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Hepatitis delta virus (HDV) is a defective agent that only infects individuals with hepatitis B virus (HBV). Around 5–10% of chronic hepatitis B patients worldwide are superinfected with HDV, which means 15–25 million people. Hepatitis delta is the most severe of all chronic viral hepatitis, leading to cirrhosis, liver cancer and/or transplantation in most patients. Despite it, many HDV patients remain undiagnosed. The only treatment available until recently was peginterferon alfa, with poor results and significant side effects. The recent approval of bulevirtide, a lipopeptide that blocks HBV/HDV entry, has revolutionized the field. Another drug, lonafarnib, already approved to treat progeria, is expected to be available soon as HDV therapy. Since there is no cell reservoir for the HDV RNA genome, hypothetically viral clearance could be achieved if complete blocking of viral replication occurs for a minimum time frame. This is what happens in hepatitis C using direct‐acting antivirals, with the achievement of cure in nearly all treated patients. We envision the cure of hepatitis delta using combination antiviral therapy. Given that sexual and parenteral transmission routes are the most frequent for the acquisition of HBV and HDV, shared with HIV infection and HBV/HDV and HIV coinfection. The clinical outcome of hepatitis delta is worst in the HIV setting, with more frequent liver complications. Since most persons infected with HIV are on regular health care follow‐up, we propose that HIV‐HDV patients should be prioritized for moving forward new and potentially curative treatments for hepatitis delta. [ABSTRACT FROM AUTHOR]

Background: A protective hepatitis B virus (HBV) vaccine has been available for four decades. Universal HBV vaccination of infants is recommended by the WHO since the 1990s. Furthermore, HBV immunization is advised for all adults with high‐risk behaviours and no seroprotection. However, HBV vaccine coverage remains globally suboptimal. The advent of new more efficacious trivalent HBV vaccines has renewed the interest in HBV vaccination. At present, the extent of current HBV susceptibility in adults remains unknown in Spain. Methods: HBV serological markers were assessed on a large and representative sample of adults in Spain, including blood donors and individuals belonging to high‐risk groups. Serum HBsAg, anti‐HBc and anti‐HBs were tested in specimens collected during the last couple of years. Results: From 13 859 consecutive adults tested at seven cities across the Spanish geography, overall 166 (1.2%) had positive HBsAg. Past HBV infection was recognized in 14% and prior vaccine immunization in 24%. Unexpectedly, 37% of blood donors and 63% of persons belonging to high‐risk groups had no serum HBV markers and therefore were potentially HBV susceptible. Conclusion: Roughly 60% of adults living in Spain seem to be HBV susceptible. Waning immunity might be more common than expected. Hence, HBV serological testing should be performed at least once in all adults regardless of risk exposures. HBV vaccine full courses or boosters should be administered to all adults lacking serological evidence of HBV protection. [ABSTRACT FROM AUTHOR]

The 2022 annual meeting of the HTLV & HIV‐2 Spanish Network was held in Madrid on December 14. We summarize here the main information presented and discussed at the workshop and review time trends for human retroviral infections in Spain. As transmissible agents, infections by human retroviruses are of obligatory declaration. Until the end of 2022, the Spanish national registry had recorded 451 cases of HTLV‐1, 821 of HTLV‐2, and 416 of HIV‐2. For HIV‐1, estimates are of 150 000 people currently living with HIV‐1 and 60 000 cumulative deaths due to AIDS. During year 2022, new diagnoses in Spain were of 22 for HTLV‐1, 6 for HTLV‐2, and 7 for HIV‐2. The last updated figures for HIV‐1 are from 2021 and counted 2786 new diagnoses. The slowdown in yearly infections for HIV‐1 in Spain points out that new strategies are needed to achieve the United Nations 95‐95‐95 targets by 2025. For the remaining neglected human retroviral infections, their control might be pushed throughout four interventions: (1) expanding testing; (2) improving education and interventions aimed to reduce risk behaviors; (3) facilitating access to antiretrovirals as treatment and prevention, including further development of long‐acting formulations; and (4) increasing vaccine research efforts. Spain is a 47 million population country in South Europe with strong migration flows from HTLV‐1 endemic regions in Latin America and Sub‐Saharan Africa. At this time universal HTLV screening has been implemented only in the transplantation setting, following the report of 5 cases of HTLV‐associated myelopathy shortly after transplantation of organs from HTLV‐1 positive donors. There are four target populations for expanding testing and unveiling asymptomatic carriers responsible for silent HTLV‐1 transmissions: (1) migrants; (2) individuals with sexually transmitted infections; (3) pregnant women; and (4) blood donors. [ABSTRACT FROM AUTHOR]

Summary: Background: Chronic hepatitis B virus (HBV) infection is a major cause of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented in Spain two decades ago, and potent oral antivirals entecavir and tenofovir were introduced around 2007. Aim: To assess the clinical benefits of these interventions nationwide. Methods: Including HBV as a diagnosis, we performed a retrospective study of all hospitalisations in Spain the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2017. Results: From 73,939,642 nationwide hospital admissions during the study period, 129,634 (0.17%) included HBV as diagnosis. Their number doubled from 2007 to 2017 and the median age increased from 44 to 58 years. Most HBV admissions recorded chronic hepatitis B. In‐hospital death occurred in 6.4%. Co‐infection with HIV or hepatitis C virus occurred in 11.9% and 23.3%, respectively. Patients with HIV‐HBV co‐infection had significantly greater mortality than individuals with HBV mono‐infection. The rate of HBV hospitalisations significantly increased over time with a transient drop around 2007, coincident with the arrival of new potent oral antivirals. Although the proportion of HBV hepatic decompensation events has declined, the rate of liver cancer continues to rise. The small subset of patients with hepatitis delta superinfection increasingly and disproportionately accounts for hepatic decompensation events and liver cancer. Conclusion: Hospital admissions of individuals with HBV infection are increasing in Spain. While hepatic decompensation events declined following the introduction of potent oral nucleos(t)ide therapy, HBV‐related liver cancer is rising. No benefit of oral antiviral therapies is seen on hepatitis delta. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is major cause of decompensated cirrhosis and liver cancer. The advent of curative new antiviral therapies since year 2015 has dramatically improved the prognosis of HCV patients. The real‐life clinical benefits at country level of these therapies have not yet been assessed. This is a retrospective study of all hospitalizations in Spain including HCV as diagnosis using the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2019. From 81,482,509 nationwide hospital admissions recorded during the study period, 1,057,582 (1.29%) included HCV as diagnosis. The median age of HCV hospitalized patients was 54 years old. Males accounted for 63.2% of cases. Most HCV admissions recorded chronic hepatitis C whereas acute hepatitis C was reported in less than 3%. In‐hospital death occurred in 6.4% of HCV admissions. Coinfection with HIV or hepatitis B virus was seen in 14.8% and 6.4%, respectively. Patients hospitalized with HIV‐HCV coinfection represented 14.8% of cases and were on average 17 years younger than HCV‐monoinfected individuals. The rate of HCV hospitalizations significantly increased until 2005, and then stabilized for one decade. A significant reduction was noticed since 2015. However, whereas the proportion of HCV‐associated hepatic decompensation events declined since then, liver cancer diagnoses increased. In conclusion, hospital admissions of HCV individuals significantly declined in Spain since 2015 following a wide prescription of new oral direct‐acting antivirals. This reduction was primarily driven by a fall of hepatic decompensation events whereas HCV‐related liver cancer continues rising. [ABSTRACT FROM AUTHOR]

Background & Aims IL15 is an essential cytokine in both innate and adaptive immune response against hepatitis C virus (HCV) infection. The aim was to analyze whether IL15 rs10833 is associated with liver disease severity and response to pegylated-interferon-alpha plus ribavirin (peg IFN-alpha/ RBV) therapy in human immunodeficiency virus ( HIV)-/HCV-co-infected patients. Methods A retrospective study was performed in 315 patients who started peg IFN-alpha/ RBV therapy. Liver fibrosis stage was characterized in 286 patients. IL15 rs10833 and IL28B rs12980275 were genotyped by GoldenGate. The primary outcomes were: (a) advanced liver fibrosis evaluated by liver biopsy (F3-F4) or transient elastography (liver stiffness values ≥9.5 Kpa); (b) sustained virological response ( SVR). The secondary outcome variable was the levels of serum biomarkers of inflammation. Results Patients with rs10833 AA genotype had increased odds of having advanced fibrosis (adjusted odds ratio ( aOR) = 2.30; P = 0.019), particularly in males ( aOR = 2.24; P = 0.040), patients with HCV serum viral load (HCV- RNA) <500 000 IU/ ml ( aOR = 5.14; P = 0.018) and patients with IL28B rs12980275 AG/ GG genotypes ( aOR = 2.51; P = 0.046). Moreover, rs10833 AA genotype was significantly associated with higher levels of hepatocyte growth factor (adjusted arithmetic mean ratio ( aAMR) = 1.50; P = 0.016), sICAM-1 ( aAMR = 1.57; P = 0.025) and sVCAM-1 ( aAMR = 1.56; P = 0.007). Finally, patients with rs10833 AA genotype had increased odds of achieving SVR ( aOR = 3.12; P = 0.006), particularly in males ( aOR = 3.69; P = 0.005), GT1/4 patients ( aOR = 3.59; P = 0.006), patients with advanced fibrosis ( aOR = 4.64; P = 0.021), HCV- RNA ≥500 000 IU/ ml ( aOR = 3.92; P = 0.007) and patients with IL28B rs12980275 AG/ GG genotype ( aOR = 2.98; P = 0.041). Conclusions The presence of IL15 rs10833 AA genotype in HIV-/ HCV-co-infected patients was associated with advanced liver fibrosis, inflammation-related biomarkers and increased rates of SVR to peg IFN-alpha/ RBV therapy. [ABSTRACT FROM AUTHOR]

Background & Aims The safety and efficacy of the interferon-free combination of faldaprevir ( NS3/A4 protease inhibitor), deleobuvir ( BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored. Methods SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a ( IL28B CC genotype only; n = 12) and genotype-1b ( n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy. Results Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events. Conclusions The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated. [ABSTRACT FROM AUTHOR]

Background & Aims Host genetic factors could play a primary role in determining risk for cirrhosis development in HCV-infected patients. The aims of this study were to discover new genetic variants associated with this trait and to replicate some associations formerly reported. Methods Three hundred and thirty-seven HCV carriers with available data about liver fibrosis status, who initiated treatment with pegylated interferon plus ribavirin, were included. Of them, 77 (22.85%) were cirrhotic. One hundred and forty-four SNPs from 40 genes related to cholesterol metabolism/transport, sustained viral response to HCV therapy, liver fibrosis, or immune response, were genotyped in all samples. Plink software was used to perform univariate association analyses. The results obtained were adjusted by other parameters related to cirrhosis using multivariate logistic regression models. Results Only the SNP rs12104272, linked to RRAS, SCAF1, IRF3 and BCL2L12 genes, was associated with cirrhosis. It was observed a higher proportion of rs12104272 A allele carriers in the non-cirrhotic group (60.63%) than in the cirrhotic group (38.15%) (adjusted OR = 0.36, 95% CI = 0.180-0.746, P = 0.006). This effect was stronger in the background of rs12979860 CC genotype of IL28B (adjusted OR = 0.069, 95% CI = 0.014-0.349, P = 0.001). Conclusion The rs12104272 SNP could have clinical value to select those individuals at lower risk for cirrhosis development. [ABSTRACT FROM AUTHOR]

Hepatitis C virus genotype 4 (HCV-4) is highly prevalent in Spain, but the information on the molecular characterization of HCV-4 in this region is scarce. Due to this, the molecular characteristics and the evolution of HCV-4 infection in Seville were analyzed (Southern Spain) and compared them with samples from Madrid. HCV genotype was determined by LIPA 2.0 assay and confirmed by sequence analysis of NS5B. Phylogenetic tree was estimated by MEGA 5.10. Bayesian coalescent-based methods were used to estimate the substitution rate and the age of the most recent common ancestor (MRCA). In the phylogenetic analysis of 50 NS5B HCV-4 from Seville and 11 from Madrid, 2 clusters were distinguished: The first cluster (HCV-4a) included 48% of the sequences from Seville and 9% of sequences from Madrid. The second cluster included the remaining sequences belonging to HCV-4d. The mean estimated substitution rate was 2.39 × 10−3 for HCV-4a and 1.81 × 10−3 for HCV-4d for Seville and 2.32 × 10−3 for HCV-4d from Madrid. The date for MRCA was estimated to be around 1981-1984 for HCV-4 from Seville. The dates for MRCA were dated before the recent flow of immigration in Spain. Therefore, the results presented in this study argues against the possibility of a foreign introduction of the HCV-4 from other regions with high prevalence, at least during the last two, decades in which there was a great flow of immigrants. Additionally, an unusual high prevalence of subtype 4a was observed in Seville. J Med. Virol. 85:1734-1740, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Assessment of HIV tropism using bioinformatic tools based on V3 sequences correlates poorly with results provided by phenotypic tropism assays, particularly for recognizing X4 viruses. This may represent an obstacle for the use of CCR5 antagonists. An algorithm combining several bioinformatic tools might improve the correlation with phenotypic tropism results. A total of 200 V3 sequences from HIV-1 subtype B, available in several databases with known phenotypic tropism results, were used to evaluate the sensitivity and specificity of seven different bioinformatic tools (PSSM, SVM, C4.5 decision tree generator and C4.5, PART, Charge Rule, and Geno2pheno). The best predictive bioinformatic tools were identified, and a model combining several of these was built. Using the 200 reference sequences, SVM and geno2-pheno showed the highest sensitivity for detecting X4 viruses (98.8% and 93.7%, respectively); however, their specificity was relatively low (62.5% and 86.6%, respectively). For R5 viruses, PSSM and C4.5 gave the same results and outperformed other bioinformatic tools (95.7% sensitivity, 82% specificity). When results from three out of these four tools were concordant, the sensitivity and specificity, taking as reference the results from phenotypic tropism assays, were over 90% in predicting either R5 or X4 viruses (AUC: 0.9701; 95% CI: 0.9358-0.9889). An algorithm combining four distinct bioinformatic tools (SVM, geno2pheno, PSSM and C4.5), improves the genotypic prediction of HIV tropism, and merits further evaluation, as it might prove useful as a screening strategy in clinical practice. J. Med. Virol. 81:763-767, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A promising approach to identify HIV-1 vaccine candidates is to dissect the natural immune response against the virus in persons controlling the infection over decades without any antiviral therapy. Here we focus on a group of such persons, eight long-term non-progressors (LTNP), in which we proved the presence of broadly neutralizing antibodies against HIV-1 in the plasma as very likely cause for their LTNP status. The aim of this study was to identify the epitopes for these neutralizing antibodies, as these should represent immunogens potentially able to elicit neutralizing antibodies upon vaccination. We screened random peptide phage libraries with plasma antibodies from eight LTNP. After several rounds of positive and negative selection, about 700 HIV-specific mimotopes were sequenced. The mimotope sequences were analyzed for homology to HIV-1 Env, in particular for their capacity to represent conformational epitopes on the surface of the gp120 structure using our software 3DEX. Related phage groups were analyzed for crossreactivity with the LTNP plasma by ELISA as well as for their capacity to induce HIV-1-neutralizing antibodies in mice. Based on this study interesting mimotopes can now be selected for further immunization studies. [ABSTRACT FROM AUTHOR]

The 3′-azido-3′-denxythymidine (AZT)-resistant phenotype of a heavily mutated human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) carrying a dipeptide (Ser-Ser) insertion between codons 69 and 70 as well as other mutations related to resistance to RT inhibitors has been studied. Recombinant virus carrying this variant RT (termed SS RT) showed reduced susceptibility to all nucleoside RT inhibitors in clinical use, particularly to AZT. In the presence of ATP, recombinant SS RT had an increased ability to remove the 3′-terminal nucleotide from AZT-terminated primers and extend the unblocked primer, compared with wild-type HIV-1 RT (BH10 isolate). Insertion of two serines in the sequence context of BH10 RT did not affect the ATP-dependent phosphorolytic activity of the enzyme, and had no influence in resistance to RT inhibitors. However, SS RT mutants lacking the dipeptide insertion or bearing a four-serine insertion showed reduced ATP-dependent phosphorolytic activity that correlated with increased AZT sensitivity, as determined using a recombinant virus assay. Therefore, the insertion appears to be critical to enhance AZT resistance in the sequence context of multidrug-resistant H1V-1 RT. [ABSTRACT FROM AUTHOR]