Abstract
HIV and AIDS have devastated the lives of millions of people worldwide. Antiretroviral therapy (ART) has completely transformed the reality of those impacted by HIV and AIDS, turning a death sentence into a much longer and healthier life. However, heavy pill burdens, drug resistance, and a lack of equity in current treatment make ART unethical as a long-term, permanent solution. It is up to biomedical engineers to find an ethical way to treat or cure the millions of people impacted by this virus. Genetically engineering humans (GEH) has shown great promise in improving treatment and finding a cure for HIV. If the engineers making these edits follow very thorough and specific guidelines, genetic engineering can be an ethical alternative to ART.
Introduction
Since it first began in 1981, the HIV epidemic has infected 84.2 million people and killed 40.1 million [1]. Over 40 years have passed since the first documented case, and no cure has yet been discovered. Current treatment has significantly improved and lengthened the lives of those afflicted by the virus, but it is far from the best treatment possible. This is why He Jiankui, a biophysicist, took matters into his own hands and conducted an experiment to make the first HIV-immune humans [2]. He used CRISPR to knock out the CCR5 gene (which enables HIV) in embryos that were carriers of the virus. While the experiment was largely condemned by the scientific community, it revealed genetic engineering as a potential alternative for treatment. If done ethically, it has the capacity to be a better treatment path – and even a cure – for those living with HIV and AIDS.
HIV and AIDS
AIDS is a retrovirus which means that it uses reverse transcriptase to transcribe and translate its RNA into human DNA [3]. It is extremely dangerous because it weaponizes DNA. Typically, DNA is made in the nucleus. Here, a process known as transcription occurs wherein the protein DNA polymerase copies a single strand of DNA [4]. This copy is then transported to a ribosome in the cytoplasm of any given cell and “translated” into mRNA [4]. This mRNA is shipped off to different parts of the cell to give them instructions and tell them what to do [4]. Simply put, if DNA is the entirety of the human code, then mRNA is the individual pieces of the code that allow different tasks to run at the same time.
When HIV enters the bloodstream, it takes advantage of mRNA by hijacking white blood cells, formally known as CD4 cells [6]. It then creates DNA in reverse order. Rather than beginning by copying DNA to make RNA, HIV starts by making RNA in the ribosomes of CD4 cells to make DNA in the nucleus. Normally functioning CD4 cells play a vital role in the immune system by triggering defenses and killing any intruders that enter the body [6]. When HIV hijacks CD4 cells, it makes copies of itself. So, every time the body tries to fight an infection, HIV increasingly reduces the body’s ability to do so [7]. A low CD4 cell count leaves the body without a functioning immune system, leaving it susceptible to viruses, bacteria, and other pathogens.The CD4 cell count in a person who has been infected by the virus is about 2.5 to 7.5 times lower than that of a person without HIV [7]. When a CD4 count drops below a certain threshold, that marks HIV’s development into AIDS – the final stage of HIV [8, 9, 10]. While there is no cure, new treatments for the virus have prevented most people from progressing to AIDS [3].
Treatment
When the virus first appeared in the 1980s, the average life expectancy of someone with an HIV/AIDS diagnosis was fewer than 18 months [11]. Now, with antiretroviral treatment (ART), two-thirds of those with HIV/AIDS live as long as the general population [1]. ART has helped reduce HIV/AIDS casualties by 68 percent while also preventing virus transmission [12].
When ART is successful, it prevents HIV from replicating in the body until HIV counts are undetectable in the blood, known as viral load suppression [13]. HIV is very adaptable and can easily become resistant to treatment, so to avoid this, patients are required to take a significant number of drugs.
Biomedical Ethics
While biomedical engineers are not the ones administering treatment, they are the ones responsible for creating innovative forms of care. Though ART is the most effective treatment to date, its ethicality could be improved. Thus, as professionals who directly contribute to the treatments used in the medical field, biomedical engineers are responsible for finding something better for those afflicted with HIV and AIDS. They are held to these standards by the Four Pillars of Biomedical Ethics [14].
Autonomy: Autonomy is the first pillar of biomedical ethics. This involves a patient’s ability to control decisions about their health and their caregiver’s responsibility to respect that decision [15]. To achieve autonomy, the patient must have a sense of health literacy: the ability to find, understand, and access health-related information [15]. Autonomy also relies on organizational health literacy which ensures that patients are accessing and understanding the provided information [16]. Thus, this pillar emphasizes informed consent.
On the patient’s side, informed consent is the ability to make fully informed medical decisions based on a thorough understanding of information. On the medical personnel’s side, this means making information accessible and understandable. Medical jargon, language barriers, lack of access to information, and a lack of patient understanding can make it easy to take advantage of patients. One study found that 59 percent of patient deaths, prolonged hospitalizations, and permanent damage were attributed to errors in communication between medical personnel and their patients with limited English proficiency [17]. Further, those with low health literacy experience more negative outcomes from medical treatment [18]. For care to be ethical, medical professionals must eliminate any barriers a patient may have to understanding their health.
Beneficence and Nonmaleficence: Beneficence is a positive right that advocates for the health of a patient [16]. Beneficence refers to a medical professional’s duty to uphold a patient’s well-being, which complements the next pillar: nonmaleficence [14]. This pillar is a medical professional’s duty to prevent a patient from harm [16]. Nonmaleficence acts as a negative right to restrict any risks that could potentially harm a patient [15]. When put together, these pillars focus on finding and providing the best form of care for a patient. Giving the best care requires that medical professionals maintain medical competence by being properly trained. A medically competent caregiver should be able to find the best treatment while assessing treatment risk and considering the wishes of the patient.
Justice: Last is the justice pillar. This pillar is inspired by another ethical framework that describes justice and fairness [19]. Under this framework, justice is defined as a person’s ability to get what they deserve. Fairness is the notion that everyone should be treated equally [15]. It also accounts for the fact that, based on their circumstances, some people need extra tools for equality to be achieved [15]. Under biomedical ethics, justice means that all patients are provided with the most effective treatment with the lowest risk factor. It also requires that the patient has given full informed consent about said treatment. Fairness is providing high-quality care to all patients regardless of their identity or socioeconomic status [15]. Those who experience more obstacles in obtaining treatment or those who are more predisposed to certain illnesses need more help, more resources, and more medical priority than the general population. The justice pillar intends to remove prejudice and bias from healthcare to promote truly equal care.
The Unethicality of ART
Adhering to these four pillars reveals the unethical aspects of ART: drug resistance, heavy pill burdens, and lack of access to treatment.
Drug Resistance: The sheer number of available drugs and the many combinations in which they can be taken offer many patients a workaround for HIV drug resistance. However, 10 percent of adults with HIV, about 3,670,000 people worldwide, still experience drug resistance [20]. Drug resistance can be transmitted to others and has a very high rate of impacting newborns with HIV [20]. Treatment options are limited for drug-resistant individuals, and if they’ve gone through too many regimen rotations, there is no guarantee that other treatments will work [21]. Therefore, drug resistance presents a violation of justice, autonomy, and nonmaleficence in HIV/AIDS treatment.
Limiting what drugs individuals can take and leaving many with no form of treatment is a violation of the justice pillar. Moreover, as a patient’s drug options dwindle, they can only take drugs with very potent side effects and must follow that regimen for the rest of their lives. These side effects can include diabetes, cardiovascular disease, kidney disease, low bone density, depression, suicidality, and more [22]. A lack of drug choice takes away a patient’s autonomy by forcing them to choose between life and death. Reported side effects that have severe and long-term consequences violate the pillar of nonmaleficence. Having to live with depression, diabetes, or high cholesterol caused by treatment conflicts with the prevention of harm that this pillar emphasizes.
ART is far from the best treatment available to those with HIV, but currently, this is the only treatment that prevents the virus from becoming lethal. The justice pillar decrees that everyone with HIV/AIDS deserves an opportunity to be treated with the best treatment available and, right now, ART excludes those who are drug resistant.
Heavy Pill Burden: To prevent drug resistance, those receiving treatment for HIV must take anywhere between 1 and 8 pills every day for the rest of their lives [23, 24, 25]. Even those who take 1 pill are taking fixed doses, meaning they have merged their multiple doses into one to lessen the pill burden [10]. However, fixed doses are more expensive than treatment with heavy pill burdens. For example, Ziagen and Epiver are commonly used in combination for ART. When taken as separate doses, the annual cost for this treatment is $14,031 [26]. Epzicom, the fixed dose of Ziagen and Epivir, costs $16,992 a year [26]. That’s an extra $2,961 a year for the rest of a patient’s life.
This is a breach of the justice pillar as studies have found that those with an STR (single-tablet regimen) are much more likely to attain regimen adherence [25]. Only those who can afford a fixed dose are receiving high-quality care while those who cannot afford a fixed dose are statistically proven to break their regimen. Beneficence and nonmaleficence are also violated as a single break in regimen could be the difference between an undetectable viral load and drug resistance, or even escalation to an AIDS diagnosis [27]. Treatment that endangers a patient after one missed dose hardly promotes their well-being, and certainly does not prevent unnecessary risks in treatment. For HIV/AIDS treatment to maximize its ethicality, treatment should focus on creating a way for the human body to fight against the virus, rather than merely preventing HIV replication with drugs.
Access: Most ART patients can barely afford their treatment. In 2018, the average cost of ART in the U.S. ranged from $36,080 to $48,000 [28]. This is especially concerning given that 87 percent of those with AIDS in the U.S. fall 400 percent below the federal poverty line [29]. A majority of those who need treatment cannot afford it without help. The inability to access treatment seems to be a recurring pattern in the history of HIV/AIDS.
When the first HIV drug, AZT, was released in the 1980s, it cost $10,000. Today, that would be equivalent to more than $27,000 [30]. The cost of AZT made it largely inaccessible to the people who needed it most. In response, ACT UP, a prominent AIDS organization at the time, staged a large protest on Wall Street [31]. The price dropped 20 percent only two weeks after the protest [30]. Scholars have observed that back then, the main reason that AZT was so inaccessible was because of whom AIDS mainly impacted: queer men and people of color [31]. The concern here lies in the fact that this demographic is still whom AIDS impacts.
Today, black and Latine people make up 53 percent of those diagnosed with HIV [32]. There is an overwhelming amount of evidence that supports the notion of disparities in medical treatment due to race and ethnicity. For instance, both groups are over 50 percent more likely than their white counterparts to experience a delay in getting care following an HIV diagnosis [33]. Latine and black people are also the least likely to have medical insurance which limits the treatments to which they have access [33]. These groups also tend to have low rates of health literacy due to a lack of access to health-related information [34]. They also experience higher levels of distrust toward medical personnel which contributes to their low rates of receiving professional treatment [35].
This total disregard for the values of justice and fairness must be resolved. Latine and black people need better help from their medical providers. The pillar of beneficence asks that medical personnel strive to give the best care possible, and it is the job of biomedical engineers to create something that will do that. As a newly emerging technology with significant potential, genetic engineering seems like a possible solution to ending HIV once and for all.
Unintentional Consequences
The greatest concern regarding the medical use of genetic engineering is its unknown consequences. Consisting of about 3.2 billion base pairs and 20,000 genes, the human genome is very large and complex [36]. The polygenic nature of most traits further reduces scientific understanding of the genome. Rather than one gene producing one specific trait, most genes depend on the expression of other genes to work properly [37]. The first sequence of the human genome was barely completed in 2022 [38]. If humans have just barely begun to paint the full scope of their genome, how could they be expected to know the function of every gene and how it interacts with all other genes? The simple answer is that they cannot. This means that there is a lot of uncertainty about how removing or editing certain genes will go on to impact the patient. Good or bad, no one will know the consequences until they are set in motion. Dr. Francis Collins, the former director of the National Institute of Health and leader of the groundbreaking Human Genome Project, summed up this concern: “Evolution has been working toward optimizing the human genome for 3.85 billion years. Do we really think that some small group of human genome tinkerers could do it better without all sorts of unintended consequences [39]?”
These unintended consequences can be seen in He Jiankui’s HIV cure research. While Jiankui’s goal was to create the first humans immune to HIV, he may have unintentionally also genetically modified the twins to have enhanced intelligence. This highlights the polygenic nature of most traits; while the CCR5 gene is strongly associated with HIV infection, it is also known to be related to brain function [2]. This was confirmed in a knockout experiment where researchers found that mice that had their CCR5 gene removed showed enhanced memory and learning capabilities [40].
Even if the consequences are beneficial, they are not understood or guaranteed to always result in positive changes. This is a violation of the bioethical code as patients cannot have autonomy over treatment if they never know how gene modification will impact them. Moreover, this lack of information is a clear violation of both beneficence and nonmaleficence because there is not enough evidence to prove that a high-risk procedure would have any redeeming results. As of now, turning to genetic engineering would be irresponsible and would not promote the well-being of patients.
More studies must be conducted to conclusively determine which parts of the genome are altered by HIV and how those alterations impact bodily functions. Only then would genetic engineering ensure patient autonomy and allow medical professionals to observe beneficence and nonmaleficence. With a more complete understanding, patients will be able to give informed consent and medical professionals will be able to make accurate treatment assessments.
Genetic Engineering as an Ethical Solution
Overall, not enough is known about the human genome to genetically modify it to cure HIV. But like any new scientific feat, research is key to its success. Thorough research will ensure future clinical trials are ethical by providing sufficient information to support decision-making.
In the meantime, genetic engineering has been used to genetically modify blood cells rather than human DNA [41, 42]. Once again, the CCR5 gene was used, but this time on donor stem cells. After the patient received the STEM cells, they were able to reproduce a small number of these CD4 cells with the CCR5 mutation for over 19 months without further gene editing [41, 42]. No side effects were reported and there were no reports of unintended genetic changes after sequencing the genomes of the new CCR5 cells [41]. However, the gene was only present in about five percent of the patient’s overall stem cell count – this means that more than 50 percent died after the transplant [41, 42]. Despite the discouraging results, the concept is important. This method presents a non-invasive way to use genetic engineering as a treatment for HIV/AIDS. With more research, biomedical engineers can find a way to increase the concentration of these resistant CD4 cells. While not a definite cure, this is a step in the right, and ethical, direction until more is known about HIV and the human genome.
By Janessi Diaz, Dornsife College of Letters, Arts, and Sciences, University of Southern California
About the Author
At the time of writing this paper, Janessi Diaz was a sophomore studying Biology. She hopes to work in the medical field someday and loves listening to music and watching movies.
References
[1] “HIV,” World Health Organization, https://www.who.int/data/gho/data/themes/hiv-aids (accessed Nov. 13, 2022).
[2] V. L. Raposo, “The first Chinese edited babies: A leap of faith in science,” JBRA Assisted Reproduction, vol. 23, no. 3, 2019, doi: 10.5935/1518-0557.20190042.
[3] M. W. Cloyd, “Human retroviruses,” PubMed, 1996. https://www.ncbi.nlm.nih.gov/books/NBK7934/#:~:text=simian%20immunodeficiency%20virus (accessed Nov. 13, 2022).
[4] “Transcription, translation and replication,” ATDBio, https://atdbio.com/nucleic-acids-book/Transcription-Translation-and-Replication (accessed Nov. 13, 2022).
[5] “Transcription and translation,” National Cancer Institute Visuals Online, https://visualsonline.cancer.gov/details.cfm?imageid=11683 (accessed Nov. 13, 2022.
[6] “CD4 lymphocyte count,” MedlinePlus, https://medlineplus.gov/lab-tests/cd4-lymphocyte-count/#:~:text=CD4%20cells%20are%20a%20type.
[7] “HIV replication,” National Institute of Allergy and Infectious Diseases, Jun. 19, 2018. https://www.niaid.nih.gov/diseases-conditions/hiv-replication-cycle.
[8] “CD4 cell count,” International Association of Providers of AIDS Care. https://www.iapac.org/fact-sheet/cd4-cell-count/#:~:text=A%20higher%20number%20indicates%20a (accessed Nov. 13, 2022).
[9] “What is HIV?,” Queen’s University Belfast, https://www.qub.ac.uk/elearning/hiv-and-pregnancy/ElearningResource/Module1-HIVawareness/WhatisHIV/.
[10] S. A. Battistini Garcia and N. Guzman, “Acquired immune deficiency syndrome CD4+ count,” PubMed, 2021. https://www.ncbi.nlm.nih.gov/books/NBK513289/#:~:text=The%20CD4%20count%20normal%20range.
[11] UNAIDS, “Global HIV & AIDS statistics — 2020 Fact Sheet,” UNAIDS, 2021. https://www.unaids.org/en/resources/fact-sheet.
[12] “HIV and AIDS – Treatment,” NHS, https://www.nhs.uk/conditions/hiv-and-aids/treatment/#:~:text=Antiretroviral%20drugs (accessed Nov. 13, 2022).
[13] “Viral load and being undetectable,” Terrence Higgins Trust, https://www.tht.org.uk/hiv-and-sexual-health/about-hiv/viral-load-and-being-undetectable#:~:text=Viral%20load%20is%20the%20amount.
[14] E. Cripps, “Crash course in biomedical ethics,” University of Colorado Boulder, https://www.colorado.edu/ceprehealth/sites/default/files/attached-files/slides_-_crash_course_in_biomedical_ethics_spring_2022_.pdf (accessed: Nov. 13, 2022).
[15] T. McCormick, “Principles of bioethics,” University of Washington, 2018. https://depts.washington.edu/bhdept/ethics-medicine/bioethics-topics/articles/principles-bioethics.
[16] E. Stone, “Evidence-based medicine and bioethics: Implications for health care organizations, clinicians, and patients,” The Permanente Journal, vol. 22, no. 18-030, 2018, doi: 10.7812/tpp/18-030.
[17] M. Wasserman et al., “Identifying and Preventing Medical Errors in Patients With Limited English Proficiency: Key Findings and Tools for the Field,” Journal For Healthcare Quality, vol. 36, no. 3, pp. 5–16, May 2014, doi: https://doi.org/10.1111/jhq.12065.
[18] N. D. Berkman, S. L. Sheridan, K. E. Donahue, D. J. Halpern, and K. Crotty, “Low Health Literacy and Health Outcomes: An updated systematic review,” Annals of Internal Medicine, vol. 155, no. 2, p. 97, 2011. doi:10.7326/0003-4819-155-2-201107190-00005.
[19] L. Nineham, “Medical ethics: Justice,” The Medic Portal, https://www.themedicportal.com/application-guide/medical-school-interview/medical-ethics/justice/#:~:text=Justice%20%E2%80%93%20in%20the%20context%20of.
[20] “HIV drug resistance,” World Health Organization, https://www.who.int/news-room/fact-sheets/detail/hiv-drug-resistance (accessed Nov. 13, 2022).
[21] “Drug resistance,” HIVinfo.nih.gov, https://hivinfo.nih.gov/understanding-hiv/fact-sheets/drug-resistance.
[22] “Table 20. Common and/or severe adverse effects associated with antiretroviral therapy,” clinicalinfo.hiv.gov. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/adverse-effects-antiretroviral-agents-full.
[23] S. Zhou et al., “Total daily pill burden in HIV-infected patients in the southern United States,” AIDS Patient Care and STDs, vol. 28, no. 6, pp. 311–317, Jun. 2014, doi: 10.1089/apc.2014.0010.
[24] “Treatment decisions for HIV,” U.S. Department of Veterans Affairs, https://www.hiv.va.gov/patient/treat/decisions-single-page.asp (accessed Nov. 13, 2022).
[25] S. Scott Sutton, J. Magagnoli, and J. W. Hardin, “Impact of pill burden on adherence, risk of hospitalization, and viral suppression in patients with HIV infection and AIDS receiving antiretroviral therapy,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, vol. 36, no. 4, pp. 385–401, Apr. 2016, doi: 10.1002/phar.1728.
[26] Adalja, Amesh. “The cost of HIV care.” MoneyGeek, www.moneygeek.com/living/resources/hiv/ (accessed Nov. 13, 2022).
[27] C. J. Cohen, J. L. Meyers, and K. L. Davis, “Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US medicaid population with HIV,” BMJ Open, vol. 3, no. 8, p. e003028, Jul. 2013, doi: 10.1136/bmjopen-2013-003028.
[28] N. C. McCann, T. H. Horn, E. P. Hyle, and R. P. Walensky, “HIV antiretroviral therapy costs in the United States, 2012-2018,” JAMA Internal Medicine, vol. 180, no. 4, pp. 601–603, Apr. 2020, doi: https://doi.org/10.1001/jamainternmed.2019.7108.
[29] R. G. Jennifer Kates, “Assessing the impact of the affordable care act on health insurance coverage of people with HIV,” KFF, https://www.kff.org/hivaids/issue-brief/assessing-the-impact-of-the-affordable-care-act-on-health-insurance-coverage-of-people-with-hiv/view/print/ (accessed Nov. 13, 2022).
[30] “AIDS activists take aim at Gilead to lower price of HIV drug PrEP,” NPR, https://www.npr.org/sections/health-shots/2019/05/30/727731380/old-fight-new-front-aids-activists-want-lower-drug-prices-now#:~:text=When%20the%20first%20HIV%20drug (accessed Nov. 13, 2022).
[31] J. Vaccaro (2021). SWMS-221 Lecture: 18 ACT UP [PowerPoint slides].
[32] “Basic statistics,” Centers for Disease Control and Prevention, https://www.cdc.gov/hiv/basics/statistics.html (accessed Nov. 13, 2022).
[33] V. E. Stone, “Physician contributions to disparities in HIV/AIDS care: The role of provider perceptions regarding adherence,” Current HIV/AIDS Reports, vol. 2, no. 4, pp. 189–193, Dec. 2005, doi: 10.1007/s11904-005-0015-5.
[34] O. Mgbako, R. Conard, C. A. Mellins, J. Dacus, and R. H. Remien, “A systematic review of factors critical for HIV health literacy, ART adherence and retention in care in the U.S. for racial and ethnic minorities,” AIDS and Behavior, Apr. 2022, doi: https://doi.org/10.1007/s10461-022-03680-y.
[35] T. R. Earl et al., “Race, relationships, and trust in providers among black patients with HIV/AIDS,” Social Work Research, vol. 37, no. 3, pp. 219–226, Aug. 2013, doi: https://doi.org/10.1093/swr/svt017.
[36] “National Institute of General Medical Sciences,” National Institute of General Medical Sciences, https://nigms.nih.gov/education/Inside-Life-Science/Pages/Genetics-by-the-Numbers.aspx.
[37] “Polygenic Trait,” National Human Genome Research Institute, https://www.genome.gov/genetics-glossary/Polygenic-Trait#:~:text=%E2%80%8BPolygenic%20Trait&text=A%20polygenic%20trait%20is%20a (accessed Nov. 13, 2022).
[38] S. Nurk et al., “The complete sequence of a human genome,” Science, vol. 376, no. 6588, pp. 44–53, Apr. 2022, doi: 10.1126/science.abj6987.
[39] P. Skerrett, “A debate: Should we edit the human germline?,” STAT, https://www.statnews.com/2015/11/30/gene-editing-crispr-germline/?s_campaign=stat:rss
[40] M. Zhou et al., “CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory,” eLife, vol. 5, Dec. 2016, doi: 10.7554/elife.20985.
[41] J. Lambert, “Scientists use gene-edited stem cells to treat HIV — with mixed success,” Nature, 2019. doi:10.1038/d41586-019-02719-w.[42] L. Xu et al., “CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia,” New England Journal of Medicine, vol. 381, no. 13, pp. 1240–1247, Sep. 2019, doi: 10.1056/nejmoa1817426.
Links for further reading
https://www.nature.com/articles/d41586-021-01506-w
https://www.nih.gov/news-events/news-releases/nih-launches-clinical-trial-three-mrna-hiv-vaccines