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Hydroxychloroquine for COVID19 in resource poor regions

*Please note this discussion is about the use of Hydroxychloroquine in developing counties. This post is in no way medical advice or a medical opinion and should not be construed as such. Please consult a licensed physician before taking any medications.

 

Finding a way forward in the management of COVID19 in resource poor regions

As the founder and leader of an international medical organization with full-time healthcare professionals in 19 countries, COVID19 has weighed heavy on my heart. If you are not familiar with Christian Health Service Corps, we are like Doctors Without Borders except our US trained medical staff stay in place for years not months. We work in poor countries, and the hospitals we serve in have little or no PPE to protect workers. Few have ventilators or even wall oxygen to which a ventilator can be connected. COVID19 has added onto an already overwhelming workload.

Caring for those in need while protecting healthcare providers 

Two questions have dominated our work of late. First, how do we protect our front-line workers serving in resource poor hospitals of the developing world? Second, are there viable treatment strategies for the care of COVID19 patients in resource poor communities? Where we work, if COVID patients become critically ill there is little or nothing that can be done for them. Providers caring for patients with severe SARS-CoV-2 in resource poor countries have been resigned to palliative care.

With PPE in short supply, the poor hospitals of the global south have struggled to locate PPE for their staff. This struggle has been much greater in resource poor regions of the world than in the fully developed nations of the global north. Many healthcare professionals in the resource poor hospitals of the developing world have turned to manufacturing their own reusable gowns and masks. As a global organization we have seen shipping costs increase exponentially because air freight carriers have dropped flights and have been trying to survive economically. Most African countries have closed their borders, and their government agencies like customs have slowed to a crawl, so PPE we have shipped to our healthcare professionals has been awaiting clearance in ports for weeks.

Is Hydroxychloroquine an Option?

Those of you who are familiar with my books and articles know that I am an advocate of evidence-based practice in global health. We must ask if this medication is a viable option for the treatment of patients in resource poor communities. Does the research support it? Sorting through the information has become especially difficult lately because of some seemingly conflicting data. The press has helped feed confusion on this topic. Information about Hydroxychloroquine is being spun to promote one political ideology or another, as if this were a political issue instead of a scientific one.  This is an issue that begs us to drop the politics and ask how do we provide compassionate care to the people who are suffering, hurting and scared.

Caring for those in poor countries

How do we find viable ways that may help people that will likely never be able to afford new therapies or vaccines? There is a race to create a vaccine in the big pharma world. But will vaccines be available for the poor in the majority world? I have serious doubts any vaccine will be made available for the world’s poor at least not in the first few years. We should also remember that vaccines against respiratory viruses are never 100% effective, usually closer to 60% to 70%, which is helpful but does not negate the need for viable treatments.  

What the research says

Despite the recent Study that has caused some divide and questions, the evidence and studies done still lead me to believe Chloroquine should be a viable option for COVID-19 patients in poor countries. It may be the only affordable and sustainable option in the developing world context. It may also be a viable option for prophylaxis to prevent infections of healthcare workers. Although, I would stress this is only my opinion after examining the literature that is available. More studies are needed but this is where the larger volume of evidence still points at present. I am including some of the literature worth reviewing later in this article as an annotated bibliography. However, I would suggest if you are a clinician, do your own research and assess the literature and not base your opinion on one retrospective chart audit study.

The study to which I am referring, that seems to have caused some questions about using chloroquine was recently published in the Lancet entitled Hydroxychloroquine or chloroquine with or without a macrolide treatment of COVID-19: a multinational registry analysis.

This study seems to conclude there is no benefit from Chloroquine in treating patients with COVID19 and even suggested a possibility for harm. Some have referred to this study as the conclusive answer on the issue, me included. However, when I dissected the study a little more it became evident to me that it is far from conclusive. Often, what studies tell us is there is a need for more research. I think that is the case with this last large observational study published in the Lancet. After reviewing it, I find it a valid study but it needs to be considered in the context of all the research. The only clear conclusion one can draw from this study is that much more research needs to be done.

Since I began this article, the study causing most of questions about validity and safety of using chloroquine was retracted by the Lancet, click he for a link to see the retraction.

Why more research needs to be done

The study published in the Lancet looked only at the charts of sick hospitalized patients. One can and should ask the question was it too little too late? Observational studies can lead us to the wrong conclusion at times, so we need to be careful that is not the case here. Retrospective chart audits can give us a lot of information, but we can’t let them drive us to specific conclusions about pharmaceutical effectiveness without controlling specific variables. The recent retraction is not a demonstration that the research was not valid, as much the conclusions reached were not valid.

Double blind controlled studies need to be done to look at potential benefits of the drug for preventing COVID infection, or treating COVID infections early in diagnosis. One study is underway now in the UK’s National Health Service looking at using Hydroxychloroquine in preventing COVID infections in health care workers. For more on this study click here.

I do not believe the research suggests it is time to abandon chloroquine or its less toxic derivative hydroxychloroquine as a viable therapy, especially in developing countries. The recent article retraction was not what led me to this conclusion, it was the quantity of literature that does seem to support its continued use. I also do not believe the evidence supports abandoning its use as a prophylactic measure to prevent transmission to healthcare workers in the developing world. At least not until more studies have been done. I would caution no one should ever take medications without the consultation of a physician. Especially, a medication like chloroquine which has shown to have cardiac toxicity in some patients. However, physicians and healthcare providers working in the hospitals of poor countries need options, and they need to protect themselves considering the vast PPE shortages.

It should be noted that the Lancet published an article in April suggesting the use of chloroquine and hydroxychloroquine in prophylaxis is likely effective for healthcare workers: Chloroquine or hydroxychloroquine for prophylaxis of COVID-19  (Esposito & Principi, 2020).

What is the theory behind Hydroxychloroquine for treating SARS-CoV-2 (COVID19)?

The literature points to a lot of theoretical benefits to giving chloroquine to COVID patients. And there are hundreds if not thousands of anecdotal reports and small studies that lead us to believe chloroquine is a viable therapy. It is a very cheap drug, especially compared to any potentially new antivirals and/or vaccine that may be developed. And it has been used safely for many years in the treatment and prevention of malaria. If it works, it seems like this would be the best option for treating patients especially in poor communities, but does it? I honestly do not think there is enough information to fully assess this currently. All indications in reviewing the literature are that it should be of some benefit.

  • First, there are many who believe there are some direct antiviral properties of hydroxychloroquine (Liu, J., Cao, R., Xu, M. Wang, X., Zhang H., Hu, H., Li, Y., Hu, Z., Zhong, W. & Wang, M., 2020).
  • It is also believed to be a Zinc Inonophore(Rahman, M.T. & Idid, S.Z., 2020). Meaning it helps move zinc into the cells. What we know about Zinc is that it has been shown to block viral replication inside cells. Therefore, some have said Zinc dosing seems to be essential for the theoretical benefits of Hydroxychloroquine to be confirmed or dismissed.
  • Hydroxychloroquine raises intercellular PH, and research indicates that higher PH also tends to inhibit viral replication (Hashem, A., Alghamdi, B., Algaissi, A., Alshehri, F., Bukhari, A., Alfaleh, M., & Memish, Z., 2020).
  • It is known to have anticoagulant properties. Postmortem examinations of patients that die of COVID have indicated that pulmonary thrombosis is part of the end of life pathology of the disease(Roldan, E. Biasiotto, G., Magro, P., Zanella, I., 2020) (Schreiber, K., Breen, K., Parmar, K., Rand, J., Wu, X., & Hunt, B., 2018) . It is theorized that the anticoagulant properties could play a role in preventing the end stage pulmonary thrombosis that comes with the severe SARS-CoV-2.
  • Hydroxychloroquine is also known to be an immune system modulator and systemic anti-inflammatory(Hashem, A., Alghamdi, B., Algaissi, A., Alshehri, F., Bukhari, A., Alfaleh, M., & Memish, Z., 2020). Many believe it should play a role in preventing the end of life septic cascade that occurs in critically ill ventilated SARS-CoV-2 patients.

There is a good amount of peer reviewed literature to support all these theoretical applications of hydroxychloroquine. The flowing is a short annotated bibliography. If you care to do your own literature review, these articles may be a good starting point.

 

Annotated Bibliography on the

Theoretical Application of Hydroxychloroquine in COVID-19

Hashem, A., Alghamdi, B., Algaissi, A., Alshehri, F., Bukhari, A., Alfaleh, M., & Memish, Z. (2020). Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review. Travel Medicine and Infectious Disease, 101735. Advance online publication. doi:10.1016/j.tmaid.2020.101735

This article comprehensively explores the different mechanisms by which hydroxychloroquine inhibit the activity of viruses such as the SARS-CoV-2. Particularly, this article provides a discussion of how hydroxychloroquine acts as an anti-inflammatory agent when administered to Covid-19 patients. During Covid-19 infection, hydroxychloroquine increases the endosomal pH which hinders the toll-like receptor (TLR) signaling pathway. The increase in pH specifically disrupt the binding of the TLR7 and TLR9 proteins to their DNA/RNA ligands. As a result, the transcription of pro-inflammatory genes is disrupted, which consequently reduces the inflammation caused by SARS-CoV-2 infection. Moreover, this article discusses the pharmacokinetics of chloroquine and hydroxychloroquine, their potential risks, and potential anti-viral properties.

Liu, J., Cao, R., Xu, M. Wang, X., Zhang H., Hu, H., Li, Y., Hu, Z., Zhong, W. & Wang, M. (2020). Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. doi:https://doi.org/10.1038/s41421-020-0156-0

Liu et al. (2020) compared the cytotoxic properties of hydroxychloroquine and chloroquine in the kidney VeroE6 cells of the African green monkey to determine the potency of hydroxychloroquine as less harmful alternative in treating Covid-19. Their study showed evidence that hydroxychloroquine, being structurally similar to chloroquine, exhibited the same anti-viral properties to chloroquine but with lesser ocular toxicity. Like chloroquine, hydroxychloroquine successfully disrupts the entry and post-entry of the SARS-CoV-2 virus in the cells by impairing the maturation of the early endosomes (EE) into endolysosomes (EL) due to increase in endosomal pH. Thus, virions remain encapsulated in the EE and the genetic material of the virus is not released into the cell.

Rahman, M.T. & Idid, S.Z. (2020). Can Zn Be a Critical Element in COVID-19 Treatment? Biological Trace Element Research, 1-9. Advance online publication. doi:10.1007/s12011-020-02194-9

In this article, Rahman and Idid (2020) discussed the immunomodulatory effect of Zn. The discussion of Rahman and Idid (2020) supplemented the discussion of Shittu et al. (2020) regarding the ability of chloroquine and hydroxychloroquine as a zinc ionophore. Specifically, the article highlights that Zn enhances the cytotoxicity of chloroquine. Thus, this result is also expected for its derivative, hydroxychloroquine. Additionally, the article discussed the important role of zinc in cell-mediated immune response and in the inhibition of SARS-CoV-2 replication. This significant role of zinc in the attenuation of Covid-19 infection also implies the important role of zinc ionophores such as chloroquine and hydroxychloroquine. Furthermore, the authors highlighted that in vitro results indicate that hydroxychloroquine is safer and has higher effectivity than chloroquine.

Roldan, E. Biasiotto, G., Magro, P., Zanella, I. (2020). The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacological Research, 158, 104904. Advance online publication. doi:https://doi.org/10.1016/j.phrs.2020.104904

This article discusses the different potential mechanisms of hydroxychloroquine and chloroquine in fighting SARS-CoV-2 infection. This article broadly reviews different researches showing the anti-viral, anti-inflammatory, and anti-thrombotic effects of hydroxychloroquine. Data from this article can be specifically used to describe the anti-thrombotic properties of hydroxychloroquine.

Roldan et al. (2020) included three major categories for hydroxychloroquine’s anti-thrombotic mechanisms. Primarily, this 4-aminoquinoline interferes with platelet aggregation, disrupts the binding of blood clotting proteins in the membrane ligands, and reduces endothelial dysfunctions which minimize the production of thrombi. The anti-thrombotic property of hydroxychloroquine is deemed as a potential treatment in micro-vascular thrombosis caused by Covid-19 complications.

Schreiber, K., Breen, K., Parmar, K., Rand, J., Wu, X., & Hunt, B. (2018). The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies. Rheumatology, 57(1), 120-124. doi:https://doi.org/10.1093/rheumatology/kex378

This research assessed the thromboelastography, anticoagulant activity of annexin A5, levels of tissue factor (TF), vascular endothelial growth factor (VEGF) and C-reactive protein of patients with aplastic anemia after administration of hydroxychloroquine. The results showed that hydroxychloroquine significantly reduced the levels of tissue factor (TF), suggesting its potency in modulating vascular coagulation. This article can be used to describe the anti-thrombotic property of hydroxychloroquine and its potential in treating hypercoagulation responses of the body to SARS-CoV-2.

Shittu, M. & Afolami, O. (2020). Improving the Efficacy ofChloroquine and Hydroxychloroquine against SARS-CoV-2 May Require Zinc Additives – A Better Synergy for Future COVID-19 Clinical Trials. Le Infezioni in Medicina, 2, 192-197.

Shittu et al. (2020) discussed the ability of hydroxychloroquine and chloroquine to transport zinc into the cell. The bioavailability of hydroxychloroquine in the cell is largely dependent on its interaction with Zn2+. Thus, the interaction of zinc ions and hydroxychloroquine primarily facilitates hydroxychloroquine’s disruption of the antigen presentation of the host cell through its impairment of endosomal and lysosomal maturation. Moreover, hydroxychloroquine, being a zinc ionophore, boosts the uptake of Zn2+ into the cell. The increase in Zn2+ concentration in the cell disrupts the replication of viruses such as the SARS-Corona virus (SARS CoV) and equine arteritis virus (EAV). Zinc ions directly interacts with the RNA-dependent RNA polymerase of these viruses which consequently results to the inhibition of viral proliferation. Hence, the synergistic effects of hydroxychloroquine and Zn2+ show a great potential in treating Covid-19 infections.

Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., Liu, X., Zhao, L., Dong, E., Song, C., Zhan, S., Lu, R., Li, H., Tan, W. & Liu, D. (2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases, ciaa237. doi:https://doi.org/10.1093/cid/ciaa237

Yao et al. (2020) used the physiologically based pharmacokinetic (PBPK) modelling in determining the pharmacological activity of hydroxychloroquine and chloroquine against SARS-CoV-2. Their findings show that the half maximal effective concentration (EC50) of hydroxychloroquine is higher than that of chloroquine. This result suggests that hydroxychloroquine has higher anti-viral potency than chloroquine against SARS-CoV-2. Moreover, Yao et al. (2020) also found that hydroxychloroquine has higher anti-viral pretreatment activity in in-vitro conditions in comparison to chloroquine. The researchers also simulated five dosing conditions for hydroxychloroquine and chloroquine to determine the recommended loading dose for both drugs. Based on the PBPK modelling results, the administration of a loading dose of 400 mg hydroxychloroquine sulfate twice a day succeeded by 200 mg maintenance dose twice daily for 4 days was recommended as it generated higher effectivity than chloroquine.

Zhao, M. (2020). Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. International Journal on Antimicrobial Agents, 105982. doi:10.1016/j.ijantimicag.2020.105982

This article demonstrated the anti-inflammatory effect of hydroxychloroquine and chloroquine against Covid-19 infection. The immunomodulatory effect of hydroxychloroquine and chloroquine primarily decrease the occurrence of cytokine storm that cause severe and even fatal inflammation in Covid-19 patients. Interleukin (IL)-1 and IL-6, together with interferon-α and tumor necrosis factor, are involved in cytokine storm manifested by patients who have Covid-19. The production of these pro-inflammatory cytokines is decreased due to the inhibitory effect of hydroxychloroquine and chloroquine to the cGAS stimulation of interferon genes via the Toll-like receptor (TLR) signaling pathway. This article showed that the anti-viral activity of hydroxychloroquine is further enhanced by its anti-inflammatory properties, which could be a promising treatment for Covid-19.

Blog Bibliography

Esposito, S., & Principi, N. (2020, April 17). Chloroquine or hydroxychloroquine for prophylaxis of COVID-19. Lancet Infectious Disease. Retrieved from https://doi.org/10.1016/S1473-3099(20)30296-6

Hashem, A., Alghamdi, B., Algaissi, A., Alshehri, F., Bukhari, A., Alfaleh, M., & Memish, Z. (2020). Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review. Travel Medicine and Infectious Disease, 101735. doi:10.1016/j.tmaid.2020.101735

Liu, J., Cao, R., Xu, M. Wang, X., Zhang H., Hu, H., Li, Y., Hu, Z., Zhong, W. & Wang, M. (2020). Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. doi:https://doi.org/10.1038/s41421-020-0156-0

Mandeep R Mehra, S. S. (2020, May 22). Hydroxychloroquine or chloroquine with or without a macrolide treatment of COVID-19: a multinational registry analysis. Retrieved from thetancet.com: https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2931180-6

Rahman, M.T. & Idid, S.Z. (2020). Can Zn Be a Critical Element in COVID-19 Treatment? Biological Trace Element Research, 1-9. doi:10.1007/s12011-020-02194-9

Roldan, E. Biasiotto, G., Magro, P., Zanella, I. (2020). The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacological Research, 158, 104904. doi:https://doi.org/10.1016/j.phrs.2020.104904

Schreiber, K., Breen, K., Parmar, K., Rand, J., Wu, X., & Hunt, B. (2018). The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies. Rheumatology, 57(1), 120-124. doi:https://doi.org/10.1093/rheumatology/kex378

Shittu, M. & Afolami, O. (2020). Improving the Efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 May Require Zinc Additives – A Better Synergy for Future COVID-19 Clinical Trials. Le Infezioni in Medicina, 2, 192-197.

Yao, X., Ye, F., Zhang, M., Cui, C., Huang, B., Niu, P., Liu, X., Zhao, L., Dong, E., Song, C., Zhan, S., Lu, R., Li, H., Tan, W. & Liu, D. (2020). In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases, ciaa237. doi:https://doi.org/10.1093/cid/ciaa237

Zhao, M. (2020). Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies. International Journal on Antimicrobial Agents, 105982. doi:10.1016/j.ijantimicag.2020.105982

 

About the Author:

Greg Seager is the author of When Healthcare Hurts: An Evidence Based Guide for Best Practices in Global Health Initiatives. When Healthcare Hurts is the first book to look seriously at the challenges of patient safety and developmental safety in global health missions, and it defines evidence-based guidelines through which these issues can be addressed.

Greg holds a Masters in Nursing/ Healthcare Leadership and Management from The George Washington University School of Medicine and Health Sciences. His graduate thesis project was on patient safety in global health and he serves as adjunct faculty in the nursing programs at King University.

Greg is also the Founder and Chief Executive Officer for the Christian Health Service Corps (CHSC), an interdenominational, healthcare related, long-term mission organization. CHSC has a growing full-time medical missionary staff in 19 countries around the world. Prior to founding Christian Health Service Corps, Greg and his wife Candi designed, monitored and implemented global health initiatives in multiple regions; first for a Miami based mission organization and then for Mercy Ships International.  Greg is part of the international working group on best practices in healthcare missions. He also serves as a founding board member for Health For All Nations.

 

 

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