OBJECTIVES:To analyse longitudinal change in motor neuron disease (MND) mortality in Australia from 1986 to 2023. DESIGN:Australian population-based study of MND mortality. SETTING:All MND mortality and Australian population data from 1 January 1986 to 31 December 2023 were obtained from the Australian Bureau of Statistics. MAIN OUTCOME MEASURES:MND mortality records were analysed, and certified deaths were summarised by year of registration. MND mortality rates, 95% confidence intervals (CIs) and Joinpoint regression trends were calculated. Data were further subset by demographic and geographical categories to report Australian MND mortality by age group, sex, state/territory location and remoteness areas classification. RESULTS:In Australia, the total number of MND deaths more than tripled over the past 37 years, from 238 in 1986 to 781 in 2023. The unadjusted mortality rate in 1986 was 1.49 (95% CI, 1.30-1.69) per 100,000 population and increased to 2.93 (95% CI, 2.73-3.14) per 100,000 population by 2023. After age standardisation, the annual percentage change across 1986-2023 was determined to be 0.47% (95% confidence limit, 0.16-0.86). Joinpoint modelling suggests a more recent reduction in adjusted mortality rates. In 2023, MND accounted for 0.43% of all-cause deaths in Australia, increasing from 0.21% in 1986. The number of MND deaths in Australia peaked at age 70-79 years. MND mortality was higher among men than women (rate ratio, 1.41; 95% CI, 1.33-1.51). MND mortality rates were similar among New South Wales, Victoria and Queensland (2.93, 3.08 and 2.85 per 100,000 population, respectively), with higher rates in South Australia and Tasmania (3.44 and 4.12 per 100,000 population, respectively). MND mortality rates were higher in inner and outer regional areas (3.90 and 3.24 per 100,000 population, respectively) compared with major cities (2.79 per 100,000 population). CONCLUSIONS:Adjusted MND mortality rates in Australia increased over 37 years.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43 kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. This study investigates the effects of the antiretroviral treatment Triumeq on ALS disease that occurs through TDP-43 pathology by utilising the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model. In this model, TDP-43 accumulation in the cytoplasm is induced after removal of Dox. Disease was assessed through measures of body weight, neurological score, motor function, urinary p75ECD and inflammatory marker expression. Mice were treated with Triumeq and TDP-43 pathology and inflammatory marker expression examined. Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Triumeq treatment transiently and modestly improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via disruption of TDP-43-driven inflammation in ALS.

Epstein-Barr virus (EBV) is strongly associated with multiple sclerosis (MS). It is likely to play a causal role in the pathogenesis of MS, possibly via triggering autoimmunity through molecular mimicry, autoantigenic presentation or immune dysregulation. Alternatively, evidence supports a direct role for EBV in driving MS disease activity via latent-lytic infection cycling either within the CNS or the periphery. We highlight the recent immunological and virological findings supporting the role of active EBV infection in MS, supporting an evaluation of anti-EBV strategies as potential treatments for MS. Anti-EBV strategies include CNS penetrant small molecule anti-viral agents targeting latent and lytic infection, and immunotherapies. Immunotherapies include EBV-specific autologous or allogeneic cytotoxic T cells (CTLs) and therapeutic EBV vaccines and/or immune checkpoint inhibitors to rejuvenate and boost endogenous EBV-targeted CTL responses. In parallel, several licensed MS disease-modifying therapies may work via mechanisms targeting EBV directly or indirectly. B-cell depleting therapies have been shown to have anti-EBV activity; additionally, new strategies to target intrathecal B cells, plasmablasts and plasma cells are being explored, including high-dose anti-CD20 therapy, cladribine, proteasome inhibitors, BTK inhibitors, CNS-penetrant anti-CD20/CD19 monoclonal antibodies and CD19-targeted CAR T cells. Innovative trial designs for proof-of-concept studies to test EBV antivirals and immunotherapies in MS are needed to catalyse a wave of drug development targeting EBV as a therapeutic strategy to prevent or treat MS.

BACKGROUND:Despite increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS, no treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551) in a pilot, proof-of-concept study. METHODS:People with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting famciclovir 500 mg twice daily for 12 weeks. Twelve saliva samples were provided on treatment and 12 following treatment. A real-time qPCR Taqman assay was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test. RESULTS:Of 30 participants (19 F; mean age 41 years; median EDSS 3.5), 29 received famciclovir, and 24 completed the 12-week course. Twenty-one participants provided at least one usable saliva sample in all epochs. Ten of the 21 had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events. CONCLUSION:No significant effect of famciclovir on EBV shedding was seen in this small pilot study. Given the low numbers, a small effect of famciclovir cannot be excluded. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies, which requires replication.

Current dogma states that multiple sclerosis (MS) is a complex disease due to the interaction of several environmental exposures with genetic variation that increase the likelihood of an autoreactive immune response that subsequently leads to an organ-specific acute focal inflammatory process ( Ramagopalan, Dobson, Meier and Giovannoni, 2010 Ramagopalan S.V. Dobson R. Meier U.C. Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010; 9: 727-739 Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar ). Focal inflammatory events cause demyelination and variable degrees of axonal loss and gliosis and result in a clinical presentation and phenotype, which we call MS ( Gafson et al., 2012 Gafson A. Giovannoni G. Hawkes C.H. The diagnostic criteria for multiple sclerosis: From Charcot to McDonald. Mult. Scler. Relat. Disord. 2012; 1: 9-14 Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar ).

Background: Given its potential antiviral activity, we investigated the effect of teriflunomide on EBV in patients with relapsing-remitting MS (RRMS). Methods: Saliva samples were collected at home and analysed for EBV DNA presence in patients with RRMS treated with teriflunomide for >= 3 months. Results: The proportion of patients with detectable EBV in the teriflunomide cohort was lower than in the reference cohorts. The proportion of samples with EBV DNA or shedding from teriflunomide-treated patients was reduced relative to each reference cohort (P<0.0001; >5.8 virus copies/mu L cut-off). Conclusion: This pilot study demonstrated the feasibility of at-home saliva sample collection and revealed a possible effect of teriflunomide on EBV shedding.

Background Behavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD. Here, we investigated the possible role of HERV-K in bvFTD. Methods We measured the HERV-K env gene in sporadic bvFTD ( N = 63), sporadic ALS ( N = 89), and control ( N = 21) serum by ddPCR. We also analyzed HERV-K env , by qPCR, and the HERV-K reverse transcriptase protein, by confocal immunofluorescence microscopy, in the disease-affected superior frontal cortex of bvFTD with TDP-43 pathology. Results Here, we show that HERV-K env levels are significantly elevated ( P = 3.5 × 10 −6 ) in bvFTD compared to control serum, differentiating cases with an AUC value of 0.867. HERV-K env levels are also specifically elevated in the superior frontal cortex of bvFTD with TDP-43 pathology, with the HERV-K reverse transcriptase protein and TDP-43 deposit localized to the neuronal cytoplasm. Furthermore, in a neuronal cell line overexpression of TDP-43 induces HERV-K env transcription. Conclusions These results suggest that manifestation of HERV-K is associated with bvFTD TDP-43 pathology. Analysis of HERV-K in bvFTD may provide insight into an unrecognized but targetable perturbed pathology.

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as ?responders?, experienced a decrease in HML-2 at week 24 of treatment compared to the pretreatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE =11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

Maria was distraught after reading about the 'potential' epidemic, yet to happen, and the horror stories on Facebook needing reassurance and certainty about what she should do. She requested an urgent appointment to review her treatment plan. Maria was a 26-year-old woman with relapsing multiple sclerosis who had recently experienced brainstem relapse with double vision and ataxia despite treatment with pegylated interferon-beta for the last 18 months. A brain MRI performed one month prior had shown 16 new T2 lesions, four of which were enhancing. One of the enhancing lesions was at the pontomedullary junction and was certainly the cause of her relapse. Treatment was to be escalated to ocrelizumab with the first dose in a week's time. In view of the emerging coronavirus pandemic, she was questioning whether or not she should go ahead with ocrelizumab. This was despite only a handful of confirmed COVID-19 cases in the country and none in her town and region. If this scenario sounds plausible what should neurologists do? Human coronaviruses are predominantly associated with respiratory tract infections and includes those that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and now the COVID-19 pandemic. In an uncertain world, where we do not have a clear evidence-base, you often have to default to scientific principles, rather than using the wisdom of the crowd. Not surprising, with Italy being one of the epicentres of the COVID-19 epidemic, the Italian society of neurology or SIN (Società Italiana di Neurologia) broke cover first producing recommendations on the management of patients with MS during the COVID-19 epidemic (see Box 1). The SIN guidelines provide relatively straightforward, and one could argue arbitrary, advice on how to manage patients with MS in the short-term, but do not address supervision of these patients in the intermediate or long-term especially those with highly active MS. If the public health measures being taken flatten the peak of the epidemic, but extend its tail, the problem of community-acquired SARS-CoV2 infection and COVID-19 may be with us for many months and potentially years. Are the SIN guidelines compatible with the best interests of our patients or a knee-jerk response to an undefined problem that may not be a problem at all? It is clear that COVID-19 is a pandemic and global health crisis with the potential to kill millions of people, particularly the elderly and people with comorbidities such as hypertension, smoking and lung disease. At present we do not know if people with MS are at increased risk acquring SARS-CoV-2, COVID-19 or developing severe COVID-19. Individuals with MS are not unique in their requirement to be treated with immunosuppressive therapies. We discussed the COVID-19 epidemic with our renal transplant team who informed us that at present they are not taking any specific action about the levels of immunosuppression for their transplant patients during the epidemic. Basic measures are recommended namely: to improve hand and home hygiene, to avoid high-risk travel and unnecessary contacts, to self-isolate if necessary and to reduce contact with the hospital and other medical institutions as much as possible, because they are more likely to be sources of COVID-19. It is business as usual. Nor are they necessarily halting their transplant programme. Their argument is that transplanted kidneys and other transplanted organs are too precious not to protect them with relevant immunosuppressive drugs. Why would we not have the same attitude about the brains and spinal cords of our patients with active multiple sclerosis? We could argue that solid-organ transplant patients are significantly more immunocompromised than pwMS on disease modifying treatment (DMT). Most transplant patients are on triple immunotherapy, compared to pwMS who are on monotherapy and even then, the level of immunosuppression is generally low. Hence, the mortality/morbidity risk to an individual on a DMT, infected with COVID-19, may be actually quite moderate to low. Another hypothesis being considered is that moderate immunosuppression may prevent severe complications associated with COVID-19 infection. The severe pulmonary complications of COVID-19 infection are consistent with ARDS (acute respiratory distress syndrome) caused by an over-exuberant immune response to the virus (Ramanathan et al., 2020Ramanathan K. Antognini D. Combes A. Paden M. Zakhary B. Ogino M. MacLaren G. Brodie D. Shekar K. Planning and provision of ECMO services for severe ARDS during the COVID-19 pandemic and other outbreaks of emerging infectious diseases.Lancet Respir. Med. 2020; (https://doi.org/)https://doi.org/10.1016/s2213-2600(20)30121-1Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). As a result, several exploratory trials are currently being undertaken in China and elsewhere using immunosuppressants to try and dampen the immune response to the virus. Interestingly, fingolimod, a S1P modulator licensed for MS, is being tested as a treatment for COVID-19 associated ARDS (ClinicalTrials.gov Identifier: NCT04280588). Interferon beta is also being trialled in COVID-19 based on its antiviral properties (ClinicalTrials.gov Identifier: NCT04276688). Then there is the virology to take into account. SARS-CoV-2, the cause of COVID-19, is a new human pathogen that is likely to have recently crossed species (Andersen et al., 2020Andersen K.G. Rambaut A. Ian Lipkin W. Holmes E.C. Garry R.F. The proximal origin of SARS-CoV-2.Nat. Med. 2020; (https://doi.org/)https://doi.org/10.1038/s41591-020-0820-9Crossref PubMed Scopus (3144) Google Scholar). COVID-19 will eventually become endemic and hence pose a seasonal risk to patients on immunosuppressive therapies. As it is a small RNA virus with low fidelity it is likely to mutate rapidly making a one-off vaccine only a partial solution. Vaccines take time to be developed, tested and introduced at a population level. Delaying treatment, de-escalating therapy by switching to immunomodulatory DMTs, such as interferon-beta, glatiramer acetate or teriflunomide, or interrupting dosing of DMTs to wait for a vaccine will delay the adequate treatment of MS, especially as it may take 12–18 months to develop a vaccine. We, therefore, need a pragmatic response on management of the potential threat of COVID-19 in individuals with MS. If patients have active MS they need to be treated based on the clinical evidence at hand and hence may need to be treated with higher efficacy DMTs. This should be implemented in conjunction with appropriate behavioural modifications to reduce or ideally prevent exposure to the virus. It is essential to consider the potential risk of morbidity and possible mortality for each MS patient, who may be infected with SARS-CoV-2 and develops COVID-19. The individual's risk profile is multifactorial; their DMT and consequent immune response is one of the factors. Other aspects to consider, when assessing a respiratory viral infection include: smoking practices (increased cigarette smoking increases risk); ambulatory status (less mobility increases risk, especially if the patient is in a wheelchair); age (increasing age increases risk); weight (increasing weight impacts on ambulation and respiratory function); underlying respiratory illnesses, such as asthma or COPD. Also, the frequency of necessary attendance at a hospital or healthcare facility for laboratory or MRI testing, but also for infusions may place the patient at a higher risk of exposure. In the context of these factors the health care professionals should weigh the potential risks of SARS-CoV-1 exposure and manage their DMT accordingly. Visits for MS care should preferably be done by telemedicine or phone. The potential hazards posed by each DMT differ and, rather than imposing a blanket rule, decisions regarding treatment should be individualised (See Table 1) and discussed with patients. For some patients having their MS treated and controlled may be more important than the potential danger of being exposed to and acquiring a more severe COVID-19 infection. Table 1 is our attempt to define the risks associated with the different classes of DMTs in the event of a patient acquiring a COVID-19 infection.Table 1Main attributes of licensed MS DMTs in relation to the COVID-19 pandemicAt risk categoryClassTrade nameMode of actionEfficacyClassSafe to start treatmentAdvice regarding treatmentIn the event of COVID-19 infection?Immuosuppression?Attributes and caveatsVery lowInterferon-betaBetaferon, Avonex, Rebif, PlegridyImmunomodulatoy (not immunosuppressive), pleitropic immune effectsModerateMaintenance immunomodulatoyYesContinueContinueNoHas antiviral properties that may be beneficial in the case of COVID-19Very lowGlatiramer acetateCopaxoneImmunomodulatoy (not immunosuppressive), pleitropic immune effectsModerateMaintenance immunomodulatoyYesContinueContinueNoVery lowTeriflunomideAubagioDihydro-orotate dehydrogenase inhibitor (reduced de novo pyrimidine synthesis), anti-proliferativeModerate (1st-line) / Moderate to high (2nd-3rd-line)Maintenance immunomodulatoyYesContinueContinuePossible (no well-defined immunosupressive signature)Has antiviral properties that may be beneficial in the case of COVID-19LowDimethyl fumarateTecfideraPleotropic, NRF2 activation, downregulation of NFΚβModerate (2nd-3rd-line) / High (1st-line)Maintenance immunosuppressiveProbablyContinue / Switch if lymphopaenicContinueYes, continousThe risk can only be considered low in paients who don't develop a persistent lymphopaenia. Patients with a total lymphocyte count of less than 800/mm3 should be considered be at a higher risk of develping complications from COVID19 infection.LowNatalizumabTysabriAnti-VLA4, selective adhesion molecule inhibitorVery highMaintenance immunosuppressiveYesContinueContinue or miss infusion depending on timingYes, continousLow risk, but theoretical concerns of creating an environment in mucosal surfaces and the gut that may promote prolonged viral shedding. Also risk that as COVID-19/SARS-CoV-2 is neurotropic it may prevent viral clearance from the CNS.IntermediateS1P modulatorsFingolimod (Gilenya), Siponimod (Mazent), Ozanimod, PonesimodSelective S1P modulator, prevents egress of lymphocytes from lymph nodesHighMaintenance immunosuppressiveProbablyContinueContinue or temporary suspension of dosingYes, continousTheoretical risk that S1P modulators may result in prolonged viral shedding. Paradoxically S1P modulators may reduce the severity of COVID-19; fingolimod is currently being trialed.IntermediateAnti-CD20Ocrelizumab (Ocrevus), Ofatumumab. Rituximab, UblituximabAnti-CD20, B-cell depleterVery highMaintenance immunosuppressiveProbablyRisk assessment - continue or suspend dosingTemporary suspension of dosing depending on timingYes, continousTheoretical risk that ocrelizumab and other anti-CD20 therapies may result in prolonged viral shedding.IntermediateCladribineMavencladDeoxyadenosine (purine) analogue, adenosine deaminase inhibitor, selective T and B cell depletionHigh / Very high (highly-active RMS)IRT (semi-selective)ProbablyRisk assessment - continue or suspend dosingTemporary suspension of dosing depending on timingYes, intermittentTheoretical risk that in the immune depletion phase cladribine may result in prolonged viral shedding.High*risk refers to acquiring an infection during the immunodepletion phase. Post immune reconstitution the risk is low.MitoxantroneNovatroneImmune depleter (topoisomerase inhibitor)Very highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentTheoretical risk that in the immune depletion phase mitoxantrone may result in prolonged viral shedding.High*risk refers to acquiring an infection during the immunodepletion phase. Post immune reconstitution the risk is low.AlemtuzumabLemtradaAnti-CD52, non-selective immune depleterVery highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentTheoretical risk that in the immune depletion phase alemtuzumab may result in prolonged viral shedding.High*risk refers to acquiring an infection during the immunodepletion phase. Post immune reconstitution the risk is low.HSCT-Immune depletion and haemopoietic stem cell reconstitutionVery highIRT (non-selective)NoSuspend dosingSuspend dosingYes, intermittentTheoretical risk that in the immune depletion phase HSCT may result in prolonged viral shedding. risk refers to acquiring an infection during the immunodepletion phase. Post immune reconstitution the risk is low. Open table in a new tab Assuming that antiviral responses are driven mainly by T-cells, in particular CD8+ cytotoxic T-lymphocytes, and natural-killer cells and less so, at least initially, by B-cells, allows one to construct a hierarchy of immunosuppression of DMTs. The highest risk are the immune reconstitution therapies during the depletion phase of the treatment, i.e. haematopoietic stem cell transplantation (HSCT), alemtuzumab (Lemtrada), mitoxantrone (Novantrone) and cladribine (Mavenclad). After immune reconstitution, once the total lymphocyte counts have returned to normal or near normal the risk of severe viral infections are probably no higher than expected for the background population and would be associated with age and other comorbidities. Please note, immune reconstitution takes months to years, so if the patient's last course of treatment was in the previous 6–12 months they may still be immunocompromised. A total lymphocyte count less 1.1 × 109/L or 1100/mm3 is associated with an increased risk of infection and infection-related mortality (Warny et al., 2018Warny M. Helby J. Nordestgaard B.G. Birgens H. Bojesen S.E. Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study.PLoS Med. 2018; 15e1002685Crossref PubMed Scopus (105) Google Scholar). This risk increases progressively the lower the absolute lymphocyte counts; particularly when the lymphocyte count drops below 800/mm3 (>50% risk) (Warny et al., 2018Warny M. Helby J. Nordestgaard B.G. Birgens H. Bojesen S.E. Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study.PLoS Med. 2018; 15e1002685Crossref PubMed Scopus (105) Google Scholar). As a rough guide, pwMS with a lymphocyte count above 800/mm3 (WHO grade 2) are able to deal with viral infections reasonably well provided they have no other comorbidities and are relatively young. Of the immune reconstitution therapies, cladribine (Mavenclad) is classed as intermediate risk, because it is a relatively poor T-cell depleting agent (Stuve et al., 2019Stuve O. Soelberg Soerensen P. Leist T. Giovannoni G. Hyvert Y. Damian D. Dangond F. Boschert U. Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers.Ther. Adv. Neurol. Disord. 2019; 121756286419854986Crossref Scopus (75) Google Scholar). T-cells are only depleted post-cladribine by an average of 50% with the CD4+ population being more sensitive than the CD8+ population. In the phase 3 CLARITY study, viral infections were uncommon post-cladribine and apart from herpes zoster, infections were no more frequent in cladribine-treated subjects compared to placebo (Cook et al., 2011Cook S. Vermersch P. Comi G. Giovannoni G. Rammohan K. Rieckmann P. Sørensen P.S. Hamlett A. Miret M. Weiner J. Viglietta V. Musch B. Greenberg S.J. CLARITY Study GroupSafety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.Mult. Scler. 2011; 17: 578-593Crossref PubMed Scopus (99) Google Scholar). When viral infections occurred post-cladribine they tended to be mild or moderate in severity. Similarly, anti-CD20 therapies such as ocrelizumab have a minor impact on T-cell counts and are not associated with severe viral infections (Mayer et al., 2019Mayer L. Kappos L. Racke M.K. Rammohan K. Traboulsee A. Hauser S.L. Julian L. Köndgen H. Li C. Napieralski J. Zheng H. Wolinsky J.S. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies.Mult. Scler. Relat. Disord. 2019; 30: 236-243Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). In the phase 3 relapsing-remitting and primary progressive trials, infections were slightly more frequent on ocrelizumab compared to comparator arms (interferon-beta-1a or placebo) (Hauser et al., 2017Hauser S.L. Bar-Or A. Comi G. Giovannoni G. Hartung H.-P. Hemmer B. Lublin F. Montalban X. Rammohan K.W. Selmaj K. Traboulsee A. Wolinsky J.S. Arnold D.L. Klingelschmitt G. Masterman D. Fontoura P. Belachew S. Chin P. Mairon N. Garren H. Kappos L. OPERA I OPERA II Clinical InvestigatorsOcrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N. Engl. J. Med. 2017; 376: 221-234Crossref PubMed Scopus (1171) Google Scholar; Montalban et al., 2017Montalban X. Hauser S.L. Kappos L. Arnold D.L. Bar-Or A. Comi G. de Seze J. Giovannoni G. Hartung H.-P. Hemmer B. Lublin F. Rammohan K.W. Selmaj K. Traboulsee A. Sauter A. Masterman D. Fontoura P. Belachew S. Garren H. Mairon N. Chin P. Wolinsky J.S. ORATORIO Clinical InvestigatorsOcrelizumab versus Placebo in primary progressive multiple sclerosis.N. Engl. J. Med. 2017; 376: 209-220Crossref PubMed Scopus (1172) Google Scholar). Most of these infections were mild and moderate with the severe infections being bacterial in nature (pneumonia, urinary tract infections and cellulitis). We therefore feel that both cladribine and anti-CD20 therapies are relatively safe to use during the COVID-19 pandemic based on their profiles defined in phase 3 trials. The sphingosine-1-phosphate (S1P) modulators (fingolimod, siponimod, ozanimod, ponesimod) work by reducing the egress of lymphocytes from secondary lymphoid organs into the circulation (Stepanovska and Huwiler, 2019Stepanovska B. Huwiler A. Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseases.Pharmacol. Res. 2019; 104170PubMed Google Scholar). The actual degree of lymphopaenia is not associated with their efficacy nor the risk of infection (Francis et al., 2014Francis G. Kappos L. O'Connor P. Collins W. Tang D. Mercier F. Cohen J.A. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy.Mult. Scler. 2014; 20: 471-480Crossref PubMed Scopus (114) Google Scholar). Overall infectious complications are relatively low on S1P modulators, with opportunistic infections emerging over time (Epstein et al., 2018Epstein D.J. Dunn J. Deresinski S. Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management.Open Forum Infect. Dis. 2018; 5: ofy174Crossref PubMed Scopus (100) Google Scholar; Luna et al., 2019Luna G. Alping P. Burman J. Fink K. Fogdell-Hahn A. Gunnarsson M. Hillert J. Langer-Gould A. Lycke J. Nilsson P. Salzer J. Svenningsson A. Vrethem M. Olsson T. Piehl F. Frisell T. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies.JAMA Neurol. 2019; (https://doi.org/)https://doi.org/10.1001/jamaneurol.2019.3365Crossref PubMed Scopus (315) Google Scholar). Importantly, the vast majority of patients on S1P modulators do not have a problem dealing with community acquired viral infections. Patients on fingolimod who are exposed to and acquire exotic viral infections such as dengue fever seem to deal with them without complications (Fragoso et al., 2016aFragoso Y.D. Gama P.D.da Gomes S. Khouri J.M.N. Matta A.P. da C. Fernanda Mendes M. Stella C.R.A.V. Dengue fever in patients with multiple sclerosis taking fingolimod or natalizumab.Mult. Scler. Relat. Disord. 2016; 6: 64-65Abstract Full Text Full Text PDF PubMed Google Scholar). This is why patients on S1P modulators should be at relatively low risk of complications from COVID-19 infection and why it may be safe to continue these treatments during the epidemic. Fingolimod does however blunt vaccine responses (Kappos et al., 2015Kappos L. Mehling M. Arroyo R. Izquierdo G. Selmaj K. Curovic-Perisic V. Keil A. Bijarnia M. Singh A. von Rosenstiel P. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis.Neurology. 2015; 84: 872-879Crossref PubMed Scopus (124) Google Scholar) indicating that both the priming and effector arms of the immune system are affected, whether this will impact on COVID-19 outcomes is at present unknown. Although most neurologists consider natalizumab relatively safe there is a small increased risk of upper respiratory tract infections on this medication (Kapoor et al., 2018Kapoor R. Ho P.-R. Campbell N. Chang I. Deykin A. Forrestal F. Lucas N. Yu B. Arnold D.L. Freedman M.S. Goldman M.D. Hartung H.-P. Havrdová E.K. Jeffery D. Miller A. Sellebjerg F. Cadavid D. Mikol D. Steiner D. ASCEND investigatorsEffect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.Lancet Neurol. 2018; 17: 405-415Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar; Polman et al., 2006Polman C.H. O'Connor P.W. Havrdova E. Hutchinson M. Kappos L. Miller D.H. Theodore Phillips J. Lublin F.D. Giovannoni G. Wajgt A. Toal M. Lynn F. Panzara M.A. Sandrock A.W. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.N. Engl. J. Med. 2006; (https://doi.org/)https://doi.org/10.1056/nejmoa044397Crossref Google Scholar; Rudick et al., 2006Rudick R.A. Stuart W.H. Calabresi P.A. Confavreux C. Galetta S.L. Radue E.-W. Lublin F.D. Weinstock-Guttman B. Wynn D.R. Lynn F. Panzara M.A. Sandrock A.W. SENTINEL InvestigatorsNatalizumab plus interferon beta-1a for relapsing multiple sclerosis.N. Engl. J. Med. 2006; 354: 911-923Crossref PubMed Scopus (1188) Google Scholar) and there are theoretical reasons why it may reduce trafficking of lymphocytes in the lung and mucosa (Woodside and Vanderslice, 2008Woodside D.G. Vanderslice P. Cell adhesion antagonists: therapeutic potential in asthma and chronic obstructive pulmonary disease.BioDrugs. 2008; 22: 85-100Crossref PubMed Scopus (63) Google Scholar). It is clear that natalizumab blocks immune surveillance of the CNS, hence a person on natalizumab who develops a COVID-19 encephalitis could be in danger of major complications of this infection. The latter is analogous to PML, which is also a viral encephalitis, and similar to herpes-simplex and varicella -zoster encephalitis resulting from natalizumab exposure (Fine et al., 2013Fine A.J. Sorbello A. Kortepeter C. Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients.Clin. Infect. Dis. 2013; 57: 849-852Crossref PubMed Scopus (86) Google Scholar). Coronaviruses are potentially neurotropic and there has been one online case report of a 56-year old Chinese man developing COVID-19 encephalitis. He developed a decreased level of consciousness with a normal CT scan of the brain. Spinal fluid analysis revealed SARS-CoV-2. He subsequently made a recovery and was discharged (Xinhua, 2020Xinhua Beijing hospital confirms nervous system infections by novel coronavirus [WWW Document].XinhuaNet. 2020; (URL) (accessed 11.3.20)http://www.xinhuanet.com/english/2020-03/05/c_138846529.htmGoogle Scholar). There is also clear evidence from the large Chinese cohort that anosmia may be an early sign of COVID-19 infection, suggesting involvement of the neuraxis. Another human coronavirus HCoV-OC43, which is generally associated with mild upper respiratory tract infections, has been shown to have neuroinvasive properties. Studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis and cause persistent infections in human neural-cell lines (Arbour et al., 1999Arbour N. Côté G. Lachance C. Tardieu M. Cashman N.R. Talbot P.J. Acute and persistent infection of human neural cell lines by human coronavirus OC43.J. Virol. 1999; 73: 3338-3350Crossref PubMed Google Scholar). There are case reports identifying HCoV-OC43 RNA in the cerebrospinal fluid or brain of children with acute disseminated encephalomyelitis (Yeh et al., 2004Yeh E.A. Collins A. Cohen M.E. Duffner P.K. Faden H. Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis.Pediatrics. 2004; 113: e73-e76Crossref PubMed Scopus (253) Google Scholar) and acute encephalomyelitis (Morfopoulou et al., 2016Morfopoulou S. Brown J.R. Davies E.G. Anderson G. Virasami A. Qasim W. Chong W.K. Hubank M. Plagnol V. Desforges M. Jacques T.S. Talbot P.J. Breuer J. Human coronavirus OC43 associated with fatal encephalitis.N. Engl. J. Med. 2016; 375: 497-498Crossref PubMed Scopus (202) Google Scholar). Coronaviruses mutate very rapidly and hence may produce neurotropic strains quite quickly. The latter is a potential issue in the context of natalizumab, which creates an immune privileged site that may allow for the selection of these neurotropic mutants. Another aspect that needs to be considered is what happens in the gut. SARS-CoV-2 infects the gastrointestinal tract, with about 3–4% of people with COVID-19 developing diarrhoea (Guan et al., 2020Guan W.-J. Ni Z.-Y. Hu Y. Liang W.-H. Ou C.-Q. He J.-X. Liu L. Shan H. Lei C.-L. Hui D.S.C. Du B. Li L.-J. Zeng G. Yuen K.-Y. Chen R.-C. Tang C.-L. Wang T. Chen P.-Y. Xiang J. Li S.-Y. Wang J.-L. Liang Z.-J. Peng Y.-X. Wei L. Liu Y. Hu Y.-H. Peng P. Wang J.-M. Liu J.-Y. Chen Z. Li G. Zheng Z.-J. Qiu S.-Q. Luo J. Ye C.-J. Zhu S.-Y. Zhong N.-S. China Medical Treatment Expert Group for Covid-19Clinical characteristics of coronavirus disease 2019 in China.N. Engl. J. Med. 2020; (https://doi.org/)https://doi.org/10.1056/NEJMoa2002032Crossref Scopus (20093) Google Scholar). SARS-CoV-2 is shed in the stool (Holshue et al., 2020Holshue M.L. DeBolt C. Lindquist S. Lofy K.H. Wiesman J. Bruce H. Spitters C. Ericson K. Wilkerson S. Tural A. Diaz G. Cohn A. Fox L. Patel A. Gerber S.I. Kim L. Tong S. Lu X. Lindstrom S. Pallansch M.A. Weldon W.C. Biggs H.M. Uyeki T.M. Pillai S.K. Washington State 2019-nCoV Case Investigation TeamFirst case of 2019 novel coronavirus in the United States.N. Engl. J. Med. 2020; 382: 929-936Crossref PubMed Scopus (4257) Google Scholar). Natalizumab also reduces lymphocyte trafficking to the gut and is a licensed treatment for Crohn's disease (Ghosh et al., 2003Ghosh S. Goldin E. Gordon F.H. Malchow H.A. Rask-Madsen J. Rutgeerts P. Vyhnálek P. Zádorová Z. Palmer T. Donoghue S. Natalizumab Pan-European Study GroupNatalizumab for active Crohn's disease.N. Engl. J. Med. 2003; 348: 24-32Crossref PubMed Scopus (797) Google Scholar). Will patients on natalizumab and other DMTs have increased viral replication in the gut and shedding in the stool? Will patients on natalizumab and other DMTs infected with the virus become superspreaders? Despite these questions the current science indicates that patients on natalizumab should be able to deal with a novel viral infection such as dengue (Fragoso et al., 2016bFragoso Y.D. Gama P.D.da Gomes S. Khouri J.M.N. Matta A.P. da C. Fernanda Mendes M. Stella C.R.A.V. Dengue fever in patients with multiple sclerosis taking fingolimod or natalizumab.Mult. Scler. Relat. Disord. 2016; 6: 64-65Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Reassuringly, five patients on natalizumab infected with dengue virus cleared the virus without complications similar to those on fingolimod (Fragoso et al., 2016bFragoso Y.D. Gama P.D.da Gomes S. Khouri J.M.N. Matta A.P. da C. Fernanda Mendes M. Stella C.R.A.V. Dengue fever in patients with multiple sclerosis taking fingolimod or natalizumab.Mult. Scler. Relat. Disord. 2016; 6: 64-65Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Clearly, any decision to start a DMT during the COVID-19 pandemic will need to be taken carefully and will depend on the state of the COVID-19 pandemic, not only in the particular country concerned, but in the specific area the patient lives and receives therapy. For example, aggressive public health steps to contain the spread of the virus locally may make it relatively safe for a patient to start an immunosuppressive therapy. Our concern is that the COVID-19 pandemic may trigger a large number of neurologists and patients to reconsider treatment strategy and choice of initial DMT and to opt for less effective immunomodulatory DMTs. This change needs to be considered carefully. The COVID-19 pandemic in all likelihood will be short lived and it would be unfair to patients treated during the epidemic to be disadvantaged in the long term regarding the management of their MS. Neurologists have spent an extraordinary amount of time and effort to activate the MS community: to advance the principle that 'time is brain', to treat MS proactively to a target of no evident disease activity (NEDA) and more recently, to flip the pyramid and use higher efficacy treatments first line. These treatment principles are evidence-based and should not be thrown out in the context of a potential, but yet undefined, risk to our patients. Box 1Recommendations on the management of Italian MS patients during the COVID-19 epidemicsThese are recommendations made by neurologists and infectious diseases specialists whilst we have no evidence-based data at present.Treatment of MS patientsGiven the lack of knowledge or data on the COVID-19 disease course in MS patients receiving DMTs, at present there is no recommendation to stop the different DMTs and therefore expose MS patients to the risk of MS exacerbations. We, therefore, recommend continuing the current DMT specifically with:-First-line DMTs (beta-interferons, glatiramer acetate, teriflunomide or dimethyl fumarate). These DMTs can be prescribed as usual.-Fingolimod-NatalizumabFor 'lymphodepleting' DMTs: Any decisions about these DMTS should be based on individual circumstances.-Temporarily delay the start of lymphodepleting DMTs such as ocrelizumab, alemtuzumab, rituximab or cladribine.-Temporarily delay (between 6 and 12 months depending on the DMT) re-dosing of alemtuzumab, ocrelizumab and cladribine. This decision should be made according to individual factors such as disease severity and activity. For anti-CD2O DMTs it is recommended to delay the next dose even beyond 6 months if CD19+ and CD20+ lymphocyte counts are severely decreased at the time the next dose is due.-Some special considerations: for patients who have already received the first dose of the first cycle, it is recommended to give the second dose (i.e. complete the first cycle) and 'extra precautions' should be taken.Patients with confirmed COVID-19 infection: Withhold any first or second-line DMT until clinical resolution and/or approval to continue treatment by an infectious disease specialist. Note: given the potential antiviral activity of beta-interferons, the decision to continue this treatment rests with the treating neurologist.Symptoms of potential COVID-19 infection: headache, anosmia, fever, dry cough and asthenia.What to do in the event of COVID-19 symptoms?Instruct your patients not to attend accident and emergency services to avoid overcrowding and further spreading of the virus. Instruct your patients to call the local emergency number, describe their symptoms and wait for instructions.Evaluate the temporary withdrawal of current DMT based on the guidelines provided above.Recommendations for MS patients and healthcare professionals at MS centres:-If possible, avoid crowded places such as cinemas, theatres, schools, etc.-In high risk areas, restrict access to MS centres to MS patients only.-For patients on immunosuppressive infusion therapies, the use of protective surgical-grade masks is recommended.-If travelling long distances or using public transport is absolutely necessary, it is recommended to use protective masks and hand sanitizing (particularly for patients on fingolimod, alemtuzumab, ocrelizumab, cladribine or rituximab).-If possible, work from home.-Good personal hygiene is always important, specifically, it is recommended to wash your hands frequently, ideally in an alcohol-based gel (>60% alcohol).These recommendations are provided as a guideline only, please always refer to your local government advice. These recommendations are likely to change depending on the evolution of the epidemics. These are recommendations made by neurologists and infectious diseases specialists whilst we have no evidence-based data at present. Given the lack of knowledge or data on the COVID-19 disease course in MS patients receiving DMTs, at present there is no recommendation to stop the different DMTs and therefore expose MS patients to the risk of MS exacerbations. We, therefore, recommend continuing the current DMT specifically with:-First-line DMTs (beta-interferons, glatiramer acetate, teriflunomide or dimethyl fumarate). These DMTs can be prescribed as usual.-Fingolimod-Natalizumab For 'lymphodepleting' DMTs: Any decisions about these DMTS should be based on individual circumstances.-Temporarily delay the start of lymphodepleting DMTs such as ocrelizumab, alemtuzumab, rituximab or cladribine.-Temporarily delay (between 6 and 12 months depending on the DMT) re-dosing of alemtuzumab, ocrelizumab and cladribine. This decision should be made according to individual factors such as disease severity and activity. For anti-CD2O DMTs it is recommended to delay the next dose even beyond 6 months if CD19+ and CD20+ lymphocyte counts are severely decreased at the time the next dose is due.-Some special considerations: for patients who have already received the first dose of the first cycle, it is recommended to give the second dose (i.e. complete the first cycle) and 'extra precautions' should be taken. Patients with confirmed COVID-19 infection: Withhold any first or second-line DMT until clinical resolution and/or approval to continue treatment by an infectious disease specialist. Note: given the potential antiviral activity of beta-interferons, the decision to continue this treatment rests with the treating neurologist. Symptoms of potential COVID-19 infection: headache, anosmia, fever, dry cough and asthenia. Instruct your patients not to attend accident and emergency services to avoid overcrowding and further spreading of the virus. Instruct your patients to call the local emergency number, describe their symptoms and wait for instructions. Evaluate the temporary withdrawal of current DMT based on the guidelines provided above. Recommendations for MS patients and healthcare professionals at MS centres:-If possible, avoid crowded places such as cinemas, theatres, schools, etc.-In high risk areas, restrict access to MS centres to MS patients only.-For patients on immunosuppressive infusion therapies, the use of protective surgical-grade masks is recommended.-If travelling long distances or using public transport is absolutely necessary, it is recommended to use protective masks and hand sanitizing (particularly for patients on fingolimod, alemtuzumab, ocrelizumab, cladribine or rituximab).-If possible, work from home.-Good personal hygiene is always important, specifically, it is recommended to wash your hands frequently, ideally in an alcohol-based gel (>60% alcohol). These recommendations are provided as a guideline only, please always refer to your local government advice. These recommendations are likely to change depending on the evolution of the epidemics.

Background: Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75(ECD) levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75(ECD) measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.

Background: Epstein Barr Virus (EBV) infection is closely associated with multiple sclerosis (MS), but the relationship between viral load and disease activity is unclear. This study tested the observed levels of salivary EBV in MS, as a first step in investigating this relationship. Methods: Real-time quantitative PCR (qPCR) was used to measure EBV DNA levels in saliva samples from three separate Multiple Sclerosis (MS) patient cohorts. Results: The qPCR assay was used to delineate EBV shedding, defined here as a reliably detectable level of extracellular EBV DNA in saliva. Frequency of EBV shedding was found to be similar across the groups, with 20-25% of subjects releasing virus on any given sampling date. Diurnal variation in EBV count was tested in one of the cohorts, in which 26% of subjects showed more than a 10-fold difference between the highest and lowest EBV levels on a single day. In the same cohort, elevated viral levels at one time point did not predict elevated viral levels at a subsequent time point. Conclusions: These results indicate that EBV lyric activity in a subject cannot be inferred from a single measure of EBV in saliva. Also, subjects do not appear to be behave constantly as "EBV shedders" or "non-shedders". The assay is useful in giving a clear indication of salivary gland EBV lyric activity across a patient cohort - for example, in testing anti-viral drugs in MS.

Background: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. Objectives: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. Methods: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1 beta, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. Conclusions: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.

The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

Background: The exponential growth in the reach and development of new technologies over the past decade means that mobile technologies and social media play an increasingly important role in service delivery models to maximise HIV testing and access to treatment and care. This systematic review examines the impact of electronic and mobile technologies in medical care (eHealth) in the linkage to and retention of priority populations in the HIV treatment and care cascade, focussing on the Asia-Pacific region. Methods: The review was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement from the Cochrane Collaboration guidelines. Both grey and published scientific literature from five different databases were searched for all original articles in English published from 2010 to 2017. Studies conducted outside the Asia-Pacific region or not including HIV priority populations were excluded. The methodological quality of studies included in the review was assessed using the Quality Assessment Tool for Quantitative Studies. Results: The database search identified 7309 records. Of the 224 peer-reviewed articles identified for full text review, 16 studies from seven countries met inclusion criteria. Six cross sectional studies found evidence to support the use of eHealth, via text messages, instant messaging, social media and health promotion websites, to increase rates of HIV testing and re-testing among men who have sex with men (MSM). Evidence regarding the efficacy of eHealth interventions to improve antiretroviral treatment (ART) adherence was mixed, where one randomised controlled trial (RCT) showed significant benefit of weekly phone call reminders on improving ART adherence. Three further RCTs found that biofeedback eHealth interventions that provided estimated ART plasma concentration levels, showed promising results for ART adherence. Conclusions: This review found encouraging evidence about how eHealth can be used across the HIV treatment and care cascade in the Asia-Pacific region, including increasing HIV testing and re-testing in priority populations as well as ART adherence. eHealth interventions have an important role to play in the movement towards the end of AIDS, particularly to target harder-to-reach HIV priority populations, such as MSM.

The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.

In recent times the world has faced several potential pandemics – SARS, avian (bird) flu, swine flu, and most recently Ebola. The risk of a disease pandemic presents an important challenge for social marketing –to this point, health-related social marketing has focused on chronic diseases (such as cancer, asthma, obesity) and their risk factors (such as tobacco use, physical inactivity, and dietary intake). In the communicable disease field, most of the challenges we have addressed have had simple and proven preventive strategies (such as immunisation and the use of condoms). However, emerging pandemic diseases pose new challenges – notably in the global scale of the threat, the rapid nature of transmission, and (often) the absence of a known cure or vaccine. In this context, people’s quality of life has scope to be shaped by immense physical and social influences. This chapter reports on a comprehensive study undertaken to inform government policy and practice in the event of an avian influenza pandemic – specifically how to prepare (but not panic) the general public. The research phases included: a media analysis of coverage of a potential pandemic; extensive qualitative formative research; two population CATI surveys; two airport intercept surveys; message development; and message testing. While this research was undertaken in the context of a specific disease, the findings and recommendations are equally relevant to current and future pandemic threats.

Objectives Even though multiple sclerosis (MS) and HIV infection are well-documented conditions in clinical medicine, there is only a single case report of a patient with MS and HIV treated with HIV antiretroviral therapies. In this report, the patient's MS symptoms resolved completely after starting combination antiretroviral therapy and remain subsided for more than 12 years. Authors hypothesised that because the pathogenesis of MS has been linked to human endogenous retroviruses, antiretroviral therapy for HIV may be coincidentally treating or preventing progression of MS. This led researchers from Denmark to conduct an epidemiological study on the incidence of MS in a newly diagnosed HIV population (5018 HIV cases compared with 50 149 controls followed for 31 875 and 393 871 person-years, respectively). The incidence rate ratio for an HIV patient acquiring MS was low at 0.3 (95% CI 0.04 to 2.20) but did not reach statistical significance possibly due to the relatively small numbers in both groups. Our study was designed to further investigate the possible association between HIV and MS. Methods We conducted a comparative cohort study accessing one of the world’s largest linked medical data sets with a cohort of 21 207 HIV-positive patients and 5 298 496 controls stratified by age, sex, year of first hospital admission, region of residence and socioeconomic status and ‘followed up’ by record linkage. Results Overall, the rate ratio of developing MS in people with HIV, relative to those without HIV, was 0.38 (95% CI 0.15 to 0.79). Conclusions HIV infection is associated with a significantly decreased risk of developing MS. Mechanisms of this observed possibly protective association may include immunosuppression induced by chronic HIV infection and antiretroviral medications.

A 58-year old white female with multiple sclerosis was treated with antiretroviral therapy (ART) of raltegravir and lamividine. Over two years prior to the commencement of ART the patient reported progressive worsening of weakness in right arm and legs requiring use of a walking stick, burning sensations in limbs and persistent fatigue. MRI showed areas of demyelination in the spine but without involvement of the brain. CSF analysis showed oligoclonal IgG bands. The /INS;patient was treated with interferon beta for seven years but it was stopped due to disease progression. No other disease modifying therapy had been used.