Category Archives: Transhuman News

When oncologists talk about cancer targets, theyre usually referring to mutated genes that can be thwarted with drugs. Researchers at the University of Pennsylvania used gene-editing technology CRISPR to elucidate a different sort of target in acute myeloid leukemia (AML)and to uncover a way to target it with drugs.

A team at Penns medical school discovered that an epigenetic regulatory protein called ZMYND8 governs the expression of genes that are critical for the growth and survival of AML cells. Inhibiting ZMYND8 in mouse models shrank tumors. The researchers also found a biomarker that they believe could predict which patients are likely to respond to ZMYND8 inhibition, they reported in the journal Molecular Cell.

AML is one of the hardest leukemias to treat, with a five-year survival rate of about 27% in adults. The Penn team had been searching for precision medicine approaches that could improve the prognosis for adults with AML, and they turned to CRISPR for help.

ZMYND8 is known as a histone reader in cancer that can recognize epigenetic changes and influence gene expression involved in metastasis.

Using CRISPR, the Penn team disrupted various functions of proteins in cancer cells and mapped their functions on a molecular level. When they blocked the epigenetic reader function of ZMYND8 in mouse models, it not only caused tumors to shrink, but also improved survival, they said in a statement. With CRISPR, they were able to pinpoint a pocket on ZMYND8 that they believe could be targeted with drugs.

RELATED: Novartis-backed Penn study proposes boosting CAR-T responses in CLL by waking up 'war weary' T cells

Several efforts to develop new treatments for AML have hit roadblocks of late. The FDA placed a hold on trials of Aprea Therapeutics eprenetapopt in AML after worrisome side effects appeared in a trial of the drug in myelodysplastic syndrome. Amgen had been developing a bispecific antibody for AML, AMG 427, but stopped a phase 1 trial after some patients developed the dangerous side effect cytokine release syndrome. The company is now investigating ways to optimize the treatment approach, a spokesperson said earlier this month.

Several immuno-oncology approaches to AML are under development, including engineered natural killer cell therapies, and researchers are investigating a range of targeted approaches such as combining MDM2 and BET blockers.

The Penn researchers wanted to see whether they could predict how sensitive AML cells might be to ZMYND8 inhibition, so they turned to blood samples from patients treated at Penn Medicine. They found that high expression of a particular gene in those cells, IRF8, could serve as a biomarker of response to ZMYND8 inhibition.

CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on, and one that we can potentially manipulate, said co-author Shelley Berger, Ph.D., professor at the Perelman School of Medicine and director of the Penn Epigenetics Institute, in the statement. It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.

Continue reading here:
CRISPR pinpoints new leukemia target and a 'pocket' that could make it druggable - FierceBiotech

We live in a unique time when for the first time in human history there is a real opportunity to extend our lives dramatically. Recent scientific discoveries and technological breakthroughs that soon will translate into affordable and accessible life-extending tools will let us break the sound barrier of the current known record of 122 years. I am talking about breakthroughs in genetic engineering, regenerative medicine, healthcare hardware, and health data.

Very soon, slowing, reversing, or even ending aging will become a universally accepted ambition within the healthcare community. Technology is converging to make this a certainty. Developments in the understanding and manipulation of our genes and cells, in the development of small-scale health diagnostics, and in the leveraging of data for everything from drug discovery to precision treatment of disease are radically changing how we think about healthcare and aging.

When I speak of the Longevity Revolution, what I really mean is the cumulative effect of multiple breakthroughs currently underway across several fields of science and technology. Together, these parallel developments are forming the beginning of a hockey-stick growth curve that will deliver world-changing outcomes.

Completed in 2003, the Human Genome Project successfully sequenced the entire human genomeall 3 billion nucleotide base pairs representing some 25,000 individual genes. The project, arguably one of the most ambitious scientific undertakings in history, cost billions of dollars and took 13 years to complete. Today, your own genome can be sequenced in as little time as a single afternoon, at a laboratory cost of as little as $200.

The consequences of this feat are nothing short of revolutionary. Gene sequencing allows us to predict many hereditary diseases and the probability of getting cancer. This early benefit of gene sequencing became widely known when Angelina Jolie famously had a preventative double mastectomy after her personal genome sequencing indicated a high vulnerability to breast cancer. Genome sequencing helps scientists and doctors understand and develop treatments for scores of common and rare diseases. Along with advances in artificial intelligence, it helps determine medical treatments precisely tailored to the individual patient.

Longevity scientists have even identified a number of so-called longevity genes that can promise long and healthy lives to those who possess them. Scientists now understand far better than ever before the relationship between genes and aging. And while our genes do not significantly change from birth to death, our epigenomethe system of chemical modifications around our genes that determine how our genes are expresseddoes. The date on your birth certificate, it turns out, is but a single way to determine age. The biological age of your epigenome, many longevity scientists now believe, is far more important.

Best of all, however, science is beginning to offer ways to alter both your genome and epigenome for a healthier, longer life. New technologies like CRISPR-Cas9 and other gene-editing tools are empowering doctors with the extraordinary ability to actually insert, delete, or alter an individuals genes. In the not terribly distant future, we will be able to remove or suppress genes responsible for diseases and insert or amplify genes responsible for long life and health.

Gene editing is just one of the emerging technologies of the genetic revolution: Gene therapy works by effectively providing cells with genes that produce necessary proteins in patients whose own genes cannot produce them. This process is already being applied to a few rare diseases, but it will soon become a common and incredibly effective medical approach. The FDA expects to approve 10 to 20 such therapies by the year 2025.

Another major transformation driving the Longevity Revolution is the field of regenerative medicine. During aging, the bodys systems and tissues break down, as does the bodys ability to repair and replenish itself. For that reason, even those who live very long and healthy lives ultimately succumb to heart failure, immune system decline, muscle atrophy, and other degenerative conditions. In order to achieve our ambition of living to 200, we need a way to restore the body in the same way we repair a car or refurbish a home.

Several promising technologies are now pointing the way to doing just that. While it is still quite early, there are already a few FDA-approved stem cell therapies in the United States targeting very specific conditions. Stem cellscells whose job it is to generate all the cells, tissues, and organs of your bodygradually lose their ability to create new cells as we age. But new therapies, using patients own stem cells, are working to extend the bodys ability to regenerate itself. These therapies hold promise for preserving our vision, cardiac function, joint flexibility, and kidney and liver health; they can also be used to repair spinal injuries and help treat a range of conditions from diabetes to Alzheimers disease. The FDA has approved 10 stem cell treatments, with more likely on the way.

Its one thing to replenish or restore existing tissues and organs using stem cells, but how about growing entirely new organs? As futuristic as that sounds, it is already beginning to happen. Millions of people around the world who are waiting for a new heart, kidney, lung, pancreas, or liver will soon have their own replacement organs made to order through 3D bio-printing, internal bioreactors, or new methods of xenotransplantation, such as using collagen scaffoldings from pig lungs and hearts that are populated with the recipients own human cells.

Even if this generation of new biological organs fails, mechanical solutions will not. Modern bioengineering has successfully restored lost vision and hearing in humans using computer sensors and electrode arrays that send visual and auditory information directly to the brain. A prosthetic arm developed at Johns Hopkins is one of a number of mechanical limbs that not only closely replicate the strength and dexterity of a real arm but also can be controlled directly by the wearers mindjust by thinking about the desired movement. Today, mechanical exoskeletons allow paraplegics to run marathons, while artificial kidneys and mechanical hearts let those with organ failure live on for years beyond what was ever previously thought possible!

The third development underpinning the Longevity Revolution will look more familiar to most: connected devices. You are perhaps already familiar with common wearable health-monitoring devices like the Fitbit, Apple Watch, and ura Ring. These devices empower users to quickly obtain data on ones own health. At the moment, most of these insights are relatively trivial. But the world of small-scale health diagnostics is advancing rapidly. Very soon, wearable, portable, and embeddable devices will radically reduce premature death from diseases like cancer and cardiovascular disease, and in doing so, add years, if not decades, to global life expectancy.

[Photo: BenBella Books]The key to this part of the revolution is early diagnosis. Of the nearly 60 million lives lost around the globe each year, more than 30 million are attributed to conditions that are reversible if caught early. Most of those are noncommunicable diseases like coronary heart disease, stroke, and chronic obstructive pulmonary disease (bronchitis and emphysema). At the moment, once you have gone for your yearly physical exams, stopped smoking, started eating healthy, and refrained from having unprotected sex, avoiding life-threatening disease is a matter that is largely out of your hands. We live in a world of reactive medicine. Most people do not have advanced batteries of diagnostic tests unless theyre experiencing problems. And for a large percentage of the worlds population, who live in poor, rural, and remote areas with little to no access to diagnostic resources, early diagnosis of medical conditions simply isnt an option.

But not for long. Soon, healthcare will move from being reactive to being proactive. The key to this shift will be low-cost, ubiquitous, connected devices that constantly monitor your health. While some of these devices will remain external or wearable, others will be embedded under your skin, swallowed with your breakfast, or remain swimming through your bloodstream at all times. They will constantly monitor your heart rate, your respiration, your temperature, your skin secretions, the contents of your urine and feces, free-floating DNA in your blood that may indicate cancer or other disease, and even the organic contents of your breath. These devices will be connected to each other, to apps that you and your healthcare provider can monitor, and to massive global databases of health knowledge. Before any type of disease has a chance to take a foothold within your body, this armory of diagnostic devices will identify exactly what is going on and provide a precise, custom-made remedy that is ideal just for you.

As a result, the chance of your disease being diagnosed early will become radically unshackled from the limitations of cost, convenience, and medical knowledge. The condition of your body will be maintained as immaculately as a five-star hotel, and almost nobody will die prematurely of preventable disease.

There is one final seismic shift underpinning the Longevity Revolution, and its a real game-changer. Pouring forth from all of these digital diagnostic devices, together with conventional medical records and digitized research results, is a torrent of data so large it is hard for the human mind to even fathom it. This data will soon become grist for the mill of powerful artificial intelligence that will radically reshape every aspect of healthcare as we know it.

Take drug discovery, for instance. In the present day, it takes about 12 years and $2 billion to develop a new pharmaceutical. Researchers must painstakingly test various organic and chemical substances, in myriad combinations, to try to determine the material candidates that have the best chance of executing the desired medical effect. The drugs must be considered for the widest range of possible disease presentations, genetic makeup, and diets of targeted patients, side effects, and drug interactions. There are so many variables that it is little short of miraculous that our scientists have done so much in the field of pharmaceutical development on their own. But developing drugs and obtaining regulatory approval is a long and cash-intensive process. The result is expensive drugs that largely ignore rarer conditions.

AI and data change that reality. Computer models now look at massive databases of patient genes, symptoms, disease species, and millions of eligible compounds to quickly determine which material candidates have the greatest chance of success, for which conditions, and according to what dose and administration. In addition to major investments by Big Pharma, there are currently hundreds of startups working to implement the use of AI to radically reshape drug discovery, just as we saw happen in the race to develop COVID-19 vaccines. The impact that this use of AI and data will have on treating or even eliminating life-threatening diseases cannot be overstated.

But that is not the only way that artificial intelligence is set to disrupt healthcare and help set the Longevity Revolution in motion. It will also form the foundation of precision medicinethe practice of custom-tailoring health treatments to the specific, personal characteristics of the individual.

Today, healthcare largely follows a one-size-fits-all practice. But each of us has a very unique set of personal characteristics, including our genes, microbiome, blood type, age, gender, size, and so on. AI will soon be able to access and analyze enormous aggregations of patient data pulled together from medical records, personal diagnostic devices, research studies, and other sources to deliver highly accurate predictions, diagnoses, and treatments, custom-tailored to the individual. As a result, healthcare will increasingly penetrate remote areas, becoming accessible to billions of people who today lack adequate access to medical care.

I predict that the development of AI in healthcare will change how we live longer, healthier lives as radically as the introduction of personal computers and the internet changed how we work, shop, and interact. Artificial intelligence will eliminate misdiagnosis; detect cancer, blood disease, diabetes, and other killers as early as possible; radically accelerate researchers understanding of aging and disease; and reestablish doctors as holistic care providers who actually have time for their patients. In as little as 10 years time, we will look back at the treatment of aging and disease today as quite naive.

The Longevity Revolution lives not in the realm of science fiction but in the reality of academic research laboratories and commercial technology R&D centers. The idea of aging as a fixed and immutable quality of life that we have no influence upon is ready to be tossed into the dustbin of history.

Sergey Young is a renowned VC, longevity visionary, and founder of the $100 million Longevity Vision Fund. This is an adapted excerpt from The Science and Technology of Growing Young, with permission by BenBella Books.

Read more:
These 4 tech breakthroughs could help end aging - Fast Company

BEIJING, Aug. 23, 2021 (GLOBE NEWSWIRE) -- Genetron Holdings Limited (Genetron Health or the Company, NASDAQ: GTH), a leading precision oncology platform company in China that specializes in offering molecular profiling tests, early cancer screening products and companion diagnostics development, today announced the signing of a strategic partnership with Shanghai Yikon Genomics Technology Co., Ltd. (Yikon Genomics), a company that focuses on reproductive health diagnostic testing. Genetron Health expects this partnership to contribute to its 2021 revenues.

Under the agreement, Yikon Genomics will have the exclusive rights to use Genetron Healths S5 instrument for reproductive health applications in the China market. Yikon Genomics currently offers pre-pregnancy, prenatal and inheritance disorder testing solutions for a network of over 400 hospital partners in China. The partners will cooperate with each other to drive forward registration processes for new assays that are developed on the S5 platform. Genetron Health will also support Yikon Genomics commercialization efforts. GENETRON S5 has been successfully used in many different oncology settings, and through this partnership, will be expanding its applications to include reproductive health, widening the Companys scope of precision medicine.

Approved by the NMPA in 2019 and based on new semiconductor sequencing technology, GENETRON S5 is Chinas desktop, clinical-grade, medium-throughput next generation sequencing (NGS) platform. GENETRON S5s advantages lie in its fast detection, flexible throughput, low initial sample size requirements, and comprehensive range of different applications. Genetron Health has used this platform to develop in-vitro diagnostic (IVD) kits that cover multiple cancer types and different sample types, including the 8-gene Lung Cancer (Tissue) assay. With GENETRON S5, the Company has developed an integrated solution for molecular diagnostics laboratories, and carried out clinical trials and scientific research partnerships with many different organizations. These efforts have enabled hospitals in China to adopt NGS technology for independent, clinical diagnostic use.

Story continues

"GENETRON S5s flexible and open characteristics have laid the groundwork for clinical applications in the reproductive health field. We are committed to using an open platform to provide versatile, multi-dimensional solutions for our hospital partners, said Sizhen Wang, co-founder and CEO of Genetron Health. We are pleased to become Yikon Genomics strategic partner. We hope to leverage our respective strengths so that we can introduce a comprehensive range of high-performance, personalized, precision medicine solutions to patients, making innovative genetic technology more accessible to the public."

"Genetron Health focuses on precision medicine and genomics research, possesses a high-quality innovation platform, and has a strong track record of successfully commercializing new technologies, said Sijia Lu, co-founder and CEO of Yikon Genomics. We think there are significant synergies in this partnership, and we are excited to adopt the 'platform + reagent' strategy for Chinas reproductive health market."

About Genetron Holdings Limited

Genetron Holdings Limited (Genetron Health or the Company) (Nasdaq:GTH) is a leading precision oncology platform company in China that specializes in cancer molecular profiling and harnesses advanced technologies in molecular biology and data science to transform cancer treatment. The Company has developed a comprehensive oncology portfolio that covers the entire spectrum of cancer management, addressing needs and challenges from early screening, diagnosis and treatment recommendations, as well as continuous disease monitoring and care. Genetron Health also partners with global biopharmaceutical companies and offers customized services and products. For more information, please visit ir.genetronhealth.com.

About Yikon Genomics

Yikon Genomics, established in 2012, is dedicated to the development and application of single-cell whole-genome amplification and sequencing technologies. The companys primary focus is reproductive health, providing sophisticated testing solutions for pre-pregnancy, prenatal and inheritance disorders in China. Yikon Genomics have partnered with over 400 medical institutions and hospitals in China, as well as a number of world-class research institutes. Its business covers 32 provinces and municipalities in China, and through partnerships with international reproductive medicine centers, has expanded to more than 20 countries worldwide, including the United States, United Kingdom, Russia, and Japan.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of federal securities laws which involve risks and uncertainties that could cause the actual results to differ materially from the anticipated results and expectations expressed in these forward-looking statements. These statements are made under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Statements that are not historical facts, including statements about the Companys beliefs and expectations, are forward-looking statements. Forward-looking statements involve inherent risks and uncertainties, and a number of factors could cause actual results to differ materially from those contained in any forward-looking statement. In some cases, forward-looking statements can be identified by words or phrases such as may, will, expect, anticipate, target, aim, estimate, intend, plan, believe, potential, continue, is/are likely to or other similar expressions. Further information regarding these and other risks, uncertainties or factors is included in the Companys filings with the SEC. All information provided in this press release is as of the date of this press release, and the Company does not undertake any duty to update such information, except as required under applicable law.

Media Relations ContactYanrong Zhaoyanrong.zhao@genetronhealth.com

Investor Relations ContactHoki Lukhoki.luk@genetronhealth.com

Read the original:
Genetron Health Reaches Strategic Partnership with Yikon Genomics, Expanding S5 Platforms Reach to Reproductive Health Field - Yahoo Finance

SOUTH PLAINFIELD, N.J., Aug. 23, 2021 /PRNewswire/ --PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced the publication of a manuscript, "Gene Therapy in the Putamen for Curing AADC Deficiency and Parkinson's Disease," in the European Molecular Biology Organization Journal. The paper describes a pioneering approach that delivers gene therapy to a specific part of the brain called the putamen, which is helping successfully treat a previously intractable, devastating disorder and transforming the lives of children born with AADC deficiency (AADC-d)1.

"I am excited about what the success of this new approach means for the children and families living with AADC deficiency," said Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics. "AADC deficiency is a terrible, life-shortening condition that requires around-the-clock care. The data reported in this article show that the surgical approach of delivering our novel PTC-AADC gene therapy directly to the putamen robustly produces dopamine in the brain that results in sustained and substantial functional improvements in children with AADC deficiency."

Currently there are no approved disease-modifying therapies for treating AADC-d, and the success of symptomatic treatment using combinations of vitamin B6, dopamine (DA) agonists, and monoamine oxidase inhibitors is very limited, especially in severe cases2.

The paper, authored by global experts in the United States, Taiwan, France, Germany, and Japan, describes three clinical trials in which AAV2-hAADC was infused into the putamen of children with AADC-d via brain surgery. Prior to treatment, most of the children with AADC-d had never developed muscle control, could not lift their heads, move on their own or talk, and nearly all were bed ridden. Every child in the trials showed significant improvements following treatment with PTC's novel gene therapy, PTC-AADC1.

The clinical benefits and safety profile of PTC-AADC has been demonstrated across multiple trials, with the first patient dosed more than 10 years ago, in 2010. The trials together represent the largest cohort of AADC-d patients ever studied.

"The remarkable results published have been life-changing for the children we have treated," said co-author and investigator Paul Wuh-Liang Hwu, National Taiwan University Hospital. "Before this treatment, the children with AADC deficiency couldn't lift their heads, but now some can sit and stand with help, and have even begun learning to talk."

AADC deficiency is a debilitating neurological disorder that involve motor dysfunction caused by dopamine deficiencies. Dopamine is a neurotransmitter that is critical for motor and mental development1. The studies demonstrate that the restoration of DA synthesis in the putamen via gene therapy using low doses of AAV2-hAADC is well tolerated, leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency, and beneficial for the patients. The novel gene therapy, PTC-AADC was delivered to the putamen because it is more easily accessible via surgery than other sites, and therefore, may result in fewer surgical complications. In neurological disorders such as AADC-d, the putamen is directly impacted by the loss of DA synthesis in the striatum1.

PTC-AADC is currently under review by the European Medicines Agency's Committee for Medicinal Products for Human Use with an opinion expected in the fourth quarter of 2021.

About aromatic L-amino acid decarboxylase (AADC) deficiencyAADC deficiency is a fatal, ultra-rare genetic disorder that causes severe disability and suffering from the first months of life, affecting every aspect of life physical, mental, and behavioral1,2,[3]. The suffering of children with AADC deficiency is exacerbated by episodes of distressing seizure-like oculogyric crises, which can happen daily and last for hours, causing the eyes to roll up in the head, frequent vomiting, behavioral problems, difficulty sleeping, and life-threatening complications such as respiratory infections and gastrointestinal problems2,[4],[5],[6].

Current management options yield limited improvement for the majority of patients with AADC-d.2Managing patients with AADC-d requires a multidisciplinary team of specialists and complex coordination of care to address significant health issues, including developmental delays, infections, orthopaedic and cardiac complications, and other comorbidities2

While several diagnostic tests for AADC deficiency are available, the condition remains largely undiagnosed or misdiagnosed for other conditions with similar symptoms, such as cerebral palsy and some forms of epilepsy4,[7].

About PTC Therapeutics, Inc.PTC Therapeutics is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's mission is to provide access to best-in-class treatments for patients with an unmet medical need, using its ability to globally commercialize products as the foundation to drive investment in a robust and diversified pipeline of transformative medicines. The Company's strategy is to leverage its strong scientific expertise and global commercial infrastructure to maximize value for its patients and other stakeholders. To learn more about PTC, please visit us at http://www.ptcbio.com and follow it on Facebook, on Twitter at @PTCBio, and on LinkedIn.

For More Information:

Investors Kylie O'Keefe+1 (908) 300-0691[emailprotected]

Media Jane Baj+1 (908) 912-9167[emailprotected]

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of clinical trials and studies, availability of data, regulatory submissions and responses and other matters; expectations with respect to PTC's gene therapy platform, including any regulatory submissions and manufacturing capabilities; PTC's expectations with respect to the licensing, regulatory submissions and commercialization of its other products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions.

PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; expectations with respect to PTC's gene therapy platform, including any regulatory submissions and potential approvals, manufacturing capabilities and the potential financial impact and benefits of its leased biologics manufacturing facility and the potential achievement of development, regulatory and sales milestones and contingent payments that PTC may be obligated to make; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's most recent Quarterly Report on Form 10-Q and Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors.

As with any pharmaceutical under development, there are significant risks in the development, regulatory approval, and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including PTC-AADC.

The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law.

1Hwu WL, Kiening K, Anselm I et al. Gene Therapy in thePutamen forCuring AADC Deficiency and Parkinson Disease'. EMBOMolecMedicine. 2021. DOI 10.15252/emmm.202114712. Available at: https://www.embopress.org/doi/10.15252/emmm.202114712. Last accessed August 2021.2Wassenberg T, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12.3Williams K et al. Symptoms and impacts of aromatic l-amino decarboxylase (AADC) deficiency: A qualitative study. Poster presented at ISPOR 2021, May 17-20, 20214Pearson T et al. AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020 Sep;43(5):1121-1130.5Chien YH, et al. 3-O-methyldopa levels in newborns: Result of newborn screening for aromaticl-amino-acid decarboxylase deficiency. Mol Genet Metab. August 2016;118(4):259-263.6Buesch K et al. Caring for an Individual with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: Analysis of Reported Time for Practical and Emotional Care and Paid/Unpaid Help. Poster presented at ISPOR 2021, May 17-20, 2021.7Chien YH, et al. 3-O-methyldopa levels in newborns: Result of newborn screening for aromaticl-amino-acid decarboxylase deficiency. Mol Genet Metab. August 2016;118(4):259-263

SOURCE PTC Therapeutics, Inc.

Homepage

More here:
Targeting the Putamen with Gene Therapy Leads to Sustained Improvements in Motor and Non-Motor Functions in Children with AADC Deficiency - PRNewswire

SHANGHAI, Aug.23, 2021 /PRNewswire/ -- Hepagene Therapeutics, Inc., a clinical stage biopharmaceutical company focusing on novel therapies for patients with liver diseases, today announced positive results from its Phase I study of HPG1860 conducted in the United States. HPG1860 is a non-bile acid, potent, selective and full FXR agonist being developed for treatment of non-alcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC). Findings show that treatment with HPG1860 was safe, well-tolerated and demonstrated a robust target engagement with a favorable pharmacokinetic (PK) profile after 14 days of once daily dosing in healthy volunteers. Detailed results will be presented at upcoming AASLD international liver conference.

The Hepagene phase I trial was a first-in-human, randomized, placebo-controlled, double-blind single-ascending dose (SAD) and multiple-ascending dose (MAD) trial, in which healthy volunteers received once-daily HPG1860 doses ranging from 10 mg to 100 mg in the SAD cohorts and 5 mg to 20 mg in the MAD cohorts for 14 days. The primary objective of the trial was to evaluate safety/tolerability and the secondary objectives were to assess PK parameters and FXR target engagement, the latter through measurement of fibroblast growth factor 19 (FGF19) and 7-hydroxy-4-cholesten-3-one (C4), blood biomarkers of bile acid synthesis and metabolic homeostasis that increases and decreases respectively with FXR activation.

HPG1860 was safe and generally well-tolerated with no serious adverse events reported. Most adverse events were mild in severity. Importantly, pruritus only occurred in highest dose cohort (20 mg) and LDL-cholesterol increases were not seen at any dose level. HPG1860 exhibited a favorable PK profile as well as robust FXR target engagement with notable C4 regression 93.1%, 97.0% and 97.6% decrease observed after the last dose in MAD 5 mg, 10 mg and 20 mg cohorts compared with placebo. The magnitude of C4 decrease can be used to project potential liver fat reduction level in NASH patients, with 30% relative liver fat reduction being associated with increased likelihood of histological benefits upon liver biopsy.

"We are encouraged by the overall safety profile of HPG1860, and meaningful target engagement seen at as low as the 5 mg dose level. We plan to evaluate the 3 mg, 5mg and 8 mg dose levels in our upcoming Phase IIa trial in NASH patients," said Que Liu, M.D., PhD, Chief Medical Officer ofHepagene.

"It is encouraging to see that there was no significant increase in LDL cholesterol despite excellent FXR target engagement with sustained C4 suppression." said Rohit Loomba, MD, MHSc, Professor of Medicine, and Director, UCSD NAFLD Research Center, University of California at San Diego, La Jolla, CA.

"NASH is a complex liver disease with multiple pathways involved in liver cell injury, inflammation and fibrosis development. FXRs have been shown to impact the underlying pathology of NASH in a meaningful way. Combination therapy, involving multiple mechanisms of action, is likely going to be needed to combat this disease effectively, providing an opportunity for HPG1860. The early data presented here are very encouraging from a safety and tolerability perspective and I am looking forward to beginning the phase 2 study." said Stephen Harrison, MD, Medical Director of Pinnacle Clinical Research in San Antonio, Texas.

Based on the Phase 1 safety and PK/PD data, Hepagene plans to advance three dose levels of HPG1860 3 mg, 5 mg and 8 mg in a 12-week, randomized, placebo-controlled Phase IIa trial enrolling about 80 patients with NASH in US. The selected doses are projected to inhibit C4 to levels that are likely to result in meaningful reductions in liver fat content. The trial is scheduled to start in the last quarter of 2021, with an interim analysis planned in the first half of 2022.

About HPG1860

HPG1860 is an investigational potent and selective full FXR agonist with a non-bile acid scaffold and is currently in first-in-human clinical phase I study. Through regulation of gene expression of bile acids, FXR serves as a key controller of bile acid homeostasis. FXR has been studied for its role in modulating inflammation and the expression of FXR is down-regulated during NASH development. HPG1860 exhibited superb efficacy and safety profile in preclinical research.

About NASH

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide, with an approximate prevalence of 20-30% in western countries. An estimated 20-25% of these patients will further progress to NASH, marked by steatohepatitis, ballooning and inflammation. Typically, NASH is accompanied with liver fibrosis that can progress to liver cirrhosis and hepatocellular carcinoma.

About Hepagene Therapeutics, Inc.

Hepagene Therapeutics, Inc. devotes its drug discovery and development efforts towards discovering, developing and delivering innovative medicines that help patients prevail over liver diseases, especially non-alcoholic steatohepatitis (NASH), chronic Hepatitis B infection and liver cancer.

SOURCE Hepagene Therapeutics, Inc.

Follow this link:
Hepagene Therapeutics, Inc. Announces Positive Results from Phase I Trial of HPG1860 - PRNewswire

Introduction

The lifelong administration of combination antiretroviral therapy (ART) can effectively suppress viral replication and reduce morbidity and mortality of people living with HIV (PLWH).1 There are multiple classes of ART drugs, including nucleoside reverse transcriptase inhibitors (NRTI) including lamivudine (3TC) and azidothymidine (AZT), non-nucleoside reverse transcriptase inhibitors (NNRTI) including nevirapine (NVP), protease inhibitors (PI) including Lopinavir/Ritonavir (LPV/r) and the integrase strand transfer inhibitor (INSTI) raltegravir (RAL).2 In recent years, the rapid expansion of access to ART has led to the emergence of multi-class drug resistance (MDR), defined as a virus mutant with resistance to at least three different drug classes.3

A previous study of a large cohort of cART-experienced patients in Italy showed a dramatic drop in drug resistance from 8085% in 1999 to around 36% in 2018. In recent years (201118), the percentage of isolates with at least three classes of drug resistance has remained stable at around 5% (range 36%).4 The majority of these patients have been found to have a long history of HIV infection, with previous exposure to suboptimal therapies, and to have, over time, accumulated many mutations resistant to several drug classes.4 The viral evolutionary dynamics within these patients that leads to the development of MDR has not been well documented.

Most drug resistance data have been collected from patients infected with HIV-1 subtype B in the United States, Oceania, and Europe. When ART has become increasingly available in new geographic areas, drug resistance in a diverse group of M subtypes and distinct circulating recombinant forms (CRFs) has evolved. CRF01_AE emerged in Southeast Asia in the 1990s, expanded rapidly in China, and is now the most prevalent HIV-1 form in Southeast Asia.5,6 Previous studies have identified a 920% higher resistance mutation frequency at reverse transcriptase positions in CRF01_AE than in subtype B, and a 1218% higher predicted cross-resistance to future therapy options.7 The influence of genetic variation across subtypes has therefore become an active area of research into resistance evolution and disease progression.

In our previous study of the evolutionary patterns during ART failure, plasma and peripheral blood mononuclear cells (PBMC) were longitudinally sampled at different time points from a single patient who suffered several periods of ART failure before successful reduction of viral load. The different intrapatient evolutionary dynamics patterns of env and pol viral segments witness not only the emergence of drug resistant mutants, but also the switch of tropism.8

In the current study, the same longitudinal approach was applied to learn more about the viral evolutionary dynamics during the development of four-class MDR in a single patient infected with the CRF01_AE experiencing ART failure and subsequent mortality. The distribution and percent of drug resistance mutants in the reverse transcriptase (RT), protease (PR) and integrase (IN) genes were determined by next generation sequencing, and the demographic history of the HIV DNA reservoir in PBMC was reconstructed by applying phylodynamics methods.

A 27-year-old patient was diagnosed as HIV-positive in August 2008. PBMC and plasma samples were collected at different time points from September, 2013 to June, 2017 (Figure 1). The study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.

Figure 1 Schematic representing the treatment and sampling protocols used in this study. This patient initiated antiretroviral therapy with 3TC+AZT+NVP in August 2008, switched to 3TC+AZT+LPV/r in August 2013, and to 3TC+AZT+LPV/r+RAL in March 2015. Samples used in the study were collected at different time points shown on top of the schematic. Rectangles represent plasma and circles represent PBMC.

Plasma samples were tested for viral load during treatment. The patient had been diagnosed as HIV-positive in August 2008 and initiated ART with 3TC+AZT+NVP. The ART regimen was switched to 3TC+AZT+LPV/r in August 2013 because of unsuppressed viral load (1*105 copies/mL) and detection of reverse transcriptase resistant mutations, both to NRTI and NNRTI. One month later, in September, 2013, viral load decreased to about 1.4*103 copies/mL, and was under the detection limit (50 copies/mL) from March, 2014 to December 2014. In March, 2015, the ART regimen was changed, to 3TC+AZT+LPV/r+RAL, again due to unsuppressed viral load (5.4*104 copies/mL). By June, 2017, two years later, the viral load had increased, to 1.8*105 copies/mL (Table 1), and was followed by the patients death in August, 2017.

Table 1 Characteristics of Drug-Resistant Mutant Sequences Isolated from Plasma

All collected samples during treatment were sequenced by Sanger sequencing and Next Generation Sequencing (NGS) techniques. The purified PR/RT amplicon and IN amplicon were randomly interrupted by Covaris ultrasonic breaker and then used for library preparation (NEBNext Ultra II DNA Library Prep Kit for Illumina) according to manufacturers instructions. Sequencing was carried out by the Illumina high-throughput sequencing platform (Nova-Seq). After data processing and quality filtering performed to obtain clean data, fastq files were aligned and generated the codon frequency tables using fastq2codfreq script (https://hivdb.stanford.edu/page/codfreq/). Then, the codon frequency tables were submitted to HIVdb-NGS beta for genotypic resistance interpretations and quality control analysis. Minimum detection threshold was set to 1% for all samples, because detection below a frequency of 1% may cause failed quality assessment. ShoRAH was applied to convert NGS sequence variants into haplotypes.9

MUSCLE software (v3.8.31)10 was used to align all RT, PR and IN sequences from plasma viral RNA and cellular DNA collected during the ART therapy. Alignments were manually edited and trimmed to 297 nucleotides for PR (HBX2: 22532549), 903 nucleotides for RT (HBX2: 25503452) and 780 nucleotides for IN (HBX2: 42905069) using BioEdit software (v7.0.9). Shorter sequences and sequences with stop codons or gaps larger than a nucleotide triplet were removed from the alignments. The best-fitting nucleotide substitution model was selected with jModeltest software (v2.1.7),11 using the Akaike Information Criterion (AIC). Phylogenetic trees were inferred using PhyML software (v3.0).12 Bootstrap analysis was performed on 1000 replicates.

The demographic history of the HIV reservoir in PBMC was estimated using the BEAST software13 and implemented in the Bayesian Markov chain Monte Carlo (MCMC) method. The Bayesian skyline model14 and strict clock model were incorporated in the MCMC method. Multiple independent MCMC runs were performed and assessed for consistency. Convergence of relevant parameters and Bayesian skyline results were assessed by effective sample sizes over 200 in Tracer v1.6 (http://tree.bio.ed.ac.uk/software/tracer/).

Over the course of three periods of treatment failure, the patient developed a four-class drug resistant virus population, in which we identified thirteen mutations associated with drug resistance. Five were in the RT gene - M41L, K65R, K70T, Y181C and G190A; four in the PR gene - M46I, I54L, L76V, and I84; and four in the IN gene - E138K, G140A, S147G, Q148R.

Sampling for this study was initiated after the patient was first diagnosed with ART failure, five years after ART treatment was first initiated. By that time, In September, 2013, almost 100% of PBMC virus already had mutants resistant to NRTI and NNRTI, and these levels persisted throughout periods of treatment, even during 2014, when plasma viral load was under the limit of detection.

After the introduction of the protease inhibitor Lopinavir/Ritonavir (LPV/r) to the patients ART, PI resistant mutants developed slowly in PMBC DNA. After one month, none were found; after sixteen months, less than 20% were mutants. After three years (two months prior to the patients death) PI mutants in PMBC DNA were still under 50%. PI resistant mutants in plasma had a different pattern. At sixteen months after the introduction of the PI no sequences could yet be identified because the viral level was too low for amplification. Eventually, substantially higher PI mutant levels were able to be found in plasma - almost 100% two years after a PI drug was switched to ART, by which time viral load had increased to 5.4*104 copies/mL.

Integrase strand transfer inhibitor (INSTI) mutations evolved much more quickly, replacing approximately 75% of the wild genotype in HIV DNA one year after addition of the integrase inhibitor raltegravir to the patients ART, and almost 100% after two years.

INSTI-resistant mutations, E138K, G140A, S147G and Q148R, replaced approximately 75% of the wild genotype in HIV DNA one year after addition of RAL to ART, and almost 100% 14 months later, by which time viral load reached 1.8*105 copies/mL. These results are displayed in Table 1 and Figure 2.

Figure 2 The development of Drug Resistant Mutants in Reverse Transcriptase (RT), Protease (PR) and Integrase (IN) Sequences in DNA from PBMC. Change in percent of drug resistant mutations in RT sequences, PR sequences and IN sequences. The vertical axes represent the percent of drug resistant mutants. Time scale is in calendar years and months.

In the RT gene, K65R and K70T mutations cause low resistance to 3TC and increased susceptibility to AZT. The Y181C and G190A mutants are associated with high-level resistance to NVP. M41L is a non-polymorphic mutation selected by thymidine analogs AZT. In the PR gene, M46I, L76V and I84V are non-polymorphic mutants selected by protease inhibitors. These mutants reduce susceptibility to LPV/r. In the IN gene, E138K, G140A and Q148R are also non-polymorphic mutants, selected by INSTI (RAL). Q148R is associated with high-level reductions in RAL susceptibility, particularly when it occurs in combination with E138K or G140A mutants (Table 2). All drug resistant mutation associations are based on the Stanford drug resistance database.15

Table 2 Characteristics of Drug-Resistant Mutant Sequences Isolated from PBMC

Because there were sufficient sequence data points from PBMC HIV DNA, Bayesian skyline plots were reconstructed to infer the dynamic of the effective population of RT, PR, and IN sequences in the PBMC. The effective population of RT sequences was shown to be stable over the entire testing period. However, the effective population of protease and integrase sequences underwent a significant increase in genetic variation during the period of treatment failure. After the switch of LPV/r to ART, the effective population of PR sequences first decreased and then increased with drug mutants selected by LPV/r. The effective population of IN sequences also decreased after the administration of PI, and stayed low for about six months. After the administration of INSTI, the effective population of IN sequences increased because of the drug resistant mutants selected by RAL. (Figure 3).

Figure 3 Demographic History of RT, PR and IN Sequences in DNA from PBMC. Bayesian skyline plots showing the effective population in the RT sequences (A), PR sequences (B) and IN sequences (C). Median estimates of the effective number of infections using Bayesian skyline (black curve) are shown in each graphic together with 95% highest probability density intervals of the Bayesian skyline estimates (blue area). The vertical axes represent the estimated effective number of infections on a logarithmic scale. Time scale is in calendar years. Vertical dotted lines indicate when a protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) were added to ART.

In this study, the mutant sequences have emerged during the development of a new four-class drug resistant HIV-1 CRF01_AE variant in a single patient, during several periods of therapy failure. This is a serious and challenging development since PLWHs harboring multi-class drug resistant virus have a high burden of disease, with a worrying incidence of malignancies and poorer survival after treatment failure.3,16

By the studys first sample collection point, almost 100% of viral sequences already had mutants resistant to NRTI and NNRTI in PBMC, so no significant change in the effective population of these sequences was observed over time. However, PI and INSTI drug resistant mutants gradually replaced the wild genotype, and drove the increase of genetic variability in HIV DNA. Demographic histories of these developments were generated by Bayesian skyline plot analysis, and demonstrate the genetic diversity in viral segment sequences over time, expressed as effective population.

This studys sequencing data showed significantly reduced genetic variability in both protease and integrase PBMC-derived variants directly following the administration of PI. A study by Besson et al investigated the decay of HIV DNA on ART and showed that the infected cell populations decline initially but then achieve a steady state with the persistence of about 10% of infected cells during effective ART.17 The different phase of decay occurs from the death of infected cells with different half-lives from days to months.18 The effective population increased when the drug resistant mutants were selected.

One previous study reported that the prevalence of INSTI resistance remained low compared with PI and RT resistance in ART-treated populations, but expanded with increased INSTI use between 2009 and 2016.19 The development of INSTI resistance described in this study suggests how that resistant pathway is evolving. Here the CRF01_AE virion developed INSTI resistant mutants by changes at position Q148, the most common mutant pathways previously described in all subtypes.20 There have been numerous reports of the emergence of substitutions involving position Q148 in response to RAL pressure. As substitutions at position Q148 impart a severe fitness cost,20 they are rapidly compensated for by various secondary resistance mutants, and the addition of at least two secondary mutants seems to confer the highest fold changes in resistance to second-generation INSTIs.21 E138K and G140A, identified in our study, are two of these mutants. The prevalence of the INSTI resistance mutants in CRF01_AE needs further investigation through a larger sample.

Drug-resistant mutants in HIV DNA emerged before they appeared in plasma through the use of next generation sequencing. The difference could be caused by the higher level of cell-associated HIV-1 RNA than in plasma RNA, which may contribute to the generation of new viral genomes, when plasma virus remains below the limit of detection.22 Some mutants could also remain in HIV DNA through persistence and/or proliferation of infected cells. These integrated and unintegrated provirus in latently infected cells may have a delayed contribution to the pool of resistant virus.23

While our study is limited to a single patient and several sampling timepoints, our data set and analysis demonstrated for the first time the evolution of sequences in the development of a four-class drug resistant HIV-1 CRF01_AE virion. It revealed dynamic shifts in the viral population and in drug-resistance mutants, while under the influence of complex ART regimens. This study utilized all samples available for this patient. Collection of baseline samples prior to initiation of ART, and at more sampling time points during treatment, will help us analyze evolutionary change in patient viral population. Our findings also suggested that next generation sequencing can be a very effective tool to detect a low level of drug resistance in HIV DNA, which could be critical for the clinical management of patients, especially those already experiencing virological failure while on particular ART regimens.

Both clinicians and patients need to be aware that a wide pattern of resistance can represent a strong negative prognostic factor for survival. Early detection of the development of drug resistant mutants should become a priority to prevent the further development of resistance through modification of ART regimens and as part of patient education to strengthen adherence to therapy.

The datasets used in this study are available from the corresponding author on reasonable request.

The study was approved by the institutional review boards of the First Affiliated Hospital, School of Medicine, Zhejiang University (Reference Number: 2020265). Written informed consent was provided by the patient to allow the case details and any accompanying images to be published.

We gratefully thank Susan Joyce Herzog for assistance in editing our manuscript.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. First co-author: These authors contribute equally to this manuscript: Xiaorong Peng and Yufan Xu.

This study was supported by National Special Research Program for Important Infectious Diseases (No. 2017ZX10202102-002-002).

The authors declare no conflicts of interest for this work.

1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853860. doi:10.1056/NEJM199803263381301

2. Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR, Hughes SH. Integrase strand transfer inhibitors are effective anti-HIV drugs. Viruses. 2021;13:205. doi:10.3390/v13020205

3. Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. Aids. 2005;19:10811089. doi:10.1097/01.aids.0000174455.01369.ad

4. Armenia D, Di Carlo D, Flandre P, et al. HIV MDR is still a relevant issue despite its dramatic drop over the years. J Antimicrob Chemother. 2020;75:13011310. doi:10.1093/jac/dkz554

5. Feng Y, He X, Hsi JH, et al. The rapidly expanding CRF01_AE epidemic in China is driven by multiple lineages of HIV-1 viruses introduced in the 1990s. Aids. 2013;27:17931802. doi:10.1097/QAD.0b013e328360db2d

6. Peng X, Wu H, Peng X, Jin C, Wu N. Heterogeneous evolution of HIV-1 CRF01_AE in men who have sex with men (MSM) and other populations in China. PLoS One. 2015;10:e0143699. doi:10.1371/journal.pone.0143699

7. Huang A, Hogan JW, Luo X, et al. Global comparison of drug resistance mutations after first-line antiretroviral therapy across human immunodeficiency virus-1 subtypes. Open Forum Infect Dis. 2016;3:ofv158. doi:10.1093/ofid/ofv158

8. Peng X, Xu Y, Huang Y, Zhu B. Intrapatient evolutionary dynamics in an individual infected with HIV-1 CRF01_AE who experienced periods of treatment failure. AIDS Res Hum Retroviruses. 2021;37:139146. doi:10.1089/aid.2020.0213

9. Zagordi O, Bhattacharya A, Eriksson N, Beerenwinkel N. ShoRAH: estimating the genetic diversity of a mixed sample from next-generation sequencing data. BMC Bioinform. 2011;12:119. doi:10.1186/1471-2105-12-119

10. Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinform. 2004;5:113. doi:10.1186/1471-2105-5-113

11. Darriba D, Taboada GL, Doallo R, Posada D. jModelTest 2: more models, new heuristics and parallel computing. Nat Methods. 2012;9:772. doi:10.1038/nmeth.2109

12. Guindon S, Dufayard JF, Lefort V, Anisimova M, Hordijk W, Gascuel O. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol. 2010;59:307321. doi:10.1093/sysbio/syq010

13. Drummond AJ, Suchard MA, Xie D, Rambaut A. Bayesian phylogenetics with BEAUti and the BEAST 1.7. Mol Biol Evol. 2012;29:19691973. doi:10.1093/molbev/mss075

14. Minin VN, Bloomquist EW, Suchard MA. Smooth skyride through a rough skyline: bayesian coalescent-based inference of population dynamics. Mol Biol Evol. 2008;25:14591471. doi:10.1093/molbev/msn090

15. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis. 2006;194(Suppl 1):S518. doi:10.1086/505356

16. Galli L, Parisi MR, Poli A, et al. Burden of disease in PWH harboring a multidrug-resistant virus: data from the PRESTIGIO registry. Open Forum Infect Dis. 2020;7:ofaa456. doi:10.1093/ofid/ofaa456

17. Besson GJ, Lalama CM, Bosch RJ, et al. HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014;59:13121321. doi:10.1093/cid/ciu585

18. van Zyl G, Bale MJ, Kearney MF. HIV evolution and diversity in ART-treated patients. Retrovirology. 2018;15:14. doi:10.1186/s12977-018-0395-4

19. Kamelian K, Lepik KJ, Chau W, et al. Prevalence of human immunodeficiency virus-1 integrase strand transfer inhibitor resistance in British Columbia, Canada between 2009 and 2016: a longitudinal analysis. Open Forum Infect Dis. 2019;6:ofz060. doi:10.1093/ofid/ofz060

20. Anstett K, Brenner B, Mesplede T, Wainberg MA. HIV drug resistance against strand transfer integrase inhibitors. Retrovirology. 2017;14:36. doi:10.1186/s12977-017-0360-7

21. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60:70867097. doi:10.1128/AAC.01474-16

22. Scully EP, Gandhi M, Johnston R, et al. Sex-based differences in human immunodeficiency virus type 1 reservoir activity and residual immune activation. J Infect Dis. 2019;219:10841094. doi:10.1093/infdis/jiy617

23. Wang YM, Dyer WB, Workman C, Wang B, Sullivan JS, Saksena NK. Molecular evidence for drug-induced compartmentalization of HIV-1 quasispecies in a patient with periodic changes to HAART. Aids. 2000;14:22652272. doi:10.1097/00002030-200010200-00007

Read the rest here:
Early detection of the development of drug resistance | IDR - Dove Medical Press