Clinical Presentation of Individuals With Human T-Cell Leukemia Virus Type-1 Infection in Spain

Background: although only 8%-10% of persons infected with human T-cell leukemia virus type 1 (HTLV-1) may develop virus-associated diseases lifelong, misdiagnosis of asymptomatic infected carriers frequently leads to late diagnoses. Methods: a nationwide HTLV-1 register was created in Spain in 1989. A total of 351 infected persons had been reported by the end of 2017. We examined all new HTLV-1 diagnoses during the last decade and compared their clinical presentation. Results: a total of 247 individuals with HTLV-1 infection had been reported in Spain since year 2008. The incidence has remained stable with 20-25 new diagnoses yearly. Women represented 62%. Only 12% were native Spaniards, most of whom were foreigners from Latin America (72.5%). Up to 57 (23%) individuals presented clinically with HTLV-1-associated conditions, including subacute myelopathy (n = 24; 42.1%), T-cell lymphoma (n = 19; 33.3%), or Strongyloides stercoralis infestation (n = 8; 14%). Human T-cell leukemia virus type 1 diagnosis had been made either at blood banks (n = 109; 44%) or at clinics (n = 138; 56%). It is interesting to note that Spaniards and especially Africans were overrepresented among patients presenting with HTLV-1-associated illnesses, suggesting that misdiagnosis and late presentation are more frequent in these populations compared to Latin Americans. Conclusions: given that 23% of new HTLV-1 diagnoses in Spain are symptomatic, underdiagnosis must be common. Although screening in blood banks mostly identifies asymptomatic Latin American carriers, a disproportionately high number of Spaniards and Africans are unveiled too late, that is, they already suffer from classic HTLV-1 illnesses

HTLV-1 Infection Still A Neglected Disease

Infection with Human T-lymphotropic virus (HTLV)-1, the first discovered human retrovirus, affects 10-15 millon people worldwide

Gene editing for HIV cure at the edge

Whereas advances in antiretroviral therapy and its widespread use are providing huge benefits in terms of prventing new HIV transmissions to uninfected individuals as well as halting disease progression in patients, the elimination of HIV from carries remains elusive and requires new approaches

Why Not an Opioid Epidemic in Europe Like in the USA?

The CDC reported 70,237 drug overdose deaths in the United States in 2017 (Scholl et al., MMWR 2018; 67: 1419-27). Sadly, this yearly rate has been increasing significantly during the past two decades. Opioids, mostly synthetic drugs other than methadone, and particularly fentanyl, are currently the major responsible of drug overdose deaths (Fig. 1). The US states with the highest fatality rates due to drug overdose are West Virginia, Ohio, Pennsylvania, the District of Columbia, and Kentucky

The Source of New HIV Infections are People not being Treated or Unaware of their Status

The advent of antiretroviral therapy has represented a major breakthrough in infectious diseases. The use of HAART prevents HIV disease progression and restores immunity in HIV carriers. In addition, further transmissions are halted (treatment as prevention [TAP]). More recently, the use of antiretrovirals by uninfected individuals at risk (pre-exposure prophylaxis [PrEP]) has shown to drastically reduce the chances of HIV acquisition. Despite all these tremendous advances, the figures for the HIV pandemic remain dreadful, with estimates of 38 million people living with HIV worldwide and 1.8 million new infections occurring each year. Looking at this scenario, the call from the UNAIDS toward a 95-95-95 goal for 2030 seems unachievable, unless new strategies are set up

Jerome Lejeune passed away 25 years ago

During the past 60 years, modern genetics has steadily evolved from diagnostics to therapeutics. However, treatment of genetic disorders is still in its infancy, with the advent of genome editing as its greatest promise

Sexually Transmitted Infections in Men having Sex with Men - Rising Numbers and Wider Etiologies

Classical sexually transmitted infections (STI), namely, syphilis, gonorrhea, trichomonas, and chlamydia, are on the rise worldwide

Hepatitis B Gene Therapy Coming to Age

The major pandemics caused by chronic viral infections is produced by HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV), with estimates of 38, 70, and 250 million people worldwide, respectively (Fig. 1). During the last couple of years, the advent of direct oral antivirals has allowed pursuing global HCV eradication. In an unprecedented manner, these drugs cure more than 95% of hepatitis C patients when given for only 2-3 months. The enthusiasm on HCV has renewed the interest for curative strategies for both HIV and HBV. However, important biological differences between all three viruses may preclude envisioning a similar rapid success for either HIV or HBV than for HCV infection. As shown in figure 1, once infection of targeted cells has occurred, the viral genetic material only replicates in the cytosol for HCV whereas it enters the nucleus and integrates into the chromosomes as provirus for HIV or is converted in a circular covalently closed form (cccDNA) for HBV (Fig. 1). Blocking viral nucleic acid replication for a minimum lag of time allows definitive clearance of HCV infection, with degradation of residual cytoplasmic HCV-RNA strands. In contrast, blocking viral replication has only a transient effect on HIV or HBV, as mRNA expression resumes following treatment discontinuation, given the stability of the HIV provirus or the HBV cccDNA, respectively. The European Liver meeting took held in Paris on April 2018. A relatively large number of presentations addressed distinct new hepatitis B therapeutic strategies. Table 1 summarizes some of the molecules that have been investigated so far with more promising results, grouping them into distinct drug classes (Soriano et al. Exp Op Inv Drugs 2017;26:843-51), based on their distinct mechanism of action and targeted steps in the HBV life cycle (Fig. 2). Considering the pros and cons of novel HBV therapeutic candidates, it has become apparent new HBV gene therapies among the most attractive. Several advances have contributed to position gene therapy in front within the experimental HBV armamentarium. First, progresses in delivery systems, including the use of polymers and nanoformulations have allowed developing easier forms of administration that now are becoming subcutaneous and monthly. Second, the synthetic production of oligonucleotide formulations has reduced costs. Third, the specificity against HBV is higher than for other experimental agents, as immune modulators that enhance innate immunity, such as TLR agonists (i.e., GS-9620) or checkpoint inhibitors (i.e., nivolumab). Fourth, significant declines in serum hepatitis B surface antigen (HBsAg) are demonstrated during gene therapy, which have never been seen using the most potent polymerase inhibitors (i.e., tenofovir or entecavir). Finally, unanticipated significant reductions in cccDNA are seen with HBV gene therapy, most likely as prove of an indirect benefit of waning the immunosuppressive effect of large over amounts of HBsAg released by infected hepatocytes that contributes to T-cell exhaustion. In a pioneering study, Roche was the first to publish the potent effect of an oral small molecule that blocked HBV gene expression (Mueller et al. J Hepatol 2018;68:412-20). The drug belonged to the dihydroquinolizinone class, and directly or indirectly modified viral RNAs, promoting their degradation. This posttranscriptional silencing was accompanied by rapid drops in HBV-DNA and more importantly in serum HBsAg in the humanized mice. However, Roche decided to discontinue any further clinical development of the drug. Nowadays, two major groups of agents are being developed as HBV gene therapies. At this time, interference RNA (iRNA) molecules and nucleic acid polymers (NAPs) are the most promising. Overall, iRNA is double-stranded RNA molecules, 20 nucleotides long. One strand matches a segment of specific HBV mRNA and induces its degradation. Several iRNA molecules have entered into Phase II clinical trials (Flisiak et al. Exp Op Biol Ther, in press), including ARB-1467 and AB-729 (Arbutus), ARO-HBV (Arrowhead), ALN-HBV (Alnylam), and IONIS-HBVRx (Ionis). In most cases, they are tested as part of combination therapy with nucleos(t)ide analogs and/or peginterferon. NAPs are phosphorothioate 40 length oligonucleotides that no map any HBV sequence. However, they interact with a liver host target protein (apolipoprotein-like) and result in specific inhibition of HBV mRNAs. This is followed by rapid suppression of HBsAg release (Roehl et al. Mol Ther Nuc Acids 2017;8:1-12). In a pilot study with intravenous REP-2139, investigators from Replicor demonstrated strong reductions in HBV-DNA along with significant drops in HBsAg and seroconversion in some patients. More interestingly was the recognition of significant reductions in hepatic cccDNA, most likely a result of an indirect effect following the removal of large amounts of HBsAg from the bloodstream that contributes to impaired T-cell responses in chronic hepatitis B patients (Bazinet et al. EASL, Paris 2018; abstract FRI-343). An improved NAP, named REP-2165 and subcutaneous administration are currently being tested

The opioid epidemic during the COVID-19 pandemic: Impact on HIV and HCV control

The opioid epidemic is a tragedy in the United States. In the 12-month period that ended in April 2021, more than 100,000 US citizens died of drug overdose, up almost 30% from the 78,000 deaths in the prior year

A greater virulent HIV-1 subtype B variant has circulated in The Netherlands since the 1990’s

Despite being COVID-19 the global focus of attention nowadays, other pandemics caused by RNA viruses are ongoing. This is the case for AIDS. Roughly, 38 million people are, at present, living with HIV-1 infection worldwide and more than 33 million have died since the beginning of the pandemic 40 years ago (de Cock K. Emerg Infect Dis 2021; 27: 1553-60)