Prospects for Controlling Hepatitis B Globally.

Infection with the hepatitis B virus (HBV) is highly prevalent globally. Over 250 million people suffer from chronic hepatitis B, and more than 800,000 patients die each year due to hepatitis B complications, including liver cancer. Although protective HBV vaccines are recommended for all newborns, global coverage is suboptimal. In adults, sexual transmission is by far the most frequent route of contagion. The WHO estimates that 1.5 million new HBV infections occur annually. Oral nucleos(t)ide analogues entecavir and tenofovir are the most frequent antivirals prescribed as HBV therapy. Almost all patients adherent to the medication achieve undetectable plasma viremia beyond 6 months of monotherapy. However, less than 5% achieve anti-HBs seroconversion, and viral rebound occurs following drug discontinuation. Therefore, nucleos(t)ide analogues need to be lifelong. New long-acting formulations of tenofovir and entecavir are being developed that will maximize treatment benefit and overcome adherence barriers. Furthermore, new antiviral agents are in development, including entry inhibitors, capside assembly modulators, and RNA interference molecules. The use of combination therapy pursues a functional HBV cure, meaning it is negative for both circulating HBV-DNA and HBsAg. Even when this goal is achieved, the cccDNA reservoir within infected hepatocytes remains a signal of past infection, and HBV can reactivate under immune suppression. Therefore, new gene therapies, including gene editing, are eagerly being pursued to silence or definitively disrupt HBV genomes within infected hepatocytes and, in this way, ultimately cure hepatitis B. At this time, three actions can be taken to push HBV eradication globally: (1) expand universal newborn HBV vaccination; (2) perform once-in-life testing of all adults to identify susceptible HBV persons that could be vaccinated (or re-vaccinated) and unveil asymptomatic carriers that could benefit from treatment; and (3) provide earlier antiviral therapy to chronic HBV carriers, as being aviremic reduces the risk of both clinical progression and transmission.

Prevalence of HTLV-1/2 infection in pregnant women in Central and South America and the Caribbean: a systematic review and meta-analysis.

BACKGROUND: Human T-lymphotropic viruses (HTLV)-1 infection is endemic in many countries of Central and South America and Caribbean (CSA&C). Neither screening nor surveillance programs exist for HTLV-1/2 infection among pregnant women in this region. Neither in Western nations with large migrant flows from HTLV-1/2 endemic regions. METHODS: Systematic review and meta-analysis of the prevalence of HTLV-1/2 infection among CSA&C pregnant women. We included studies searching EMBASE, PubMed/MEDLINE, Scopus, and Web of Science from inception to February 15, 2023. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. RESULTS: We identified a total of 620 studies. Only 41 were finally included in the meta-analysis. Most studies (61.0%) were from Brazil and Peru (14.6%). The total number of participants was 343,707. The pooled prevalence of HTLV-1/2 infection among CSA&C pregnant women was 1.30% (95% CI: 0.96-1.69) using anti-HTLV-1/2 antibody screening tests. There was a high heterogeneity (I2 = 98.6%). Confirmatory tests gave an HTLV-1 infection rate of 1.02% (95% CI: 0.75-1.33). CONCLUSIONS: The prevalence of HTLV-1/2 infection among CSA&C pregnant women is 1.3%, most cases being HTLV-1. This rate is greater than for other microbial agents regularly checked as part of antenatal screening (such as HIV, hepatitis B, or syphilis). Thus, HTLV-1/2 antenatal testing should be mandatory among CSA&C pregnant women everywhere.

Human T-lymphotropic virus-1 infection among Latin American pregnant women living in Spain.

Objectives: Human T-lymphotropic virus (HTLV) antenatal screening is not mandatory in Spain. Surveys conducted decades ago reported HTLV-1 seroprevalence rates of 0.2% among foreign pregnant women in Spain. The migrant flow to Spain from HTLV-1 endemic regions in Latin America and sub-Saharan Africa has increased during the last decade. Currently, 25% of pregnant women in Spain are foreigners. Methods: From January 2021 to October 2023 a cross-sectional study was carried out in all consecutive pregnant women attended at eleven Spanish clinics. A commercial enzyme immunoassay (EIA) was used for screening of serum HTLV-1/2 antibodies. Reactive samples were confirmed by immunoblot. Results: A total of 9813 pregnant women with a median age of 34 years-old were examined. Native Spaniards were 6977 (76.5%). Of 2147 foreigners (23.5%), 903566 (9.9%) were Latin Americans, 416 (4.5%) North Africans, 293 (3.2%) from Romania, and 196 (2.1%) from sub-Saharan Africa. A total of 47 samples were EIA reactive but only five were confirmed as HTLV-1 positive using immunoblot. Infected women came from Paraguay, Colombia, the Dominican Republic, Venezuela and Peru. All but one were primigravida, with ages ranging from 20 to 33 years-old. One was HIV-1 positive, and another was infected with Chlamydia trachomatis. Conclusion: The overall seroprevalence for HTLV-1 among pregnant women in Spain is 0.05% but rises ten-fold (0.55%) among Latin Americans. This rate is higher than in surveys conducted decades ago. Our results support that anti-HTLV testing should be part of antenatal screening in Spain in pregnant women coming from Latin America, as it is already done with Chagas disease.

Current Challenges for Conscientious Objection by Physicians in Spain.

The College of Physicians of Madrid organized an open debate on conscientious objection (CO) in the medical profession on September 14, 2022. We summarize here the main arguments discussed. CO is defined as the right to raise exceptions to the performance of legal duties when they involve a contravention of personal convictions, whether religious, moral, or philosophical. It is not insubordination. Some authors contend that any decision by elected authorities should be uniformly followed by all citizens, physicians not being an exception. However, suppressing the ethical dimension of medical care may have an unacceptable cost with harm to physicians, their patients, and ultimately society. Health professionals are not blind instruments or mere "executors." The practice of medicine must follow the aim of the profession, namely the pursuit of the patient's good. Medical care must conform to medical ethics, which was first defined twenty-five centuries ago in the Hippocratic oath, and summarized with the triad of precepts "cure, relief, accompaniment." Since then and particularly in light of the Nuremberg trials, most medical declarations have highlighted the duty of defending human life and the importance of CO. In modern societies, there may be medical services that are not health care, even if they are legal. Then, which comes first law or ethics? Ultimately, CO is the tool that protects the freedom of the physician to refuse to perform actions that go against the values of medical ethics. With respect to the recent Spanish laws on abortion, euthanasia, and sex re-assignment of minors, if administrators want to know who is available for a health service that raises issues of conformity to medical ethics, requesting a list of volunteers is preferable to producing an objector list. Asking for registration of conscientious objectors goes against the right to privacy and is coercive, intrusive, and abusive.

Screening for HTLV-1 infection should be expanded in Europe.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is spreading globally at an uncertain speed. Sexual, mother-to-child, and parenteral exposure are the major transmission routes. Neither vaccines nor antivirals have been developed to confront HTLV-1, despite infecting over 10 million people globally and causing life-threatening illnesses in 10% of carriers. It is time to place this long-neglected disease firmly into the 2030 elimination agenda. Current evidence supports once-in-life testing for HTLV-1, as recommended for HIV, hepatitis B and C, along with targeted screening of pregnant women, blood donors, and people who attended clinics for sexually transmitted infections (STIs). Similar targeted screening strategies are already being performed for Chagas disease in some Western countries in persons from Latin America. Given the high risk of rapid-onset HTLV-1-associated myelopathy, universal screening of solid organ donors is warranted. To minimize organ wastage, however, the specificity of HTLV screening tests must be improved. HTLV screening of organ donors in Europe has become mandatory in Spain and the United Kingdom. The advent of HTLV point-of-care kits would facilitate testing. Finally, increasing awareness of HTLV-1 will help those living with HTLV-1 to be tested, clinically monitored, and informed about transmission-preventive measures.

Pre-exposure prophylaxis of non-HIV viral infections and the role of long-acting antivirals.

Viruses cause a large burden of human infectious diseases. During the past 50 years, antivirals have been developed to treat many pathogenic viruses, including herpesviruses, retroviruses, hepatitis viruses, and influenza. Besides being used as treatment, antivirals have shown efficacy for preventing certain viral infections. Following the success in the HIV field, a renewed interest has emerged on the use of antivirals as prophylaxis for other viruses. The development of formulations with extended half-life has pushed further this consideration in persons at risk for a wide range of viral infections. In this way, long-acting antivirals might behave as "chemovaccines" when classical vaccines do not exist, cannot be recommended, immune responses are suboptimal, escape mutants emerge, and/or immunity wanes. Five main caveats would temper its use, namely, selection of drug resistance, drug interactions, short- and long-term side effects, potential teratogenicity in women of child-bearing age, and high cost. Herein, we discuss the prospects for long-acting antivirals as prophylaxis of human viral infections other than HIV.

Testing a vaccine candidate against Hepatitis C virus designed by combinatorial optimization.

This paper presents a new procedure for vaccine design against highly variable viruses such as Hepatitis C. The procedure uses an optimization algorithm to design vaccines that maximize the coverage of epitopes across different virus variants. Weighted epitopes based on the success ratio of immunological assays are used to prioritize the selection of epitopes for vaccine design. The procedure was successfully applied to design DC vaccines loaded with two HCV peptides, STG and DYP, which were shown to be safe, immunogenic, and able to induce significant levels of anti-viral cytokines, peptide-specific cellular immune responses and IgG antibodies. The procedure could potentially be applied to other highly variable viruses that currently lack effective vaccines.

HTLV infection in persons with sexually transmitted diseases in Spain.

Background: HTLV-1 infection is a neglected disease, despite estimates of 10 million people infected worldwide and producing life-threatening illnesses in 10% of carriers. Sexual transmission is the main route of contagion. However, HTLV-1 is not listed among sexually transmitted infections (STIs). Methods: Serum from all consecutive individuals who had attended six STI clinics across Spain during the last 12 months were tested for HTLV antibodies using a commercial enzyme immunoassay (EIA). Reactive samples were confirmed by immunoblot. Results: A total of 2,524 samples were examined. The majority (1,936; 76.7%) belonged to men, of whom 676 (34.9%) were men who have sex with men (MSM) receiving HIV pre-exposure prophylaxis. Although native Spaniards predominated (1,470; 58.2%), up to 593 (23.5%) came from Latin America and 139 (5.5%) were African. A total of 26 individuals were initially EIA reactive and immunoblot confirmed 5 as HTLV-1 and 7 as HTLV-2. All but one HTLV-1+ case came from Latin America. Three were men and two were women. Among Latin Americans, the HTLV-1 seroprevalence was 0.67%. In contrast, all seven HTLV-2+ were native Spaniards and former injection drug users, and all but one were HIV+. Conclusion: The rate of HTLV infection among individuals with STIs in Spain is 0.5%, which is greater than in the general population. These results support the introduction of universal HTLV screening in persons who attend clinics for STIs.

HTLV-1-associated myelopathy in Spain.

BACKGROUND: HTLV-1 infection is a neglected disease. Over 10 million people are infected worldwide, with hot spots of high endemicity across all continents. Roughly 5% of HTLV-1 carriers develop HTLV-1-associated myelopathy (HAM), a progressive subacute neurological disabling disease. METHODS: We report the main features of patients diagnosed with HAM up to date in Spain, a non-endemic country with a relatively high migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. RESULTS: A total of 451 cases of HTLV-1 had been recorded in Spain until the end of year 2022. HAM had been diagnosed in 58 (12.9%). The current incidence is of 2-3 new cases per year. Women represent 76%. Mean age at diagnosis is 49 years-old. Nearly 60% are Latin Americans. Although sexual transmission is the most likely route of HTLV-1 acquisition, up to 6 individuals had been infected following solid organ transplantation. Rapid onset myelopathy developed in all but one of these transplant recipients from three HTLV-1-positive donors. HTLV-1 subtype 1a transcontinental was the only variant recognized in HAM patients. HTLV-1 proviral load was significantly greater in HAM patients than in asymptomatic HTLV-1 carriers (677 vs 104 HTLV-1 DNA copies/104 PBMC; p = 0.012). Symptom relief medications and physiotherapy have been the only treatment providing some benefit to HAM patients. Neither significant clinical nor virological efficacy was noticed using antiretrovirals in at least 9 HAM patients. Two thirds of HAM patients ended up in a wheelchair and with urinary/fecal sphincter incontinence. CONCLUSION: HAM is the most frequent clinical manifestation of HTLV-1 infection in Spain, a non-endemic country. Middle aged women migrants from Latin America are the most frequently affected. Two thirds end up in a wheelchair despite using antiretroviral therapy.

Rebound in sexually transmitted infections after the COVID-19 pandemic.

Sexually transmitted infections (STIs) have become the second in the global rating of infectious diseases after respiratory infections. Globally, over 1 million, new STI is diagnosed every day. Although four conditions are the most representative and of obligatory declaration (gonorrhea, syphilis, chlamydia, and human immunodeficiency virus [HIV]), there are many other prevalent STI, including trichomona, herpes simplex, papillomavirus, and viral hepatitis. Herein, we perform a narrative and retrospective review, analyzing information from public databases from distinct Spanish government institutions. STI significantly declined in Spain during 2020 as a result of lockdown and social isolation measures dictated in response to the COVID-19 pandemic. After releasing restrictions, a major STI rebound occurred in 2021. Increases were 49% for gonorrhea, 45% for HIV, 39% for chlamydia, and 32% for syphilis. Based on nationwide statistics, we build a narrative review of the recent STI surge after COVID-19. In summary, we propose a holistic approach to confront the current re-emergence of STI. On one hand, new innovative medical advances must be implemented, including new rapid tests, novel vaccines, pre-exposure prophylaxis beyond HIV, and long-acting antivirals. On the other hand, information to citizens needs to be reformulated with interventions aimed to build a healthier society, alike it has been undertaken with tobacco, alcohol, diet, and lifestyle. STI determines important sexual, reproductive, and maternal-child health consequences. To promote human well-being or flourishing, the education of adolescents and young adults should be aligned with human ecology. Therefore, it is urgent to address new approaches in sexual health that represent a clear benefit for individual persons and society. In this way, favoring a cultural evolution aimed to delay the age of first sexual intercourse and the avoidance of multiple sex partners should be prioritized.

Triple Threat: HDV, HBV, HIV Coinfection.

Hepatitis delta virus (HDV) only infects patients with hepatitis B virus (HBV) due to its reliance on HBV surface proteins to form its envelope. With shared routes of transmission, HDV coinfection is estimated to occur in 15% of patients with HIV and HBV. However, HDV is often underdiagnosed and may be missed particularly in people living with HIV (PLWH) who are already on antiretroviral therapy with anti-HBV activity and coincidental HBV suppression. At the same time, HDV causes the most severe form of chronic viral hepatitis and leads to faster progression of liver disease and hepatocellular carcinoma. Thus, increased recognition and effective treatment are paramount, and as novel treatment options approach global markets, the study of their efficacy in PLWH should be pursued.

Adult T-cell leukemia/lymphoma in HTLV-1 non-endemic regions.

BACKGROUND: HTLV-1 infection is a neglected disease, despite producing neurological and lymphoproliferative severe illnesses and affect over 10 million people worldwide. Roughly 5% of HTLV-1 carriers develop Adult T-cell leukemia/lymphoma (ATLL), one of the most aggressive hematological malignancies. METHODS: A national HTLV-1 register exists since 1989 in Spain, a non-endemic country with a large migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. The main features of all patients diagnosed with ATLL in Spain up to date are reported. RESULTS: A total of 451 cases of HTLV-1 infection had been reported in Spain until the end of year 2022. ATLL had been diagnosed in 35 (7.8%). The current average incidence of ATLL in Spain is of two cases per year. Women represent 57% of ATLL patients. Mean age at diagnosis was 47 years-old. Roughly 57% were Latin Americans and 26% Africans. At diagnosis, the majority presented with acute or lymphoma clinical forms. Survival was shorter than one year in most of them. Mean HTLV-1 proviral load was significantly greater in ATLL patients than in asymptomatic HTLV-1 carriers (2,305 vs 104 copies/104 PBMC). HTLV-1 subtyping in 6 ATLL patients found the 1a transcontinental variant (n = 4) and the Japanese variant (n = 2). All ATLL patients were negative for HIV-1, did not develop HTLV-1-associated myelopathy and were not transplant recipients. CONCLUSION: The rate of ATLL is very low in Spain and mostly associated to migrants from HTLV-1 endemic regions. Given the poor clinical outcome of ATLL, HTLV-1 testing should be performed at least once in all migrants coming from HTLV-1 endemic countries and in natives who have lived in or had sex partners from such regions.

Genetic signature detected in T cell receptors from patients with severe COVID-19.

Characterization of host genetic factors contributing to COVID-19 severity promises advances on drug discovery to fight the disease. Most genetic analyses to date have identified genome-wide significant associations involving loss-of-function variants for immune response pathways. Despite accumulating evidence supporting a role for T cells in COVID-19 severity, no definitive genetic markers have been found to support an involvement of T cell responses. We analyzed 205 whole exomes from both a well-characterized cohort of hospitalized severe COVID-19 patients and controls. Significantly enriched high impact alleles were found for 25 variants within the T cell receptor beta (TRB) locus on chromosome 7. Although most of these alleles were found in heterozygosis, at least three or more in TRBV6-5, TRBV7-3, TRBV7-6, TRBV7-7, and TRBV10-1 suggested a possible TRB loss of function via compound heterozygosis. This loss-of-function in TRB genes supports suboptimal or dysfunctional T cell responses as a major contributor to severe COVID-19 pathogenesis.