What the EIB InnovFin award means for Cavidi and HIV management

Speaking on behalf of the entire Cavidi team, we are honored to be chosen by the European Investment Bank (EIB) as recipient of their Infectious Diseases Innovation Loan for 2015. This €10 million award will provide a substantial portion of the investment required to bring Ziva™ to market in 2016. Just as importantly, it underscores the importance of the groundbreaking work Cavidi is doing in the area of HIV management.

Viral load monitoring is an essential part of HIV treatment, but it has always been difficult to administer in near-patient settings. Ziva™ changes that. Building off of Cavidi’s proprietary Reverse Transcriptase (RT) technology, we have designed Ziva™ as a medium throughput, fully-automated viral load monitoring system. It is purpose-built to meet the requirements of decentralized labs like those in district hospitals. When it reaches the market, Ziva™ will be a game changer, making routine viral load testing accessible to millions of people around the globe. 

In providing the loan, the EIB recognized the importance of viral load testing and the groundbreaking work Cavidi has been doing in the treatment of HIV. The EIB is the European Union's bank. They are the only bank owned by and representing the interests of the European Union Member States. The bank makes long-term financing available for sound investments in order to contribute toward EU policy goals. As part of that aim, the EIB has set up a program to help innovative firms access financing more easily. Over the next seven years, "InnovFin – EU Finance for Innovators" will make more than €24 billion EUR of financial support available for research and innovation (R&I) by small, medium-sized, and large companies.

Thank you to all those involved with InnovFin at EIB. And, thank you to my team at Cavidi for once again making history in the area of HIV diagnostics. 

World Aids Day 2013: Halfway to Zero

Each year World Aids Day helps raise awareness around the world. It’s also a time for everyone involved in the fight against HIV to step back and assess our progress. Looking at the HIV community as a whole and Cavidi in particular, I can say it’s been a good year overall. We have seen great progress in the treatment of HIV worldwide. At the same time, these developments have further clarified the challenges that remain to providing universal access to proper HIV treatment and prevention. 

World Aids Day Graphic from http://worldaidsdaynw.org/

World Aids Day 2013 marks the halfway point of UNAIDS’ Getting to Zero initiative. This ambitious initiative has three core objectives to achieve by 2015:

• Zero new HIV infections
• Zero AIDS-related deaths
• Zero HIV-related discrimination

So where does the world stand at the halfway mark? Many of the statistics coming from the WHO are cause for optimism taken at face value. But with an estimated 2 million people contracting HIV each year and over 1.5 million deaths attributed to AIDS, it’s clear that we are still a long way from zero. 

Given the complexity of these issues and the limitations of the available data, it’s often quite difficult to get a fix on where we are on our journey to zero. Roger Tatoud explains just how difficult this task can be in an excellent post he wrote a few weeks ago on the 0 Incidence blog. In his post, Roger boils down a sea of data into three clear graphs that together start to give us insight into where we stand today. I was particularly interested in his analysis of how we are doing in terms of providing access to HIV treatment. The year-on-year increase in the number of people able to access HIV treatment has been rising steadily since 2006. That’s all good. However, the rate of change year-on-year over the same period has been in steady decline, meaning that although more people are accessing HIV treatment each year, the rate at which people are accessing HIV treatment is slowing down. That’s not good. Roger concludes, “This suggests that current approaches to deliver treatment are reaching a limit (or that something is limiting further expansion) and that for treatment to reach more people more effort will be needed or that we will need to do things differently.” 

Part of that difference may well be an increased role for viral load monitoring in the treatment of HIV. 2013 saw viral load monitoring receiving increased attention among the world’s most influential healthcare bodies such as WHO, UNAIDS, UNITAID and MSF. A decade after acknowledging the importance of HIV viral load monitoring, the World Health Organization 2013 revised guidelines, calling for developing countries to roll out routine virological monitoring, with viral load tests at both six and twelve months after treatment initiation, and then at least every twelve months thereafter. In this way, treatment adherence problems are corrected more quickly and patient treatment can be adjusted if the viral infection is not responding to therapy. 

This decision was further supported by a report from Médecins Sans Frontières (MSF) that highlights the importance of routine HIV viral load monitoring in low-income countries. Today, most clinics in resource-limited settings try to monitor disease progression with CD4 tests alone. The MSF research provides ten specific benefits that programs in developing nations can hope to achieve by adopting the WHO recommendation for routine HIV viral load testing. Among them are confirmation of treatment failure, prevention of HIV mother-to-child transmission, and improvement in HIV treatment outcomes in low-income countries. If realized, the benefits outlined in the MSF report would certainly move us closer to UNAIDS Getting to Zero goals. 

The increased interest in viral load monitoring witnessed over the past year has been accompanied by increased interest in point-of-care solutions. The idea is to get the HIV monitoring test out to where the problem is. I sense this is a reaction to address the inadequacies of centralized testing, particularly in resource-limited settings where simply transporting samples to a central lab can be a limiting factor. While the point-of-care initiatives are a welcome development to dysfunctional centralized options, there is middle ground that needs to be kept in mind.

Any solutions for HIV treatment have to work with the realities of existing laboratory infrastructure. The WHO has designated five tiers of laboratory infrastructure.  Each has its capabilities in terms of what types of tests can be run and the throughput that is possible. This, in turn, influences the access to testing that we can expect from any tier. For instance Tiers 0 and 1 may interact with a large population of people living with HIV, but since there is no lab infrastructure and a shortage of skilled staff exists at that level, testing is limited to one-at-a-time, point of care testing with low throughput.  We have drawn on throughput projections and population geography to provide a picture of  potential access to monitoring at the different levels. 

If we estimate the global population of people living with HIV to be at around 34 million, we can divide them by this type of access. There we see that the centralized testing schemes used by reference labs in Tier 4 could access about 6 million people living with HIV and this is where, traditionally, much of the emphasis has been placed. Primary care facilities and community outreach programs in Tier 0 and 1 could reach about 8 million people living with HIV and this is where point-of-care solutions can have the greatest impact. But with near-patient testing, regional and district-level facilities in Tier 2 and 3 could provide access to over 20 million or 60 % of cases. Today, Cavidi’s ExaVir™ Load test is the only test capable of providing viral load monitoring coverage on a regional and district level.

These middle tiers are where Cavidi focuses its efforts both with our current product, ExaVir™ Load, and with our R&D efforts to develop new monitoring solutions that will increase throughput and access even further. I’m pleased to announce that we have made significant progress in both areas over the past year. 

In 2013 we reached another milestone with our ExaVir™ Load HIV viral load monitoring kit as we began shipping to the Philippines. This marks the 25^th country to adopt ExaVir™ Load for clinical use in addition to over a dozen other countries where the test is currently being evaluated for use. The test offers the same sensitivity and accuracy of Tier 4 reference tests but, unlike those tests, it can be run in Tier 2 and 3 facilities – and at a fraction of the cost. 

Cavidi’s new Automated Monitoring System will provide viral load and be adding other optional HIV test kits, such as CD4, EID, and drug resistance in one robust bench-top unit.

We are also making steady progress on the next generation of HIV viral load monitoring diagnostics. Codenamed the Automated Monitoring System, the new system is now in the prototype stage. This new product uses the same proven RT-technology found in our ExaVir™ Load test but it is fully automated, requiring less time from lab technicians and greater throughput. In addition to viral load testing, we will be adding other optional HIV test kits like CD4, EID, and drug resistance in one bench-top unit.  Like ExaVir™ Load, our new system is ideally suited to the near-patient testing needs of Tier 2 and 3 regional and district level facilities. Bringing this product to market will be a game changer for increasing both access and quality of HIV treatment globally. I look forward to sharing more news on the project throughout 2014. 

While 2013 saw progress in the battle against HIV, it’s clear that we still have lots of work ahead of us. That’s why we need to ensure that the public remains aware and vigilant. My colleagues and I at Cavidi will continue to work to increase awareness, access, and quality of HIV treatment worldwide. In the interest of raising awareness among your peer network, I hope you will share this post. If you would like more information about Cavidi’s work in this area, feel free to contact me directly. 

Time for a new gold standard in HIV viral load monitoring

This past year has brought more good news in the battle against HIV/AIDS with UNAIDS stating, “On the cusp of the fourth decade of the AIDS epidemic, the world has turned the corner—it has halted and begun to reverse the spread of HIV.” UNAID’s 2012 report cited 700,000 fewer new HIV infections in 2011 than in 2001. AIDS-related deaths have been reduced by one-third in the past six years. And access to antiretroviral therapy (ART) continues to grow at unprecedented rates. But as the battle against HIV enters a new phase, it introduces new challenges to the healthcare community, particularly with regard to diagnostics. In response, the World Health Organization and UNITAID have dubbed the next ten years, “the decade of diagnostics.” In their session at AIDS 2012 in Washington D.C. they emphasized the important role that cheaper, simplified diagnostics must play in the next phase of the campaign to stem the HIV pandemic. This emphasis is redefining the role of HIV viral load testing in treatment and is placing new demands on how these tests are conducted. 

Number of people newly infected with HIV, Global, 1990-2011

UNAIDS Report (2012)

For decades the gold standard for HIV viral load diagnostics have been RNA-based tests. But in this new diagnostic landscape I see centralized RNA-based testing rapidly losing relevance to tools that are better suited to meet the diagnostics challenges that we see today in both the developed and developing world. Most notable among these are: a) the need to scale HIV viral load monitoring in step with the burgeoning number of men, women and children entering treatment, b) managing the rise in drug-resistant HIV strains that accompany greater access to ARV treatment and c) address the diagnostic needs of infants born to HIV-positive mothers. 

In low-to-middle income countries, access to HIV viral load testing has become a more critical issue given the recent increase in access to ART.  According to the World Health Organization (WHO), there was a 20-fold increase in the number of people receiving ART in developing countries between 2003 and 2011, and a 20% increase in just one year (from 6.6 million in 2010 to more than 8 million in 2011). The rapid increase in access to Antiretroviral drugs (ARV) has triggered a corresponding increase in the need to monitor those receiving treatment. This helps to ensure the virus is being suppressed and helps the doctor know when the patient needs to be switched to a new treatment regimen.  

Originally developed for use in North America and Europe, RNA-based tests are proving impractical for decentralized use in low-to-middle income countries. Around 70% of the world’s HIV population live in sub-Saharan Africa. As a result, district hospitals and clinics outside the capital have to either send blood samples away to a central reference hospital or, more likely, forgo HIV viral load monitoring altogether. In light of this, it seems the gold standard is shifting in favor of a HIV viral load monitoring solution that can deliver the same reliability in a decentralized model with testing conducted near-patient.

This has created a flurry of innovation in the HIV viral load POC testing arena. Maurine Murtagh has identified 13 different entrants in this area in the 2nd edition of UNITAID Diagnostic Technology Landscape Report.  Of the options available today, Reverse Transcriptase (RT)-based testing seems to offer the most plausible solution on several fronts. First, RT is a very stable marker since it is not affected by mutation and is always present when the HIV virus is replicating. Since RT-based tests do not target a specific nucleic acid sequence, they are able to quantify all types and subtypes of HIV, including new strains, without any modification to the test. RT-based tests have historically been significantly less expensive than RNA tests both in terms of start-up and running costs. Further, the RT platform has an unmatched track record among this next generation of HIV viral load tests. It has been in the field for over a decade with more than 40 peer-reviewed journal articles and over 350,000 tests run. Several studies over the past decade have compared ExaVir™ Load to the gold standard PCR tests and all have found excellent correlation with RNA-based tests. 

The benefits of RT-based HIV viral load testing go beyond resource-limited settings. In the developed world, HIV viral load monitoring is a main line of defense against the rise in drug resistant strains of HIV.  Eric Rubin, professor of immunology and infectious diseases at HSPH put it eloquently, "Drug resistance is the product of success: With treatment, we have drug resistance." Since ARV treatment has been more prevalent in developed countries, resistance has mainly been a problem for these nations.  For instance, a recent study in San Francisco revealed that 60 percent of new HIV infections are drug resistant. One of the key factors in stemming this tide is early detection of treatment failure through HIV viral load monitoring of all HIV positive patients. Since healthcare systems the world over are straining to manage budgets, a more cost-effective decentralized HIV viral load monitoring solution may benefit developed nations as much as it does low-to-middle income countries.  

In areas where the subtype of the individual may be unknown RT-based testing provides additional advantages. This has not been much of a concern in the US where the vast majority of HIV-1 infections are subtype B—98 percent according to some surveys. But an article from CAP Foundation asserts that it may be time for the US to  “catch up to what’s happening in Tanzania and elsewhere in Africa. Specifically, HIV-1 subtypes common in Africa may be making inroads in the United States, as they have in Europe.”  Of the testing options available, only RT-based testing is able to detect any HIV activity without modifying the test — including new HIV strains.

World map of Global distribution of HIV-1 strains

IAVI Report (2003)

Lastly, with half of the world’s HIV population being women and many of them of child-bearing age, there has been increased focus in recent years on mother-to-child transmission. Here too we see great strides have been made with 57% of HIV positive pregnant woman living in low-and middle-income countries receiving treatment in 2011. One persistent problem has been the early infant diagnosis (EID) since standard rapid tests won’t work on newborns. This is another area where RT-based testing has been found to convey an advantage. Over the past year more studies have confirmed that in addition to RT-based EID solutions being significantly less expensive than RNA-based tests, they are also able to detect and quantify HIV infection in infants more reliably and at a much younger age.  

This World AIDS Day, as Cavidi celebrates the 25^th Anniversary of our RT-technology, I’m pleased to report that we are making steady progress on three fronts to address the challenges above.  First, we continue to support the increasing uptake of our manual ExaVir Load HIV viral load monitoring test which is increasing access to affordable HIV viral load testing around the world.  Second, we have made excellent progress developing a new automated platform for near patient HIV viral load monitoring. The platform design is now entering final stages of prototype development and testing. And third, over this past year we have initiated further studies into the development of an RT-based EID test. I look forward to sharing more details on these exciting developments over the next year.

New challenges require new solutions. As we enter the decade of diagnostics I hope to see a new gold standard emerge that will make HIV viral load testing more accessible and reliable. My team will do their part as they continue to bring innovative RT-based diagnostics to the world in 2013 and beyond. 

 John Reisky de Dubnic

CEO

Cavidi

Could RT technology help close the EID gap?

As the CEO of a life science company I am constantly amazed at the resourcefulness and tenacity of people in this field and I am very proud to be a part of it. When it comes to our area of HIV diagnostics, few issues are as compelling in this regard as the ongoing struggle to provide proper HIV diagnostics to infants often referred to as HIV early infant diagnosis or EID.

HIV positive mothers can pass the infection to their children before, during, or after birth via breast milk. Mother-to-child transmission (MTCT) of HIV-1 results in approximately 370,000 infant infections worldwide each year. 2.5 million children were living with HIV at the end of 2009, with 90% in Sub-Saharan Africa. The good news is that researchers Dr. Avy Violari and Prof. Mark Cotton have shown that if an HIV-positive infant is started on antiretroviral drugs before 12 weeks of age we can reduce mortality by 76% and disease progression by 75% compared to those who start treatment later. The problem for these infants today isn’t a matter of access to antiretroviral drugs (ARVs). It’s a matter of access to an HIV diagnostic test.

Diagnostics for adults is a fairly routine affair even in resource-limited settings, thanks to antibody testing. These types of tests are often referred to as “rapid tests” because they provide on-the-spot results. They work by measuring HIV-specific antibodies in the blood and making a yes/no determination of infection from there. They are accurate, easy to administer and inexpensive. In fact the US FDA has recently approved a do-it-yourself home test to diagnose HIV infection.

However, antibody testing doesn’t work on children under 18 months of age. That’s because up to that age the child still has its mother's antibodies in its blood and the test can’t tell if they are from the mother or the child. Therefore, in developed countries early diagnosis is made using the HIV DNA PCR assay, which can be used at six weeks of age. Access to HIV DNA PCR tests is restricted in resource-limited countries because they require centralized laboratories and specialized equipment. Additionally, DNA PCR produces false negative results for unrecognized HIV-1 subtypes or HIV-2.

The sad consequence of waiting to diagnose children is increased mortality and disease progression. In some regions of Africa the coverage rate for testing a child younger than 8 weeks from an HIV-positive mother is less than 4%. 1 out of 10 pregnant women in Sub-Saharan Africa are infected with HIV and 1 in 3 children born to these mothers will contract HIV. At 6 months of age, the probability of death after starting ART is 7.8% if the HIV-infected infant is already showing signs of immune deficiency (e.g. low CD4 count) but only 1.8% if the infant is asymptomatic. Most of those deaths will occur by the age of 12 months. In India, we see a similar situation.

To be clear, Cavidi does NOT market an EID test or any test to determine if a person is infected with HIV. Our ExaVir™ Load test is intended to monitor patients who have been diagnosed with other products. However, several enterprising researchers have realized the promise of RT technology for EID and have conducted independent EID studies using our RT-based monitoring test as an HIV EID tool. There is now a convincing body of evidence suggesting that Cavidi’s RT-technology may provide an important key to expanding access for EID in resource-limited settings. One of these studies by Dr. Sivapalasingam of New York University found that among HIV-exposed infants younger than 18 months old, the RT assay performed as well as DNA PCR. In 55% of cases the RT assay diagnosed HIV infection 6 weeks earlier than the DNA PCR assay with the added benefit of being subtype independent. To quote from the paper:

“Our finding that a significant number of HIV infections are undiagnosed using DNA PCR testing at 6 weeks of age is important for several reasons. First, in resource-limited settings where access to medical care can be intermittent, accurate and early diagnosis of HIV when the child does present for care (during birth or routine immunization visits at 6 weeks) is especially critical. In a recent study conducted in Kenya, 65% of HIV-exposed infants were lost to follow-up by age 18 months, of whom 43% were lost to care by age 4 months. Therefore, if a 6-week DNA PCR test result is falsely negative, it is very likely that the child will not return for a repeat DNA PCR test or a confirmatory antibody test. An assay, such as the RT assay, that could detect infection soon after transmission occurs, such as at birth or 6 weeks, could dramatically increase the number of infected children initiated on ART."

Based on this research, I did a quick calculation on the impact an RT-based EID test could have: Assume you have 10,000 perinatally infected infants and detect all of them using an assay and start all 10,000 infants on antiretroviral therapy. Based on the 4% mortality rate reported by Violari et al., there would be 400 deaths. Based on the Sivapalasingam study, using DNA PCR alone at 6 weeks would have misdiagnosed 6,000 infants as HIV uninfected and therefore would not receive ART. In this group, there would be a total of 1,120 deaths (4% of 4,000 infants + 16% of 6,000 infants = 1,120). Therefore, using the RT assay at 6 weeks of age could lead to a 64% reduced mortality rate (720/1120) through better and earlier detection and treatment of HIV infection. Consider that HIV-1 results in approximately 370,000 new infant infections worldwide each year and you can begin to appreciate the benefits RT-technology can add.

I’d like to restate that the Cavidi ExaVir™Load test used in these studies is an HIV Viral Load monitoring test and is not approved for use as an HIV diagnostic test. However, the results of several studies indicate that the underlying RT-technology could provide several advantages over RNA-based tests and thus increase access to the test for tens of thousands of infants each year. In response to these promising studies we are currently seeking the funding required to adapt and re-label our current viral load test for possible use in EID. Your input is more than welcome on this. I’ll keep you posted on further developments.

John Reisky de Dubnic

CEO

Cavidi