By Siddharth Yarlagadda ’18

THURJ Staff

In an important piece calling for a redefinition of global health care delivery, Harvard Professors Jim Kim, Paul Farmer, and Michael Porter have described global health care as “the provision of a limited set of health services to underserved populations in resource-poor areas of the world” (2013). They go on to detail how the most difficult part about tackling a global health issue is usually delivery to local individuals: “financial, social, or geographical obstacles render facilities inaccessible” (2013). Here, the emphasis is placed on the importance of recognizing the complexity of global health issues and the need to solve them through a thorough set of interventions and evaluations. One particularly complex global health issue over the past 30 years has been the Human Immunodeficiency Virus (HIV), an infection for which an effective drug treatment exists yet remains problematic due to newly arising obstacles such as drug resistance and cost-effective implementation of essential tools to counter the spread of the disease. In order to combat these issues, Dr. Iain MacLeod, a Harvard School of Public Health research fellow at the Botswana-Harvard AIDS Institute, created a novel, economical drug resistance test that could potentially reallocate resources with more efficiency while ensuring a higher percentage of HIV patients receive proper HIV treatment. We will trace the evolution of the HIV problem and Dr. MacLeod’s solution to gain an understanding of how diverse the components of global health can be.

HIV weakens an individual’s response to infections and certain types of cancer by targeting the immune system. With 2.1 million new infected cases in 2013, bringing the total prevalence worldwide to over 35 million people, finding effective ways to combat the disease is a pressing issue. In terms of diagnosis, doctors look at viral load (how many HIV particles are in the patient’s blood) and CD4 cell count in determining whether a patient has HIV. CD4 cells are T lymphocytes, which are a part of an individual’s immune system, and are a good indicator of how well the immune system functions and a good predictor of the progression of HIV. Healthy individuals have anywhere between 500-1200 cells/microliter, while a CD4 count of below 200 cells/microliter indicates the progression of HIV to AIDS, a syndrome associated with HIV infection wherein the immune system is unable to fight off many infections. While there is no cure for HIV/AIDS, the disease can be managed with antiretroviral drugs (ARVs), which are incredibly effective in substantially slowing the progression of the disease by inhibiting the virus from replicating easily. Those under effective antiretroviral therapy (ART) can enjoy a productive and healthy lifestyle. ART is a combination therapy consisting of at least three different ARVs, each of which attack different parts of the HIV replication cycle simultaneously. Combination therapy is employed when creating an ART regimen, in part, to mitigate the likelihood of a genetic mutation occurring in the viral genome that would confer resistance to any single ARV drug. Thus, by containing multiple drugs, an ART regimen is more effective since it attacks the virus through multiple biochemical mechanisms and lasts longer since it more effectively fends off drug resistance. The World Health Organization recently announced that every HIV patient should receive ART regardless of the stage of HIV infection, whereas previously, ART was administered only when the patient’s CD4 count dropped below 350 cells/microliter.

Since the drugs have been developed, it would seem all that remains is to administer them to the areas of the world that need it most. Unfortunately, only about 11.7 million of the nearly 33 million individuals (36%) infected with HIV in low to middle-income countries were on ART as of 2013 due to problems with access and administration. However, this number is expected to rise to 15 million by the end of 2015. Specifically, in Sub-Saharan Africa, where 70% of new infections occur, approximately 120,000 individuals begin ART treatment monthly. With such a rapid influx of ARTs into Sub-Saharan Africa, a systematic and simplified administration of drugs has been implemented across the board to minimize decision-making and cost: a single regimen as the “first-line” ART with one option for a “second-line” ART in case first-line therapy fails.

But what does it mean for the drugs to fail? Failure to an ART regimen can occur due to lack of adherence or drug resistance. A few factors that contribute to an HIV patient missing ARV doses include inconsistency in ARV supply, the burden of swallowing multiple pills daily, the unwanted side effects of ARVs (including psychiatric conditions, diarrhea, and nausea), and HIV’s social stigma in a given cultural context. Missing doses results in sub-optimal concentrations of ARVs in the patient’s bloodstream, which loosens the “grip” on HIV, allowing low-level replication that permits drug resistance mutations to be acquired, then those drug resistant variants begin to replicate to a high level. Lack of adherence accounts for 10% of failed ART regimens annually. But improving adherence alone will not solve the problem: even when patients successfully follow their ART regimen, continued use of the same drugs can lead to selection of a drug resistant strain of HIV, which can be transmitted to others. Once an individual acquires drug resistant HIV, he or she is more than twice as likely to have virological failure despite first-line ART treatment. Drug resistant HIV transmission has increased by 14% per year in Southern Africa, which is so alarming that it threatens the success of ART scale-up.

This pressing issue suggests that effective provision of ART requires not just increasing distribution in the areas of the world that need it most but also curbing the rapid growth of drug resistance. When trying to contain drug resistance, the key issue is detection. Clinicians must be able to identify resistant strains, ideally before beginning ART treatment or as soon after resistance happens as possible, in order to get patients on a new, effective ART regimen immediately. Currently, testing for the presence of HIV is done through a viral load test that ascertains the number of HIV virus particles in a milliliter of blood. While this test can show whether ART is effective, it cannot differentiate between the at least 10% of patients who are having ART failure due to lack of adherence and those patients who have developed drug resistance and need to be switched to a new line of ART treatment. Thus, in order to effectively administer ART without facilitating drug resistance, clinicians must know the source of failure, which can only be found through drug resistance genotyping.

Currently, drug resistance testing for HIV is done through Sanger sequencing, which is a method of DNA sequencing in which DNA polymerase selectively incorporates chain-terminating nucleotide bases. There are two FDA-approved systems that use Sanger sequencing to test for HIV drug resistance. However, both require extensive technical knowledge, take at least two days to perform, and are labor-intensive, and above all, costly. Cost comes out to $300 per test, which is roughly the equivalent of switching to a second-line ART regimen. Thus, cost inhibits Sub-Saharan African governments from widespread implementation of resistance testing since the funds that would be wasted by unnecessarily switching to second line treatment would roughly equate to the cost of the resistance test. Furthermore, the discrepancy in resources for conducting a resistance test between a developed country and a developing country make resistance testing even less likely in the latter.

Take the USA and Botswana, for example. In the USA, drug resistance testing is performed at the point of diagnosis and then once again if viral loads remain high. Infrastructure, knowledgeable staff, and resources such as reagents allow this much needed approach to HIV drug resistance testing; thereby, allowing resistance transmission to remain low. Conversely, in Botswana, only pregnant women are given first line therapy at the point of diagnosis (in order to prevent mother-to-child transmission of HIV), while the rest of the patients are only given first-line ART when their CD4 count falls below 350 cells/microliter. If it fails, then they are given second line therapy. Once second line therapy fails, only then are they tested for drug resistance. Patients live with uncontrolled HIV for longer, the government wastes valuable money and resources on ART regimens given to drug resistant patients, risk of transmission of a drug resistant strains remains high, and more resources are wasted on giving new drugs (that are more expensive and burdensome) to patients who do not have drug resistance and are failing treatment due to adherence issues. Furthermore, current drug resistance testing mechanisms have a high failure rate and are often specific to Western or developed cultural contexts.

Assessing this situation and seeking to solve the problem of drug resistance in HIV, HSPH research fellow Dr. Iain MacLeod recognized the complex economic, sociocultural, and geographical dimensions at play. Effective global health delivery must consider the cost of a drug resistance test in order to save valuable, scarce health care resources and to ensure the continued success of ART scale-up. Furthermore, the cultural context of Sub-Saharan, and specifically Southern, Africa requires a resistance test that is compatible to the mutations, strains, testing resources, and personnel that are most prevalent in that geographic region, not those that are accessible in the USA. Only after considering all these facets did Dr. MacLeod realize that a HIV drug resistance testing assay that is user-friendly, efficient, Sub-Saharan Africa-specific, and cost-effective could potentially save Southern African governments money while putting more patients on the correct ART regimen and curbing the spread of drug resistance. Dr. MacLeod knew that a testing assay that cost less than $100 per patient to implement after failure of first line ART could save the South African government approximately $125 million over 5 years, which would come to about 10% of what the country spends annually on HIV care (Levison et al., 2013). So he got to work.

Last year, Dr. MacLeod announced the development of Pan-Degenerate Amplification and Adaptation, or PANDAA, an accurate HIV genotyping assay that can easily be plugged into existing contexts and infrastructures of Sub-Saharan Africa. Costing under $100 per test, PANDAA employs existing quantitative real-time PCR (qPCR) technology that is faster, more sensitive to frequency discrepancies of drug resistant strands, and easier to use. The biotechnology essentially operates with probes labeled with fluorescent dye that hybridize to the HIV genome if the resistant mutation is present. The hybridization then allows a laser to excite and free the fluorescent dye. Thus, if a non-mutant strain is present, hybridization would not occur and the laser would not excite the fluorescent dye. After amplification, the data can be easily interpreted from a normalized fluorescence graph. If there is fluorescence, the patient has a drug resistant HIV strain while outputs with no fluorescence indicate no resistance at the site of the genome being tested.

In fear of his groundbreaking technology losing its main benefit – cost-effectiveness – through commercialization, Dr. MacLeod joined forces with individuals from Harvard Medical School and Harvard Business School to found Aldatu Biosciences, a biotech start-up, to commercialize PANDAA properly in a way that could benefit the highest number of HIV patients possible. Their first product – PANDAATMHIV6 – uses Iain’s technology to test for six resistance mutations that comprise 99% of first line ART failures in low-to-middle income countries. Aldatu combined all the reagents required for this assay into one package that could easily be transported, opened, and implemented. Once the package arrives, a lab technician would only need to extract RNA from an HIV patient blood sample, add it to the assay plate, and then run the real-time qPCR machine. The many dimensions and variables that Dr. MacLeod and his team had to consider in creating and implementing PANDAA provides some insight into how complex and layered a single global health issue can be. He and his team are continuing to hash out strategies on how to enter the market with their new product and how to evaluate the potential success of their product through implementation trials. This includes using PANDAA for other highly polymorphic pathogens – such as tuberculosis and malaria – and holistically embodying Aldatu’s mission to provide effective, economical diagnostics for resource-limited countries.

Global health is a fascinating field. Almost every area of expertise or skill set becomes helpful in one way or another when trying to solve a global health issue, big or small. When combining diverse talents, taking the time to understand the local context in which you are operating, and thinking about the problem holistically, there is great potential to contribute innovative solutions for achieving equity in health across the globe.

References

CD4 Count. (n.d.). AIDS.gov. Retrieved November 5, 2015. https://www.aids.gov/hiv-aids-basics/just-diagnosed-with-hiv-aids/understand-your-test-results/cd4-count/

Levison, J. H., Wood, R., Scott, C. A., Ciaranello, A. L., Martinson, N. A., Rusu, C., et al. (2013). The clinical and economic impact of genotype testing at first-line antiretroviral therapy failure for HIV-infected patients in South Africa. Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 56(4), 587–597. http://doi.org/10.1093/cid/cis887

MacLeod, I. (2015, July 9). Pan Degenerate Amplification and Adaptation (PANDAA): The first HIV drug resistance technology designed specifically for Africa. Lecture presented by PowerPoint in Botswana-Harvard AIDS Institute, Gaborone, Botswana.

Macleod, I. J., Rowley, C. F., & Essex, M. PANDAA-monium: intentional violations of qPCR design for SNP detection in highly polymorphic pathogens. Manuscript Submitted

Rowley, C. F., Macleod, I. J., Maruapula, D., Lekoko, B., Gaseitsiwe, S., Mine, M., & Essex, M. (2015). Sharp Increase in Rates of HIV Transmitted Drug Resistance at Antenatal Clinics in Botswana Demonstrates the Need for Routine Surveillance. In Press.

Yew, H., Guo, W., Poladyan, A., & Tao, L. (2015). Adapting for Growth: Diagnosing HIV Drug Resistance at Aldatu Biosciences. Boston: Harvard Business School.

Yong Kim, J., Farmer, P., Porter, M.E. (2013). Redefining Global Health-Care Delivery. Lanclet, 382:1060-9.

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