Flu A, Flu B and Covid testing, CYP2C19 genotyping, and hepatitis C elimination

There are so many reasons for distributed diagnostic testing and many testing locations beyond the traditional central diagnostics lab.

In this third part of our series, we look at progress with Flu A, Flu B, Covid testing in acute care and physician’s offices – a clinical need that didn’t exist only 5 years ago, but of considerable value –, CYP2C19 genotyping in acute care (and in pharmacies), and the exciting possibility of hepatitis C elimination in hard-to-reach communities.

Flu A, Flu B and Covid testing in primary and acute care

  • Cost savings 
  • More targeted treatment 
  • Fewer hospital admissions 
  • Reduced length of hospital stay 
  • Reduction of in-hospital acquired infections

Flu infections are a huge healthcare burden all around the world. Accordingly, there has been much focus on detection via point-of-care diagnostics and many companies have devices on the market. However, the potential benefits are not always obvious as the care patients receive may overlap with that given for other similar conditions. Because of this, modelling or real-world studies of how POC devices changes patient management and outcomes are key.

In 2018, the dedicated Point of Care team at Addenbrookes Hospital, Cambridge UK, rolled out the Cepheid GeneXpert®Flu/RSV test ready that winter’s flu season. The team observed a marked decrease in the time interval between swabbing a patient and a test result; 50 minutes compared to 28 hours using the standard central lab testing.  

In addition, the Cambridge team found that the proportion of patients starting antiviral treatment in a timely manner increased while at the same time fewer patients were prescribed antivirals when they did not need them. The team also believe that the point of care testing implementation decreased hospital acquired flu infections and resultant deaths (21). 

Another UK based study conducted in 2018 looked at Flu A/B detection using the Roche Cobas Liat in acute care. The study compared 204 patients receiving the POC test to 104 patients who did not. Cost data was calculated for each individual using the hospital cost tracking system.  

The data in this study included costs of emergency room attendance and also inpatient treatment if required. The costings covered disparate areas including radiology, pathology and pharmacy and also included staffing and facilities. Cost associated with flu patient isolation or segregation were not included as were more difficult to quantify.  

Patients who received a test were found to cost the system 67 % less than those who did not. The cost savings were attributed to more targeted treatments, fewer admissions and reduced lengths of stay. The authors also comment that the cost reduction may be improved by savings on isolation or segregation of suspected flu patients​ (14)​. Modelling studies in the UK, Germany and the Netherlands report similar results. 

All of these studies were conducted prior to the Covid-19 pandemic, and of course this markedly changes the situation. There are, as yet, few published studies, however, it is likely that similar savings may be achievable with POC devices that also incorporate SARS-CoV-2 detection.  

We spoke to Chris Hole, VP Commercial at LEX Diagnostics, developers of a sub 10-minute multiplex test for the detection and differentiation of Flu A, Flu B and COVID-19. We asked Chris about the addition of SARS-CoV-2 detection and the benefit of rapid molecular point-of-care diagnostics. 

LEX Diagnostics is focussed on bringing high-speed, low-cost PCR diagnostics to urgent care centres, physician’s offices and pharmacies across the United States. One of the most widely performed tests in these locations was historically for influenza but as COVID-19 became endemic, the need to differentiate between these two diseases, which have strongly overlapping symptoms but different drug treatments and intervention criteria, became important.

Rapid diagnosis, which is possible only where the sample is tested at the point-of-care, is particularly important for clinically vulnerable patients or those at risk of spreading an infection in the community, for example care workers, healthcare staff and teachers.

There are also significant economic benefits from very rapid time to result in this market. Follow up appointments to discuss results require clinician time and create inconvenience for patients and, in cases where the sample was badly taken or lost, the patient is unavailable to provide a second sample if they have left the building. In addition, patients waiting on-site for results block treatment rooms and waiting areas and create a contagion risk for other people using those facilities.

One further benefit of rapid and accurate diagnostics is that it allows healthcare workers with less experience in diagnosis to provide high quality treatment of infectious disease. This reduces cost and improves patient access to healthcare.

In our view these benefits make it almost certain that high quality, rapid, point-of-care, diagnostics will play a large and growing role in the provision of healthcare in the future. “

CYP2C19 genotyping in acute care (and pharmacies)

  • Better treatment outcomes
  • Improved time to treatment
  • Cost savings
  • Avoiding drug side effects

Stroke is a common cause of hospital admissions and patients are generally prescribed antiplatelet medications to reduce the risk of secondary stroke. Clopidogrel is a common initial treatment, and this compound is actually a prodrug which is metabolised into its active form by Cytochrome P450 2C19.  

In a significant proportion people, the gene encoding this enzyme, CYP2C19, has a genomic loss of function variant in one or two copies, resulting in poor Clopidogrel metabolism. Therefore the drug is not effectively converted to the active form and the risk of secondary stroke may not be adequately controlled.  

Genetic testing can identify those at risk of suboptimal response to Clopidogrel and alternative treatments can be selected. However, testing in a central lab facility delays the result and the correct treatment cannot be started immediately.  

Point-of-care pharmacogenetic testing is advantageous in selecting the right treatment for the patient’s genetic make-up and starting that treatment straight away. A recent modelling study of UK stroke management pathways concluded that use of the Genedrive® CYP2C19 ID Kit in stroke units could lower the rate of secondary stokes. The data also suggested the POC strategy could be cost saving​ (3)​

Conversely, patients taking the alternative antiplatelet drugs Ticagrelor or Prasugrel may benefit from a so-called de-escalation to Clopidogrel, which is less likely to cause increased bleeding as a side effect and is also less expensive, provided that they don’t have a genotype causing poor Clopidogrel metabolism.  

A recent real-world study of 1,530 patients compared central lab testing to point-of-care genotyping. The POC group received much faster actionable results with significant savings on medication costs​ (4)​. 

Beyond acute care settings, could pharmacogenetic testing also be performed in pharmacies? A recent study looked at 144 patients tested for the CYP2C19 genotype across 27 pharmacies in the Netherlands. The test was successfully completed by 142 people and survey data suggested both patients and pharmacists viewed the process favourably​ (5)​. 

Though small, this study demonstrates the feasibility and value of pharmacogenomic testing at the pharmacy. Many drugs vary in their effectiveness and safety profile depending on the patient’s genetics and the pharmacy should be ideal location to perform testing, both for prescribed and over-the-counter treatments. 

We spoke to Gino Miele, Chief Scientific Officer of genedrive, manufacturers of point-of-care pharmacogenetic tests for CYP2C19 and MT-RNR1 running on the genedrive instrument platform.

Clinical pharmacogenomics seeks to drive delivery of the right drug to the right person at the right time.  However, as many as 90% of drugs are effective in only 30-50% of patients due to genetic variation, with 15% experiencing adverse events.  

Genotype-guided therapies can significantly improve these outcomes. However, when actionable clinical decision making is needed in time-critical emergency care, access to testing is not possible today because of the requirement for use of central laboratories.    

For example, in the UK there are 100,000 strokes each year, with up to 30,000 patients having variants that result in poorer outcomes when treated with the main antiplatelet drug Clopidogrel. 32 million antiplatelet items were prescribed in 2020/21 at a total cost to the NHS of £78 million.   

Some of this was wasted as up to 30% of individuals have variants in the CYP2C19 gene that result in ineffective metabolism of the drug. CYP2C19 genotype guided prescribing in emergency care can ensure that those patients can be triaged to an alternative antiplatelet route.  genedrive has developed a point of care test for CYP2C19, where the detected genotype predicts how a stroke patient will respond to antiplatelet therapies.  

Acute care genetic point of care paradigms require cost effective platforms and tests, able to be used directly by the healthcare practitioners (e.g. nurses) rather than trained laboratory personnel.  They need to be simple to execute, providing clear easy to interpret test results with automated clinical interpretation of what can be complex genetic tests, and fast enough not to delay the patient care pathway.”

Our vision is to enable these paradigms, and our product solutions for point of care MTRNR1 and CYP219 variants unlock emergency care pharmacogenetic testing in these indications.  Approaches such as these are the future of pharmacogenomics in emergency care and will ultimately significantly improve patient outcomes as well as being cost-effective for healthcare systems. 

Towards hepatitis C elimination  

  • Progress toward disease eradication 
  • Enabling ‘test and treat’ strategies 
  • Increased treatment uptake 

Since the World Health Organization pledged to work toward eliminating viral hepatitis in 2016​ (8)​, many countries have made significant progress.  

Viral hepatitis encompasses a number of disparate viruses (types A-E) that are either spread via the faecal-oral route or via bodily fluid contact. Vaccines for some types exist and for others effective treatments and cures are available. 

Hepatitis C is spread via contact with blood, but infected people are often asymptomatic for long periods during which they do no seek treatment and may infect others. However, hepatitis C is readily treated with direct-acting antiviral (DAA) medications, which are safe and highly effective, typically leading to complete cure.  

Many countries are ramping up testing efforts in order to identify cases. Egypt, for example, had one of the highest hepatitis C burdens in the world, but thanks to a massive screening and treatment programme, the country has made enormous strides towards its elimination.   

It is estimated that Egypt has diagnosed 87% of people living with hepatitis C and provided 93% of those with curative treatment​ (9)​. To get to this amazing result, huge numbers of people received initial screening from outreach teams using lateral flow rapid antibody tests​ (10)​. 

While Egypt’s elimination project relied on initial rapid testing in the community followed by referral to community healthcare facilities for further testing and treatment, studies show that a community-based “test and treat” strategy for hepatitis C is possible.  

A pilot study run in both a rural and city location in Egypt investigated the feasibility of one day test and treat strategies for both hepatitis C and B. The programme consisted of community awareness raising in the week before project initiation, site selection to enable proper equipment set-up and then testing with a view to initiating treatment on the same day.  

Participants initially received a rapid antigen or antibody test (~15 mins test time). Those found to be positive went on to Cepheid GeneXpert HCV or HBV PCR-based testing to detect active viremia (test time ≤ 105 minutes). Those found to be positive went on to further testing including blood chemistry, transient elastography (Fibroscan) for staging of liver disease and abdominal ultrasound for hepatocellular carcinoma. 

All of the testing was performed on-site on the same day. In both locations, the majority of people with a positive PCR result received additional screening and then initiated treatment within 3-4 hours of the initial rapid antigen or antibody test​ (11)​.  

Same day test and treat strategies may be of great value for people in remote regions or regions or countries lacking a good quality healthcare network. As has been shown with Polio, in order to have the greatest chance of truly eliminating a disease, all remaining pockets of disease must be tackled no matter how difficult to reach. 

However, while some barriers to hepatitis C detection and treatment are geographical or due to lack of healthcare facilities, barriers exist even in rich countries. Often, hepatitis C is prevalent among members of society who don’t access healthcare in the usual way, for example those without stable housing and people who use drugs.  

For hard-to-reach populations, test and treat strategies can be a great way of combating disease. People are tested using a point-of-care diagnostic device, receive their result rapidly and can then be offered immediate treatment. This one-stop approach minimises the number of people dropping out between diagnosis and treatment and can enable people to get treatment in a way that suits them.  

Several pilot hepatitis C “test and treat” programmes across the world have demonstrated improved access and take up of treatment among people who use drugs. In Sydney, Australia, the Cepheid GeneXpert HCV Viral Load Fingerstick test detected HCV in 27% of injecting drug users tested at a needle exchange venue. 81% of those testing positive went on to initiate treatment on the same day or shortly after​ (12)​.  

Test and treat programmes may also be valuable to catch other populations that might otherwise “fall through the gaps”. HCV infection is also highly prevalent in prison populations and point-of-care based “test and treat” strategies can be of value in allowing the treatment of those serving short sentences who might otherwise be missed.  

This was demonstrated by a recent pilot study conducted in HMP Perth, a prison in central Scotland. Use of the Cepheid Xpert HCV VL Fingerstick assay resulted in an average time to treatment of 19 days compared to 33 days for the conventional central lab testing model. Of the conventional testing cohort, 59% did not initiate treatment whereas in the POC cohort only 23% did not initiate treatment​ (13)​. 

Hepatitis C elimination efforts also demonstrate how treating people for diseases that can significantly harm them personally can also have a societal benefit in terms of a lower overall disease burden, likelihood of transmission and progress toward elimination.  

A number of infectious diseases are good candidates for elimination campaigns and taking diagnosis to difficult-to-reach populations will be key. The reason for isolation may be due to geography, lack of healthcare infrastructure or other societal reasons, but employing distributed diagnostics can help in all of these situations. 

We spoke to Jonas Demant, an organiser of the T’N’T HepC initiative testing drug users in Denmark about the value of point-of-care hepatitis C testing. 

The project kicked off in 2017, led by the User’s Academy, a drug user organization in Copenhagen. I was volunteering there at the time, and our motivation came from the stark difficulty in accessing testing and treatment for those at risk.  

The hurdles in accessing care were tied to the strict treatment criteria and complex care pathways lingering from the interferon era. Back then, due to interferon’s side effects, patients were treated and closely monitored in infectious disease departments and were required to schedule and show up for many appointments. This was particularly challenging for those dealing with homelessness or other social issues.  

Many of us who had experienced the simplicity of the new DAA therapy couldn’t understand why these care pathways persisted. We knew that people were kept from accessing testing and treatment because of the way testing and treatment were organized.” 

Determined to make a change, we got our hands on an old van, rigged it up, got some antibody quick tests, and began driving around Denmark. We visited shelters and methadone clinics, offering testing to those in need. 

Initially focusing on antibody testing, we did manage to help some access HCV RNA testing and treatment, but our resources fell short of aiding everyone through treatment. In its early stages, the project was more of an awareness campaign.” 

Come 2018, we joined forces with clinicians and researchers, shaping the model of care as it exists today. Now, we could offer both antibody and PCR testing in one visit. We established a fast-track clinic for those with a positive HCV RNA test.

Peer support and patient coordination were also integral components. This care model operates in greater Copenhagen and is now permanently funded from the Capital Region. The clinic’s results have been showcased in an article in the International Journal of Drug Policy.” 

In the final part of this series, we look at health economics and the less commonly measured benefits that can be expected to drive further adoption of distributed diagnostics. We also speak to Dr Giles Sanders, Head of Diagnostics at TTP, about some of the motivations for moving diagnostics closer to the patient. 

Elena Boland

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