Pharmacogenetics, HLA-B*5701 Testing, and Ethical Issues

Introduction to Pharmacogenetics and Abacavir

Pharmacogenetics revolves around a pre-determined range in how individuals react to certain drugs, with regard to both their beneficial and adverse effects. "This concept emerged when tasters and non-tasters of phenylthiocarbamide (PTC) were identified, and the ability to perceive that taste was shown to be inherited" (Luzzatto & Seneca, 2014). Since screening individuals for PTC tasting turned out to be simple and minimally invasive, PTC became one of the initial traits examined at length at the dawn of human population genetics. Since then, the field of pharmacogenomic medicine has evolved exponentially, giving scientists valuable data that has provided a more compelling road map for treatment plans than ever before.

One arena where this type of work is particularly instrumental is in the field of genetic testing for those suffering from HIV/AIDS, and it has functioned as an aspect of science that has furthered understanding of the condition (Hu et al., 1996). Much HIV medicine is newer to the market and often has side effects, some of which can be very unpleasant for the patient. The most prominent example is the drug abacavir, used alongside other antiretrovirals to treat HIV infection. While abacavir is known to be extremely successful in treating HIV — the virus responsible for AIDS — a small percentage of patients do suffer side effects such as rash, extreme fatigue, and diarrhea. Based on these reactions, scientists concluded that some patients had a hypersensitivity to the drug, attributable to their unique genetic make-up (Rauch et al., 2006). Essentially, their immune systems were producing an exaggerated reaction to the drug, almost akin to an allergic response. Based on these findings, it appeared that the genes controlling the overall response of the immune system were most likely responsible for these particular side effects.

"The scientists' theory turned out to be correct. In 2002, two groups identified a particular gene variant in the major histocompatibility complex (MHC), called HLA-B*5701, as being the key factor in hypersensitivity to abacavir. Individuals with the HLA-B*5701 allele were found to be more likely to have a hypersensitivity reaction to abacavir" (yourgenome.org, 2016). The HLA-B*5701 allele is not terribly common, but its appearance is significant: it occurs at a frequency of around five percent in people from Europe, one percent in people of Asian descent, and less than one percent in those of African descent (yourgenome.org, 2016). "Clinical trials have now shown that screening patients for HLA-B*5701 before treatment has dramatically reduced the number of side effects experienced from abacavir use. In individuals found to have the HLA-B*5701 allele, abacavir is avoided, and alternative HIV treatments are given" (yourgenome.org, 2016). This form of testing allows clinicians to avoid giving patients a substance likely to cause serious side effects based on the patient's genetic make-up, and many clinicians view it as necessary genetic screening (Lalonde et al., 2010).

HLA-B*5701 Screening Accuracy Across Racial Groups

While the test is very cost-effective and saves the medical community money in the long run, there was initial concern that it was not completely accurate for all ethnic groups. There had been concerns that such tests demonstrated less accuracy in African Americans than in Caucasians (Saag et al., 2008). A research study was therefore commenced to shed light on this issue, and it was discovered without ambiguity that the test — which determines who is likely to develop a severe allergic reaction to abacavir — demonstrates the same level of accuracy among both white and black patients (Saag et al., 2008).

This study found that black and white participants who showed physical manifestations indicating a possible hypersensitivity to abacavir had these signs confirmed via a skin patch test, which demonstrated a positive HLA-B*5701 result (Saag et al., 2008). Making this determination was important because physical manifestations indicating an allergy to abacavir can also be associated with other anti-HIV drugs, and other clinical trials have documented a large number of patients not taking abacavir who were nonetheless diagnosed with a biological aversion to the substance (Saag et al., 2008). It was therefore important to engage in this retrospective study to determine the efficiency of the test in patients of different ethnicities, using two groups.

"Patients in the first group all developed symptoms of an abacavir hypersensitivity reaction and had a skin-patch test to check for an allergic reaction to abacavir. This test exposes the skin to a small amount of abacavir to see if it provokes a reaction. Patients with a negative skin-patch test were diagnosed as having a 'clinically suspected' hypersensitivity reaction, and those with a positive skin-patch test as having an 'immunologically confirmed' hypersensitivity reaction" (Carter, 2008). These participants were then compared with a second group made up of people who had been treated with abacavir but had not developed symptoms of an allergic reaction (Saag et al., 2008). Blood samples were taken from each participant to determine whether the HLA-B*5701 gene was present. Participants of both races who showed a positive skin patch test — indicating extreme sensitivity to abacavir — all had a positive HLA-B*5701 result, denoting complete sensitivity to the substance. While results were not entirely uniform throughout the study, they did demonstrate that the effectiveness of the "HLA-B*5701 test was 96% in black patients and 99% in white patients" (Saag et al., 2008). These findings lead investigators to conclude that the presence of HLA-B*5701 is meaningfully associated with a biological aversion to abacavir, and that the HLA-B*5701 screening has a high level of generalizability and can be used with great success regardless of race (Saag et al., 2008).

Ethical Issues in Pharmacogenetic Testing

This type of testing might appear straightforward: it is designed to determine whether an individual carries a gene that will cause sensitivity to a given substance and produce unwanted side effects. In order to ensure that one does not have to deal with such side effects, genetic testing for HLA-B*5701 is ideal. However, it raises inherent ethical concerns for all participants involved in the pharmacogenomic process. One of the major concerns associated with this genetic testing is that for abacavir specifically, there are ethnic patterns to the hypersensitivity, with differences between white patients and ethnic minorities. "Being of African descent was associated with a nearly 40% reduction in the risk of hypersensitivity. In a study of 540 patients that included a predominance of ethnic and racial minorities, Hispanic ethnicity was associated with an OR of 2.77 when compared with other ethnic backgrounds. Patients of white race were found to be at significantly greater risk in another study of a population with a low percentage of ethnic minorities" (Hewitt, 2002).

The ethical concern these findings provoke is that when certain drugs are found to be more predisposed to affecting one ethnic group over another, such differentiations can influence pharmaceutical companies. This is something that occurred with the marketing of BiDiL for the treatment of cardiac failure in African Americans (Brice & Sanderson, 2006). BiDiL was dubbed by insiders as the first "ethnic drug," as it was approved for use by one particular ethnic group. "The US company NitroMed claimed that racial differences in the response to heart failure treatment are due to underlying pathophysiological differences between ethnic groups. However, there has been considerable criticism of this approach, based primarily on whether race or ethnicity can be used as adequate markers of genetic differences, and that this decision provides support for the concept of race as a distinct biological marker, with a risk of genetic discrimination" (Brice & Sanderson, 2006).

While genetic differences among distinct racial and ethnic groups do exist, these differences do not align with the superficial factors often used to describe them (Brice & Sanderson, 2006). The bulk of research has made clear that genetic differences between branches on the ethnic tree are generally slighter than the variations within these groups. Categorization by skin color, race, or ethnic group is therefore a poor substitute for determining common ancestry by concrete genetic markers (Brice & Sanderson, 2006). A growing body of research shows that variations in genes have comparable consequences across classically classified racial groups (Singer et al., 2004). Thus, ethnicity and race do not offer a consistent snapshot of genetic make-up and should not serve as a primary tool in the stratification of drug development. Moreover, focusing on genetic origins for distinctive treatment responses risks overshadowing relevant factors such as lifestyle and socioeconomic status (Brice & Sanderson, 2006).

Most professionals within healthcare and medicine are aware that pharmaceutical companies are not always the most ethically upright organizations. With the increase of pharmacogenetics, including the testing done for abacavir, there are concerns connected to drug stratification and orphan drugs (Trusheim et al., 2007). Once drug companies know they can stratify patients into specific treatment groups based solely on their genes, this could prompt these firms to redirect their focus in ways that are less than equitable. Genetic testing gives pharmaceutical companies precise intelligence on how to direct their efforts. If drug companies choose to, they can create drugs for one ethnic group over another, or for patients who are easier to treat. They can ignore those with rare genetic profiles or unusual illnesses — making genetic testing in this arena an ethical concern.

Most experts argue that pharmaceutical companies have the greatest interest in developing substances that can treat the largest number of population sub-groups (Brice & Sanderson, 2006), and such a move would make the most economic sense. However, the "orphan drug" phenomenon illustrates that circumstances are not always so simple. Orphan drugs are substances developed to treat people with exceedingly rare conditions, and legislation over the last few decades has attempted to incentivize companies to explore them. However, many drug companies are primarily profit-motivated, and such a niche market is viewed as both unattractive and unprofitable. Thus, "some have raised concerns that pharmacogenetics may exacerbate the orphan drug problem, where potentially valuable drugs are not developed because they would not have a large enough market, thus denying treatment to certain groups" (Brice & Sanderson, 2006). The orphan drug issue will remain pertinent for health boards, medical practitioners, and the entire medical community, as many scholars argue that research into these issues raises the bar of care and science (Wästfelt et al., 2006).

Health insurance companies know it is illegal to deny coverage based on genetic testing or the results of such tests. "Since 2008, with the passing of the Genetic Information Nondiscrimination Act (GINA), the federal government has barred health insurance companies from denying coverage to those with a gene mutation. But the law does not apply to life insurance companies, long-term care, or disability insurance. These companies can ask about health, family history of disease, or genetic information, and reject those deemed too risky" (Farr, 2016). This illustrates how organizations can be influenced by the results of genetic information, how it can impact the level of care or protection a patient receives, and how these dynamics can redirect the path that research and development takes.

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