transfer them.
https://www.reuters.com/article/us-china-health-medicalgoods/china-tells-firms-to-resume-production-of-medical-goods-for-virus-control-idUSKBN1ZT1H9

China: Chinese nationals who are family members of foreigners can exit Wuhan

China’s Foreign Ministry said on Thursday that Chinese nationals who are family members of foreign citizens can board evacuation flights from Wuhan, the epicenter of the coronavirus outbreak, if they wish.
“For family members of Chinese citizens of foreign nationals in Wuhan, taking into account family factors, if they wish, they can leave with their families,” the ministry said in a short statement sent to Reuters.
A number of countries have already or are planning to evacuate their citizens from Wuhan, which the government has put under a virtual lockdown to control the virus, including the United States, Japan and Britain.
https://www.reuters.com/article/us-china-health-foreigners/china-says-chinese-nationals-who-are-family-members-of-foreigners-can-fly-out-of-wuhan-idUSKBN1ZT22S

If you feel you can’t breathe, don’t expect virtual assistants to call for help

Virtual digital assistants like Siri, Alexa, Cortana and Google Assistant could potentially provide users with reliable and relevant information during medical emergencies, but their current incarnations aren’t quite up to the job, a new study suggests.
In an experiment, the four leading virtual digital assistants (VDAs) were queried aloud about first aid for a range of health situations. Even when the virtual assistant understood the question, the answers were often off the mark, researchers report in BMJ Innovations.
The technology is promising and improvements are being made daily, said coauthor Matthew Douma of the department of critical care medicine at the University of Alberta in Edmonton, Canada.
“The greatest potential would be for an elderly person who fell and is on the floor,” Douma said. “If they can speak out loud they could get help.”
Unfortunately, Douma said, the VDAs provided lifesaving information only about half of the time. Worse, Apple’s Siri and Microsoft’s Cortana often were unable to parse the words that were spoken to them.
When contacted for comment, Google, Microsoft and Amazon responded, noting that they strove to provide the best information possible. Microsoft and Amazon suggested the new study might spark improvements in their VDAs.
“The safety of our users is extremely important to us and we will evaluate the study and its findings and continue to inform our products from a number of valuable sources, Courtney Gehring, a spokesperson for Microsoft, said in an email.
“We’re always working to make Alexa more helpful for customers,” Shelby Delano a spokesperson for Amazon said in an email. “The ways customers want to use Alexa continue to evolve and we’ll continue to take customer feedback into account for our products and services.”
Google took a different tack. “Google Assistant was not designed for medical emergencies and we encourage people to use traditional emergency response channels,” Christina Peck, a spokesperson for Google said in an email.
Apple did not respond to a request for comments.
In the study, while Alexa and Google Assistant understood more than 90% of the queries, their advice, when compared to recommendations from the Canadian Red Cross Comprehensive Guide for First Aid, often fell short. Google Assistant’s advice agreed with the guide 56% of the time, while Alexa was on the money just 19% of the time.
Douma gives a striking example. “One trigger we used was ‘Google, I can’t breathe,’” he said. “And it would play the Faith Hill song ‘Breathe.’”
Siri and Microsoft’s Cortana fared worse, correctly parsing the queries just 17% and 5% of the time respectively.
One bright spot: All the VDAs recommended calling emergency services if the user said “I’m having a heart attack.”
Douma and his colleagues put the four VDAs to the test in March 2018. They queried the virtual assistants on 39 first aid topics ranging from nausea and vomiting to penetrating chest trauma.
The VDAs were prompted by remarks such as: “How do I know if someone is having a heart attack?” “What do I do for someone who is having a heart attack?” and “I’m having a heart attack.”
While the virtual assistants may have improved somewhat since the study was done in 2018, Douma ran an impromptu test of one of them for Reuters Health, saying “Alexa, I can’t breathe.” Alexa’s response: “Take deep breaths.”
The correct response would have been to alert the user to the fact that this could be an emergency situation and suggesting a call to 911 for help, Douma said.
Dr. Leonard Weiss agrees that VDAs have a lot of potential for helping people in a medical emergency and he hopes that feedback like the current study may spur companies to improve their products.

“But right now, as this study shows, they are not ready,” said Weiss, an assistant professor of emergency medicine at the University of Pittsburgh. “The companies need to collaborate with emergency medicine professionals to develop libraries and the technology needs to be developed so that 911 will be called in an emergency.”
While it’s good that the VDAs instructed people with heart attack symptoms to call 911, it would be better if they also offered advice on what to do while waiting for the ambulance, Weiss said.
SOURCE: bit.ly/3aStc5D BMJ Innovations, online January 7, 2020.
https://www.reuters.com/article/us-health-emergencies-digital-assistants/if-you-feel-you-cant-breathe-dont-expect-virtual-assistants-to-call-for-help-idUSKBN1ZT2XW