Treating Hepatitis B Virus in Times of COVID-19: The Case for Clinical Pharmacogenomics Research in Tenofovir-Induced Kidney Toxicity

Perspective

The long game for COVID-19 calls for imagining new ways of living with the virus (Butler, 2022), and importantly, creating policy interventions and research investments to fight the cross-cutting effects of SARS-CoV-2 across health systems and services, and across the nation–state borders. It is noteworthy that the pandemic has shifted the focus of the global research and development ecosystem from chronic human diseases to infectious agents such as SARS-CoV-2.

This is understandable in the short term given the scale and immediate impacts of the pandemic. However, chronic diseases, in particular those affecting the liver, such as nonalcoholic fatty liver disease (Lin et al, 2019) and liver diseases associated with hepatitis B virus (HBV) infection, continue to be leading causes of severe liver disease and death globally.

In the case of HBV, an estimated 2 billion people are exposed to HBV with ∼25% of them developing into a chronic state (Moss et al, 2014). The burden of HBV infection is highest in the World Health Organization designated western Pacific and Africa Regions.

The endemicity of HBV in sub-Saharan Africa is noteworthy, as 5–10% of the adult population have been identified as being chronically infected (Abesig et al, 2020). Chronic hepatitis B (CHB) infection increases an individual's risk of progression to liver disease and complications and is considered a significant public health threat.

In Ghana, the prevalence of HBV is estimated at 12.3% (Ofori-Asenso and Agyeman, 2016). According to the national treatment guidelines for prevention and treatment of viral hepatitis in Ghana, CHB in the immune clearance/active and immune escape/reactivation stages will require treatment. The recommended drugs for CHB treatment in Ghana are tenofovir/entecavir and Peg Interferon. Of these recommended treatments, the most common drug used at health facilities is tenofovir disoproxil fumarate (TDF).

TDF is a nucleoside analogue recommended in treatment guidelines for HIV and HBV. Its mechanism of action is to inhibit HIV-1 and HBV reverse transcription and prevent viral multiplication. It is a widely used antiviral medication as it is a key component of antiretroviral therapies, which has been demonstrated to be a potent medication and thus serves as a first line of therapy for CHB (Cui et al, 2015).

Despite TDF being an effective and relatively safe medication, it has nephrotoxic potential (Casado et al, 2016). Interindividual variations in metabolism of TDF based on human genetic variation have been linked to the mechanism by which TDF causes renal dysfunction (Dahlin et al, 2015; Li et al, 2021). TDF uptake in the epithelial cells of the kidney tubules is mediated through anion transporters through basolateral membranes (Kohler et al, 2011; Neumanova et al, 2014; Ray et al, 2006). TDF is not metabolized by the cytochrome P450 enzymes and, therefore, its clearance in the proximal tubule of the renal nephron is controlled mostly by membrane transport proteins (Moss et al, 2014).

These transporters are encoded by the SCL22A6 and SLC22A8 that act in the uptake of tenofovir into the renal proximal tubule, whereas ABCC10, ABCC2, and ABCC4 control the active efflux of the drug across the apical membrane (Neumanova et al, 2014). The genes that code for these transporters display genetic variations that can affect their function.

A separate collection of genes may be involved in the presence or absence of comorbid conditions in the systemic disease COVID-19, which affects the kidneys and the cardiovascular system in general. This has been extensively discussed in other studies during the early stage of the pandemic (Askari et al, 2021). In view of this, there is the need to focus on the genes at play in tenofovir-induced toxicity using a broad conceptual approach, in light of the many unknowns and the ways in which COVID-19 impacts the whole organism.

Hence, we underscore that clinical pharmacogenomic and precision/personalized medicine research with TDF is much needed and timely as we learn to live with both COVID-19 (Butler, 2022) and liver diseases in the coming decade. This is particularly noteworthy in a pandemic-stricken world where chronic illness such as liver diseases and attendant precision/personalized medicine diagnostics continue to be important for planetary health.

Our experience in Ghana tells us that it is important not to forget the burden of chronic diseases while advancing research on infectious diseases such as SARS-CoV-2, the virus that causes COVID-19. For the long game with COVID-19, we need to address the public health burden of infectious agents and chronic diseases in tandem. This will prevent the situation wherein there is over concentration on infectious diseases until we are overwhelmed by a significant chronic disease burden. Clinical pharmacogenomics of TDF in the mentioned context offers an apt example where resource-limited countries and regions of the world buttress the collective efforts to fight both COVID-19 and liver diseases impacting public health.