Major blood-borne viruses — human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) — still present a huge burden on global health today. To achieve worldwide control over HIV, HBV, and HCV by 2030, the World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS approved global strategies to eliminate these viruses as public health issues.
Strategies to end the burden of blood-borne viruses vary by geographic distribution but should minimally include implementing robust preventive strategies and treatment options; making sure effective antivirals are available to all infected individuals; and point-of-care HIV and HCV testing should be routinely extended to lower barriers of diagnosis and improve access to care.1
Although disease control is feasible, worldwide elimination of these viruses requires effective vaccines, which are currently only available for HBV. This article will describe the virologic criteria required for treatment of these blood-borne viruses along with effective strategies for elimination both now and in the future.
The Role of Classification in HBV, HIV, and HCV
The classification of viruses was traditionally used to guide virologic criteria for treatment and predict viral response to therapy. Today, the use of direct-acting antiviral agents (DAAs) to treat HIV and HCV instead allows physicians to target factors independent of virus category, meaning treatment is advocated for all patients infected with HIV or HCV.1 Unfortunately, evaluation of HBV still involves complex classification, which poses as an obstacle to total elimination.
Classification of HBV is based on viral load, the presence or absence of e antigen and/or e antibody, and markers of liver damage (transaminases)1; however, these levels may fluctuate during different phases of the viral infection (active or inactive), and certain interactions may mediate the prognosis, shifting patients from one category to another.1 Physicians and health organizations largely disagree on classification-based treatments, and future advances may simplify criteria or reveal interventions that do not depend on classification.
The Future of HBV Classification and Treatment
Because of the effect of DAAs on HIV and HCV treatment, researchers were hopeful for a future in which a simple and rapid treatment can be advocated for all patients with HBV. Some researchers suggested that the relatively easy quantification of surface antigen levels in plasma could be a process adapted to support monitoring and treatment algorithms.1 Because HBsAg seroconversion is the ultimate goal of HBV therapy, quantifying surface antigens directly represents a more appropriate end point.
Another valuable end point for future HBV interventions would be the elimination of covalently closed circular DNA (cccDNA), which are found in the nucleus of infected hepatocytes and prevent true virologic clearance of HBV.1 Drugs that target hepatic cccDNA are in development and aim to silence or disrupt the cccDNA through intrahepatic pathways.1 The real challenge of these drugs is finding a way to measure treatment response without requiring a liver biopsy.
Effective Nonvaccine Strategies for HIV and HCV
To eliminate the burden of HIV on a global scale, WHO and the Joint United Nations Program on HIV/AIDS recommended wide implementation of treatment as prevention.1 This strategy, in which treatment suppresses an infected individual’s viral load, has been shown to be highly effective, decreasing chances of transmission.1 This model relies on a country or region to routinely extend HIV testing, offer treatment to every infected person, and improve access to prevention in high-risk populations.
Another strategy to control the HIV epidemic is the targeted provision of preexposure and postexposure prophylaxis. Daily tenofovir disoproxil fumarate/emtricitabine taken before high-risk exposure can help individuals with high-risk behaviors or high-risk sexual contacts (eg, a partner with HIV) prevent HIV infection.1 Similarly, antiretroviral drugs provided as early in pregnancy as possible can help prevent mother-to-child transmission.1
Drug strategies for HCV have generally been successful; however, a common problem among HCV-infected individuals with ongoing risk behavior is reinfection because the treatment does not result in any protective HCV-specific immunity,1 which can compromise any treatment benefits. Eliminating HCV depends more fully on a strategy that increases access to HCV testing and harm reduction methods concurrent with treatment with DAAs.1
The Role of Vaccination in Worldwide Elimination
One notable way in which HBV infection differs from HIV and HCV infection is the availability of a highly effective vaccination strategy. Since the early 1980s, most children around the world (84%) have received the standard 3-dose hepatitis B vaccine, protecting them from HBV infection for life.1 Administration of hepatitis B immunoglobulin at birth further reduces risk for mother-to-child transmission of HBV1; however, researchers are still actively seeking an equivalent strategy for HIV and HCV.
Although current nonvaccine strategies are very promising, implementing a vaccine that is at least moderately effective — along with the above nonvaccine approaches — has the potential to achieve a more rapid and sustained elimination of HIV or HCV, especially in settings where the risk for infection is high. Currently, no widely accessible or effective vaccine is available for either HIV or HCV, but promising targets for vaccination look to effect immune response.
Such novel approaches for vaccination target T-cells or B-cells, which potentially elicit localized and durable immunity for protection against infection.2 In these strategies, recombinant DNA is exploited as a vector to help develop T- or B-cell-mediated vaccines against HIV and HCV. Moreover, DNA vaccines in development provide many advantages: They are inexpensive, easy to construct, stable at room temperature, and have minimal adverse events.2
Other Therapeutic Approaches to Eliminating Viral Infection
Although vaccination is the holy grail of virus elimination, the need for therapeutics is still evident in the high level of disease burden these viruses pose globally. A new therapeutic approach for HIV uses a “shock and kill” strategy that first stimulates the expression of latency in infected cells, then facilitates concurrent immune-mediated clearance of these cells.1 Toll-like receptor agonists present a similar strategy, in which HIV expression is induced in peripheral blood cells, activating innate and adaptive immune cell populations (such as HIV-specific T cells), which enhances antibody-mediated clearance of infected cells.
For HBV, hepatocyte surface receptors have been identified as therapeutic targets with the potential to block viral entry into the cell. In fact, an experimental drug, Myrcludex B, is a first-in-class entry inhibitor being developed to treat hepatitis B and hepatitis delta infection. Other new antiviral or immunomodulatory compounds are in the preclinical or early clinical stage of development, including the previously mentioned therapy targeting cccDNA.
In summary, effective medications cannot achieve global control over a disease by themselves. Effective vaccination, prevention of mother-to-child transmission, implementation of harm reduction interventions (such as education on safe sexual practices), and access to routine testing are the minimal requirements of a robust prevention strategy. Above all, WHO is working to ensure that treatments are affordable and accessible to all who need them.
1. Leoni MC, Ustianowski A, Farooq H, Arends JE. HIV, HCV and HBV: a review of parallels and differences. Infect Dis Ther. 2018;7(4):407-419.
2. Mekonnen ZA, Grubor-Bauk B, Masavuli MG, et al. Toward DNA-based T-cell mediated vaccines to target HIV-1 and hepatitis C virus: approaches to elicit localized immunity for protection. Front Cell Infect Microbiol. 2019;9:91.