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