Author
M Valappil
Other affiliations: Royal Victoria Infirmary, Health Protection Agency, University Hospital of Wales ...read more
Bio: M Valappil is an academic researcher from Newcastle upon Tyne Hospitals NHS Foundation Trust. The author has contributed to research in topics: HBsAg & Hepatitis B virus. The author has an hindex of 15, co-authored 31 publications receiving 1020 citations. Previous affiliations of M Valappil include Royal Victoria Infirmary & Health Protection Agency.
Topics: HBsAg, Hepatitis B virus, Population, Hepatitis C, Hepatitis B
Papers
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TL;DR: This review concludes that routine monitoring on ART for HIV‐infected patients and individuals transferring care from a different HIV healthcare setting is a viable option and should be considered.
Abstract: Table of Contents
1. Levels of evidence
1.1 Reference
2. Introduction
3. Auditable targets
4. Table summaries
4.1 Initial diagnosis
4.2 Assessment of ART-naive individuals
4.3 ART initiation
4.4 Initial assessment following commencement of ART
4.5 Routine monitoring on ART
4.6 References
5. Newly diagnosed and transferring HIV-positive individuals
5.1 Initial HIV-1 diagnosis
5.2 Tests to determine whether acquisition of HIV infection is recent
5.3 Individuals transferring care from a different HIV healthcare setting
5.4 Communication with general practitioners and shared care
5.5 Recommendations
5.6 References
6. Patient history
6.1 Initial HIV-1 diagnosis
6.2 Monitoring of ART-naive patients
6.3 Pre-ART initiation assessment
6.4 Monitoring individuals established on ART
6.5 Assessment of adherence
6.6 Recommendations
6.7 References
7. Examination
7.1 Recommendations
8. Identifying the need for psychological support
8.1 References
9. Assessment of immune status
9.1 CD4 T cell counts
9.2 CD4 T cell percentage
9.3 References
10. HIV viral load
10.1 Initial diagnosis/ART naive
10.2 Post ART initiation
10.3 Individuals established on ART
10.4 Recommendations
10.5 References
11. Technical aspects of viral load testing
11.1 References
12. Viral load kinetics during ART and viral load ‘blips’
12.1 References
13. Proviral DNA load
13.1 References
14. Resistance testing
14.1 Initial HIV-1 diagnosis
14.2 ART-naive
14.3 Post treatment initiation
14.4 ART-experienced
14.5 References
15. Subtype determination
15.1 Disease progression
15.2 Transmission
15.3 Performance of molecular diagnostic assays
15.4 Response to therapy
15.5 Development of drug resistance
15.6 References
16. Other tests to guide use of specific antiretroviral agents
16.1 Tropism testing
16.2 HLA B*5701 testing
16.3 References
17. Therapeutic drug monitoring
17.1 Recommendations
17.2 References
18. Biochemistry testing
18.1 Introduction
18.2 Liver function
18.3 Renal function
18.4 Dyslipidaemia in HIV-infected individuals
18.5 Other biomarkers
18.6 Bone disease in HIV-infected patients
18.7 References
19. Haematology
19.1 Haematological assessment and monitoring
19.2 Recommendations
19.3 References
20. Serology
20.1 Overview
20.2 Hepatitis viruses
20.3 Herpes viruses
20.4 Measles and rubella
20.5 Cytomegalovirus (CMV)
20.6 References
21. Other microbiological screening
21.1 Tuberculosis screening
21.2 Toxoplasma serology
21.3 Tropical screening
21.4 References
22. Sexual health screening including anal and cervical cytology
22.1 Sexual history taking, counselling and sexually transmitted infection (STI) screening
22.2 Cervical and anal cytology
22.3 Recommendations
22.4 References
23. Routine monitoring recommended for specific patient groups
23.1 Women
23.2 Older age
23.3 Injecting drug users
23.4 Individuals coinfected with HBV and HCV
23.5 Late presenters
23.6 References
Appendix
205 citations
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TL;DR: The findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.
Abstract: Severe infectious disease in children may be a manifestation of primary immunodeficiency. These genetic disorders represent important experiments of nature with the capacity to elucidate nonredundant mechanisms of human immunity. We hypothesized that a primary defect of innate antiviral immunity was responsible for unusually severe viral illness in two siblings; the proband developed disseminated vaccine strain measles following routine immunization, whereas an infant brother died after a 2-d febrile illness from an unknown viral infection. Patient fibroblasts were indeed abnormally permissive for viral replication in vitro, associated with profound failure of type I IFN signaling and absence of STAT2 protein. Sequencing of genomic DNA and RNA revealed a homozygous mutation in intron 4 of STAT2 that prevented correct splicing in patient cells. Subsequently, other family members were identified with the same genetic lesion. Despite documented infection by known viral pathogens, some of which have been more severe than normal, surviving STAT2-deficient individuals have remained generally healthy, with no obvious defects in their adaptive immunity or developmental abnormalities. These findings imply that type I IFN signaling [through interferon-stimulated gene factor 3 (ISGF3)] is surprisingly not essential for host defense against the majority of common childhood viral infections.
200 citations
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Royal Victoria Infirmary1, Newcastle University2, Universiti Sains Malaysia3, University of St Andrews4, Boston Children's Hospital5, University College London6, Great Ormond Street Hospital7, Great Ormond Street Hospital for Children NHS Foundation Trust8, University College Dublin9, University College Cork10, Bon Secours Hospital Cork11
TL;DR: The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.
Abstract: Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.
182 citations
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TL;DR: Assessment of rates of and risk factors for adverse outcomes following AH1N1v infection in pregnancy and the adverse effects of the antiviral drugs and vaccines used in prevention and management found earlier treatment with antiviral agents is associated with improved outcomes for pregnant women.
Abstract: BACKGROUND: In April 2009 a novel influenza A virus (AH1N1v) of swine origin (swine flu) emerged, spreading rapidly and achieving pandemic status in June 2009. Pregnant women were identified as being at high risk of severe influenza-related complications and as a priority group for vaccination against AH1N1v. Limited information was available about the maternal and fetal risks of AH1N1v infection or of antiviral drug or AH1N1v vaccine use in pregnancy.OBJECTIVES: To assess rates of and risk factors for adverse outcomes following AH1N1v infection in pregnancy and to assess the adverse effects of the antiviral drugs and vaccines used in prevention and management.METHODS: Prospective national cohort studies were conducted to identify pregnant women who were (1) suspected to be infected with AH1N1v or being treated with antiviral medication in primary care; (2) vaccinated against AH1N1v; and (3) admitted to hospital with confirmed AH1N1v. Characteristics of women with influenza-like illness (ILI) in primary care were compared with those of women without symptoms accepting or declining immunisation. Characteristics of women admitted to hospital with confirmed AH1N1v infection in pregnancy were compared with a historical cohort of over 1200 women giving birth in the UK who were uninfected with AH1N1v. Outcomes examined in hospitalised women included maternal death, admission to an intensive care unit, perinatal mortality and preterm birth. Risk factors for hospital and intensive care unit admission were examined in a full regression model.RESULTS: The weekly incidence of ILI among pregnant women averaged 51/100,000 over the study period. Antiviral drugs were offered to 4.8\% [95\% confidence interval (CI) 4.0\% to 5.9\%] and vaccination to 64.8\% (95\% CI 64.7\% to 68.9\%) of registered pregnant women. Ninety pregnant women with ILI presenting in primary care were reported to the research team, 55 of whom were prescribed antiviral drugs and in 42 (76\%) cases this was within 2 days of symptom onset. After comparison with 1329 uninfected pregnant women offered vaccination, pre-existing asthma was the only maternal factor identified as increasing risk of ILI presentation [adjusted odds ratio (OR) 2.0, 95\% CI 1.0 to 3.9]. Maternal obesity and smoking during pregnancy were also associated with hospital admission with AH1N1v infection. Overall, 241 pregnant women were admitted to hospital with laboratory-confirmed AH1N1v infection. Eighty-three per cent of these women were treated with antiviral agents, but only 6\% received antiviral treatment before hospital admission. Treatment within 2 days of symptom onset was associated with an 84\% reduction in the odds of admission to an intensive therapy unit (OR 0.16, 95\% CI 0.08 to 0.34). Women admitted to hospital with AH1N1v infection were more likely to deliver preterm; a three times increased risk was suggested compared with an uninfected population cohort (OR 3.1, 95\% CI 2.1 to 4.5).CONCLUSIONS: Earlier treatment with antiviral agents is associated with improved outcomes for pregnant women and further actions are needed in future pandemics to ensure that antiviral agents and vaccines are provided promptly to pregnant women, particularly in the primary care setting. Further research is needed on longer-term outcomes for infants exposed to AH1N1v influenza, antiviral drugs or vaccines during pregnancy.
126 citations
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TL;DR: One in six women had active HBV requiring treatment or high HBV-DNA levels that would benefit from antiviral treatment to reduce the transmission risk.
Abstract: Objective Vertical transmission of the hepatitis B virus (HBV) is the commonest mode of infection and can be prevented with immunoprophylaxis of the infant and antiviral therapy in the mother. Our aim was to review a cohort of subjects with HBV in pregnancy to determine the prevalence of active disease or high HBV-DNA levels that required treatment to prevent transmission, and to review the management of mothers and infants. Methods A retrospective case-note review was conducted of all the HBV-infected pregnant women and their infants who attended the Newcastle obstetric services from 2007 to 2011. Results There were 113 pregnancies in 81 women (median age 28 years; 15% hepatitis B e antigen (HBeAg) positive) during 2007–11. 71% of mothers were first diagnosed with HBV during pregnancy. The mothers were born in 28 different countries. 69% of mothers had an HBV-DNA level less than 2000 IU/mL and 13% had HBV-DNA levels greater than 1.0×10 7 IU/mL so would be eligible for antiviral therapy to prevent transmission to the infant. 9% had active eAg-positive HBV and 3% had active eAg-negative HBV requiring treatment. All infants born to HBeAg-positive mothers received hepatitis B immunoglobulin (HBIG) appropriately and 76% of infants received a full HBV vaccination course. One infant born to an HBeAg-negative mother was hepatitis B surface antigen positive 1 year post-delivery. Conclusions One in six women had active HBV requiring treatment or high HBV-DNA levels that would benefit from antiviral treatment to reduce the transmission risk. HBIG was administered appropriately but completion of the vaccination course was suboptimal.
114 citations
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TL;DR: The COVID Human Genetic Effort established to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance finds an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001.
Abstract: Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
1,659 citations
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Chelsea and Westminster Hospital NHS Foundation Trust1, Public Health England2, Central and North West London NHS Foundation Trust3, University College London4, Brighton and Sussex University Hospitals NHS Trust5, Central Manchester University Hospitals NHS Foundation Trust6, Imperial College Healthcare7, Hull York Medical School8, Barts Health NHS Trust9, University of Cambridge10, Guy's and St Thomas' NHS Foundation Trust11, Heart of England NHS Foundation Trust12, University of Liverpool13
TL;DR: In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting.
1,472 citations
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TL;DR: The Janus kinase (JAK)-signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules.
Abstract: The Janus kinase (JAK)–signal transducer of activators of transcription (STAT) pathway is now recognized as an evolutionarily conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. This pathway provides an elegant and remarkably straightforward mechanism whereby extracellular factors control gene expression. It thus serves as a fundamental paradigm for how cells sense environmental cues and interpret these signals to regulate cell growth and differentiation. Genetic mutations and polymorphisms are functionally relevant to a variety of human diseases, especially cancer and immune-related conditions. The clinical relevance of the pathway has been confirmed by the emergence of a new class of therapeutics that targets JAKs.
995 citations
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Erola Pairo-Castineira1, Erola Pairo-Castineira2, Sara Clohisey1, Lucija Klaric2 +1446 more•Institutions (27)
TL;DR: The GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2244 critically ill Covid-19 patients from 208 UK intensive care units is reported, finding evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease.
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice. A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.
941 citations
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TL;DR: A model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient is discussed.
608 citations