Can Persistent Infections with Hepatitis B Virus,Hepatitis C Virus,Human Immunodeficiency Virus,and Human T Lymphotropic Virus Type 1 Be Eradicated?

Abstract

Persistent viruses are hard to be eradicated, even using effective medications, and can persist for a long time in humans, sometimes regardless of treatment. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and human T cell lymphotropic virus infections, the most common in our era, are still a challenge despite the increased knowledge about their biology. Most of them are highly pathogenic, some causing acute disease or, more often, leading to chronic persistent infections, and some of the occult, carrying a high risk of morbidity and mortality. However, if such infections were discovered early, they might be eradicated in the near future with effective medications and/or vaccines. This perspective review points out some specific characteristics of the most important chronic persistent viruses. It seems that in the next few years, these persistent viruses may have control by vaccination, epidemiological strategies, and/or treatment.

Introduction

Persistent viruses are hard to be eradicated and can persist for a long time in humans.¹ The most common in our era, hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and human T lymphotropic virus 1 and 2 (HTLV-1 and HTLV-2) (Fig. 1) infections, are still a challenge despite the increased knowledge about their biology and even with highly effective treatment available nowadays.^2,3

FIG. 1.

Main characteristics of HBV, HCV, HIV, and HTLV. HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTLV, human T lymphotropic virus type.

Most of them are highly pathogenic and capable of persistent infections in human beings, some causing acute disease or leading to chronic persistent infections, sometimes occult. In addition, they may carry high morbidity and mortality risk lifelong, with substantial economic and social impacts.^4,5 Taken altogether, these infections may reach almost 1 billion people worldwide, with diverse biological outcomes. Unfortunately, these latent infections may have spread in the past century, except for HTLV-1 and HTLV-2, which is a retrovirus that appeared millions of years ago.⁶

Despite the existence of the Epstein-Barr virus, cytomegalovirus, herpes simplex virus and others, which are also considered persistent viruses,^7
–9 this review focused on the possibilities of eradicating a few major chronic infections, including HBV, HCV, HIV, and HTLV, which cause greater morbidity, mortality, and persistence, together with the high transmission/dissemination, in humans. In other words, they have a significant clinical burden, which may become long-term infections and present diverse clinical outcomes, mainly during the immunosuppressive phase in the host.

Thus, this perspective point of view is a provocative thought, aiming at updating our knowledge regarding these relevant viruses, in terms of public health, and at discussing the potential conducts for disease control, such as antiretrovirals, vaccines, or other therapeutic strategies. Table 1 describes the main characteristics and the availability of treatments or vaccines against these persistent viruses.

Table 1.

People Living with Some Persistent Viruses with the Potential for Eradication Using Vaccination, Epidemiological Approaches, or Specific Treatment

Virus	No. infected persons worldwide, 10⁶	General prevalence, %	Treatment available	Vaccine available	Projection for eradication, years	Refs.
HBV	296	5	Yes	Yes	20	^7,8
HCV	56.8	0.7	Yes	No	10	^7,9
HIV	37	0.5	Yes	No	30	⁷
HTLV-1/2 infections	5–10	0.25–2	Yes/no	No	N/A	¹⁰

10⁶: millions of people; based on serological studies.

HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTLV-1/2, human T lymphotropic virus type 1/2; N/A, not available.

How to Eliminate Viral Hepatitis

The World Health Organization (WHO) estimates that in 2019, 296 million people were living with chronic HBV infection and another 58 million with chronic HCV infection worldwide, whereas 1.5 million people were newly infected with HBV and 1.5 million with HCV that same year.¹⁰ Both hepatitis B and hepatitis C can lead to lifelong infection and are examples of persistent viruses with epidemiological importance in our era.¹¹ The WHO also estimates that 1.1 million deaths occurred in 2019 due to these infections and their effects, including liver cancer, cirrhosis, and other conditions caused by chronic viral hepatitis.¹⁰

In 2016, the World Health Assembly (WHA) adopted the Global Health Sector Strategy on viral hepatitis, in which it defined the elimination of viral infection as a 95% reduction in the incidence of HBV and 80% of HCV and a 65% reduction in mortality by 2030.¹² Each country is currently at different stages of developing its viral hepatitis elimination plans.¹³

At the 2021 WHA meeting, the WHO released the “Interim Guidance for Country Validation of Viral Hepatitis Elimination,” providing a global framework for the process and standards for validation of elimination, including absolute impact and programmatic targets for countries to develop their plan of elimination.¹⁴ Currently, both hepatitis A and hepatitis B can be prevented with safe and effective vaccines, and efforts to increase the number of children vaccinated against hepatitis B worldwide have dramatically reduced the number of new HBV infections.^15,16

Despite high prevalence among specific groups, such as people living with HIV (PLHIV), exposed to blood supplies, or during drug addiction, HCV may be eradicated using new potent anti-HCV drugs, regardless of the use of vaccines.¹⁷

Hepatitis B Virus

Among individuals with chronic HBV infection who are untreated, 15%–40% progress to cirrhosis, which may lead to liver failure and liver cancer.¹⁸ Medications to manage hepatitis B are available to help prevent liver damage and slow the progression of the disease.^19,20 HBV appears as chronic hepatitis among 10% of those individuals without vaccination, and 1 out of 10 of cases will develop liver cancer and/or higher death risk.^21,22

A large retrospective study, including 161 countries, revealed a prevalence of hepatitis B surface antigen (HBsAg) of 3.61%. This higher endemicity was found in African countries (total prevalence 8.83%) and in the Western Pacific region (total prevalence 5.26%).²³

HBV screening is recommended for pregnant women and populations with increased hepatocarcinoma risk in several countries.²⁴ However, diagnosis rates remain low, with only 33% of people with chronic hepatitis B (CHB) aware of their infection, with an estimated 0.24% prevalence of undiagnosed people. Universal HBsAg screening in adults is cost-saving compared with current practice if antiviral drug treatment costs remain below $1,000/year.²⁵

Thus, universal HBsAg screening of adults in the general population is cost-effective and likely cost-saving compared with current screening recommendations.²⁵ A good example came from a highly endemic area, such as Taiwan, where there is a universal HBV vaccination program that has been implemented since 1984.

The prevalence of HBsAg and hepatitis B core antibodies in the vaccinated birth cohort was lower than in those born before 1984, ranging from 0.4% versus 7.7%, and 2.2% versus 50.8%, respectively. They observed that high vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminating HBV transmission worldwide in a few years or decades.²⁶

Vaccinating newborn children against hepatitis B is an excellent approach, a low-cost clever strategy that has been used in most countries, aiming at the eradication of this infection.²⁷ In addition, there are some effective treatments for those with chronic HBV, especially using vaccination as soon as possible.²⁸

However, HBV has often reactivated after the discontinuation of nucleos(t)ide analogs, as antivirals do not directly target covalently closed circular DNA (cccDNA), which is the template for all viral RNAs.²⁹ Although currently available antiviral therapies suppress HBV replication in most patients, loss and seroconversion of HBsAg is rarely achieved despite long-term antiviral treatment, with lower HBsAg loss at 10% in 5 years.^29,30

In this setting, hepatocarcinoma remains a risk for those with chronic HBV infection. Several clinical trials of agents that interrupt the HBV life cycle in hepatocytes are currently ongoing.²⁹

Potential treatment strategies and new agents are emerging, such as HBV eradication with a combination of current and new anti-HBV agents that may increase the rate of HBsAg seroclearance; those optimized regimens must be validated in the clinical field, especially in developing settings.²⁹ In addition, novel treatments and their combinations have been proposed for their potential to cure HBV infection, as well as exciting new technologies that could directly target cccDNA and cure, without killing the infected cells.

Although these therapies control infection and improve the patient's quality of life, they do not cure HBV-infected hepatocytes. A complete HBV cure is currently not possible due to the formation of stable cccDNA.³¹ Current efforts are focused on achieving a functional cure, defined by the loss of HBsAg and undetectable HBV DNA levels in serum, and on exploring novel targets and molecules that currently are the object of clinical trials.

The likelihood of achieving a long-lasting functional cure, with no rebound after therapy cessation, is higher using combination therapies targeting different steps in the HBV replication cycle.³¹

Hepatitis C Virus

Hepatitis C has a relevant global impact in terms of morbidity, mortality, and economic costs, with more than 55 million people infected worldwide.^32,33 The resolution “Transforming our world: the 2030 Agenda for Sustainable Development” was included as a focus area in the health-related goal, with world leaders pledging to “combat” it by 2030. This strategy would reduce the number of deaths by two-thirds and increase treatment rates by up to 80%.³³

HCV is a positive-stranded enveloped RNA virus belonging to the Flaviviridae family. HCV infection leads to severe liver disease, cirrhosis, and hepatocellular carcinoma.³⁴ Chronic HCV can be cured with the use of specific drugs in a few months of treatment; a once-daily medication taken by mouth for 8–12 weeks can cure most infected people.³⁵ In 2019, 9.4 million people were receiving treatment for chronic HCV infection, nearly twice that of 2017.³⁶ However, the high costs of the treatment may preclude its widespread use with serious public health consequences and failure to eradicate the infection.³⁷

In the past decades, the use of interferon-based therapies did not enable the achievement of a sustained virologic response in many patients, and over 130 million people are estimated to be chronically infected with HCV worldwide.³⁸ Successful eradication of the virus was achieved for only 15%–20% of newly infected individuals, with the remainder developing a chronic infection.³⁹ The ability of the HCV to persist within the host is impressive, which is attributed to its efficient ability to evade the adaptive and innate components of the host's immune system.⁴⁰

In the past 10 years, therapeutic agents against HCV were developed, with huge success.⁴¹ Although treatments have been available for a while, due to their complexity and genetic diversity, only a few are reported to be effective against all HCV genotypes. The HCV life cycle and its immunogenic potential and various mechanisms via which the virus interferes in the signaling process are dealt with. A comprehensive overview of current anti-HCV therapeutics, such as direct-acting antiviral as well as host-targeting agents, is presented elsewhere.³⁴

Chronic infection with HCV is a major cause of liver disease and hepatocellular carcinoma worldwide.⁴² After the discovery of HCV, three decades ago, the identification of the structure of the viral proteins enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%.⁴³

Despite the availability of highly effective therapeutic regimens, based on direct-acting antivirals, many barriers to HCV eradication remain. They are related to awareness of the infection, linked to care, availability of therapeutic drug regimens, and reinfection. Overall, an effective prophylactic vaccine is not available, and HCV eradication appears difficult to achieve in the future.³³ Thus, health programs that include serological testing to identify HCV carriers should be implemented in endemic countries, especially developing countries, which may have some impact in the near future.⁴⁴

Human Immunodeficiency Virus

Reversing HIV latency and destroying the HIV reservoir

Modern antiretroviral therapies (ART) transformed HIV infection into a chronic disease, characterized by persistent inflammation and immune activation.^45,46 AIDS-related mortality has been reduced with an increase in life expectancy, but PLHIV are more likely to develop non-AIDS events, despite the achievement of complete suppression of HIV replication.⁴⁷ This suppression may be lifelong, although the viral eradication of HIV infection is still a huge challenge, involving the complete elimination of HIV from the body, including the destruction of cells infected with latent HIV.^48,49

One strategy under study would aim at replicating the virus out of its latent state, depleting the viral reservoir, so that an improved immune system or use of ART could target and eliminate HIV-infected cells. An alternative strategy would be to apply gene therapy to specifically extract or inactivate latent HIV.^50,51

Following the basic hypothesis, after the virus infects cells—especially central memory CD4⁺ cells—it may remain inactive, turning the cell into a latent reservoir, and remain so until apoptosis occurs or there is some external stimulus, inducing viral expression from latency. If this viral expression occurs, there is still the possibility that this cell will be eliminated through cytopathic or immune clearance effects. However, there is a compensation for these effects, that is, while these resting cells die, other activated infected cells become latent reservoirs.⁵²

However, clonal expansion is also responsible for the proliferation of the latent HIV proviral reservoir. This expansion may occur in a homeostatic manner, or also through T cell induction by adaptive antigen or, less commonly, through dysfunctional CD4⁺ cell proliferation triggered by HIV integration into a specific genomic site. Regardless of the cause(s), cell proliferation is an important and long-lasting mechanism for sustaining the persistent viral reservoir.^48,52,53

Researchers are looking for strategies that induce latent reservoirs to express HIV proteins on their cell surface so that the immune system or ART recognizes these proteins and eliminates the infected cell. This strategy is often referred to as “kick and kill” or “shock and kill”—it consists of exposing latent HIV through latency reversal agents, enabling the immune system or other therapies to recognize and destroy latent cells. Currently, several latency-reversing agents are under investigation in laboratory and human clinical trials.⁵⁰

In 2015, a team of scientists at the United States National Institute of Allergy and Infectious Diseases developed an immunomodulatory protein called VRC07-αCD3, which is a kind of bispecific T cell engager. One arm of this protein binds to a receptor on HIV-infected CD4 T cells, prompting that cell to display HIV proteins on its outer membrane. In a separate step, the other arm of VRC07-αCD3 then binds to these HIV membrane proteins whereas the original arm attaches to a killer T cell to activate it and bring it in proximity to the infected cell.^54,55 This strategy would be tested in the clinical field for the next few years.

HTLV-1 and HTLV-2

HTLV-1 was the first oncogenic human retrovirus identified as a cause of infectious diseases, such as HTLV-1-associated myelopathy (HAM), adult T cell leukemia/lymphoma (ATLL), and other inflammatory diseases.⁵⁶ Shortly thereafter, HTLV-2 was described in a different type of T cell leukemia,⁵⁷ whose role in oncogenesis remains to be established.⁵⁸

This infection has been neglected since the onset of the AIDS pandemic and the description of HIV-1 in the early 1980s, despite its high morbidity and mortality.⁵⁹ The detection of HTLV-1/2 infection was only possible after 1983 when serological tests were introduced to assess viral dissemination; in Brazil, those tests were included as part of routine tests in all blood banks in 1993.⁶⁰

Thus, it was possible to estimate around 1 million people living with HTLV-1/2 infections.⁶¹ However, these data are from the middle 1990s and new studies, especially using new serological screening approaches, such as rapid tests and collection of filter paper should be done soon in endemic countries, such as Brazil.

HTLV-1 preferentially infects peripheral lymphoid cells, predominantly memory CD4⁺ T lymphocytes and CD8⁺ T lymphocytes. Infected cells are transformed and immortalized by the virus in vitro. Proviral DNA can be transmitted from cell to cell not only by a proliferation of infected cells, but also by a “viral synapse” mechanism, when the virus induces cell polarization events and facilitates the junction of infected and uninfected cells, facilitating viral passage.⁶²

Like other retroviruses, HTLV-1 depends on the enzyme reverse transcriptase for its insertion into the genome, in the form of a provirus. Studies suggest that HTLV is a poorly replicating virus and that replication viral in vivo is more due to the clonal expansion of the infected cells via mitosis than via reverse transcription.⁶³ Thus, the interaction between virus and host has been the subject of several discussions in recent decades, highlighting host immunological factors as the main triggers in the immunopathological process for HAM.⁶⁴

Although the immunological events promoted by HTLV-1 are not well understood, it is believed that the cellular response triggered by CD8⁺ T cells may be crucial for the progression to HAM and keep the disease activity.⁶⁴ Despite this virus possessing a low capacity to induce disease, our group observed that some patients may present early evolution to a clinically manifested disease, around 10% lifelong.⁶⁵ Further, the mortality rate may be impacted by the presence of viral coinfections, such as HIV, HCV, and strongyloidiasis, ranging from 2% to 10%.⁶⁶

The use of anti-inflammatory drugs, such as corticosteroids, may have some beneficial impact but is not curative to HAM so far.^67,68 In addition, cancer may be an important outcome, particularly ATLL, a disease with rapid progression, in both its acute and chronic forms, with short survival, usually less than 5 years, regardless of treatment.⁶⁹ Despite the high level of genetic similarity to HTLV-1, HTLV-2 may have different pathogenesis and may not cause disease. We hypothesize that it is becoming an endogenous retrovirus.⁶

Fortunately, treatment for some persistent viruses has evolved immensely in the past decades, especially for HIV and viral hepatitis, affecting millions worldwide.^70
–72 Current antiviral treatments for viral hepatitis are curative for most of the treated patients; in the case of HIV infection, ART can keep the disease under control, but the virus remains latent, hiding in the reservoirs of long-life cells.⁷³

Such remarkable progress does not hold for HTLV-1 infection, which lacks an effective antiviral treatment. The use of anti-inflammatory drugs for patients with HAM, for instance, is only palliative for some time.⁶⁷ The challenge now is how to achieve a complete eradication, or at least treat more adequately the symptoms of the affected patients.

Figure 1 depicts the major characteristics of some persistent virus infections that could be eradicated using different strategies.

Perspectives

It is important to note that some types of viral hepatitis can be controlled or prevented by specific vaccination and using specific antiviral drugs, usually with multiple targets.^74,75 Even though no vaccine is available for HIV infection so far, ART is highly effective when applied during the first phase, with good adherence to care and medications, even in poor settings, such as Brazil.⁷⁶

However, another retrovirus, found in endemic areas of Japan and South America, named HTLV-1, has no vaccine available and the treatment for the diseases it causes, HAM or ATLL, has a poor response.^67,68 Despite these difficulties, Japan has reduced the number of people living with HTLV-1 by about 40% over the past using prevention measures, such as universal blood screening and inhibitory breastfeeding in HTLV-infected women.⁷⁷

Thus, despite these great scientific advances to control, persistent viruses possess several wise mechanisms to escape from immune control or the development of unique resistance mechanisms, especially for mutations or endogenization processes of their genome in human beings.

Footnotes

Authors' Contributions

S.V.T.: conceptualization; writing—original draft; writing—review and editing. G.P.: and writing—review and editing. L.A.M.F.: writing—review and editing. J.C.: conceptualization; writing; writing—review and editing; and supervision.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by Fapesp scholarship to Sandy Vieira Teixeira, number 2021/12316-9; grant: 2020/05758-2; grant to Jorge Casseb: 301275/2019-0. Scholarship provided by Fundação Faculdade de Medicina.

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