Feasibility of an Intervention to Support Hearing and Vision in Dementia:The SENSE-Cog Field Trial

OBJECTIVES: People with dementia (PwD) frequently experience hearing and vision impairment that is underrecognized and undertreated, resulting in reduced quality of life. Managing these impairments may be an important strategy to improve outcomes in PwD. Our objective was to field-trial a multifaceted sensory intervention (SI) to enhance hearing and vision in PwD. DESIGN: An international single-arm open-label feasibility, acceptability, and tolerability study. SETTING: Home-based setting in the United Kingdom, France, and Cyprus. PARTICIPANTS: Adults aged 60 years and older with mild-to-moderate dementia and uncorrected or suboptimally corrected hearing and/or vision impairment, and their study partners (n = 19 dyads). INTERVENTION: A sensory intervention (SI), comprising assessment of hearing and vision, fitting of corrective devices (glasses, hearing aids), and home-based support from a sensory support therapist for device adherence and maintenance, communication training, referral to support services, environmental sensory modification, and optimization of social inclusion. MEASUREMENTS: Ratings of study procedure feasibility, and intervention acceptability/tolerability, ascertained through questionnaires, participant diaries, therapist logbooks, and semistructured interviews. RESULTS: We successfully delivered all intervention components, and these were received and enacted as intended in all those who completed the intervention. No serious adverse events were reported. Acceptability (ie, understanding, motivation, sense of achievement) and tolerability (ie, effort, fatigue) ratings of the intervention were within a priori target ranges. We met recruitment and retention (93.8%) targets in two of the three sites. Participants completed more than 95% of diary entries, representing minimal missing data. Delays in the logistics circuit for the assessment and delivery of hearing aids and glasses were identified, requiring modification. The need for minor modifications to some outcome measures and the inclusion criteria were identified. CONCLUSION: This is the first study combining home-based hearing and vision remediation in PwD. The positive feasibility, acceptability, and tolerability findings suggest that a full-scale efficacy trial, with certain modifications, is achievable

PLoS Pathog

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models

Int J Geriatr Psychiatry

Objectives Hearing, vision, and cognitive impairment commonly co‐occur in older adults. Improving sensory function may positively impact outcomes in people with dementia (PwD). We developed a “sensory intervention” (SI) to support hearing and vision in PwD. Here, we report the findings of an international open‐label field trial, and nested case series, to explore the impact of the SI on dementia‐related outcomes. Methods This was a home‐based trial conducted in France, England, and Cyprus. Participants were people with mild‐to‐moderate dementia and hearing and/or vision impairment (n = 19) and their study partners (unpaid carers; n = 19). The “basic” SI included a hearing and vision assessment and provision of glasses and/or hearing aids. A subsample received the “extended” SI with additional weekly visits from a sensory support therapist (SST). Exploratory analyses of dementia‐related, health utility and resource utilisation outcomes were performed. Results Quality of life (QoL) and sensory functional ability improved. Change in QoL exceeded the threshold for a minimum clinically important difference. There was a modest improvement (in absolute terms) post intervention in behavioural disturbance, self‐efficacy, and relationship satisfaction. Study partner time assisting instrumental activities of daily living (iADL) and supervision decreased by about 22 and 38 hours per month, respectively, although time for personal ADL support increased. Qualitative data supported effectiveness of the intervention: PwD were more socially engaged, less isolated, less dependent on study partners, and had improved functional ability and communication. Conclusions These findings support the need for a definitive randomised controlled trial (RCT) to evaluate the effectiveness of the intervention

J Virol

The HIV-2 long terminal repeat (LTR) region contains several transcription factor (TF) binding sites. Efficient LTR transactivation by cellular TF and viral proteins is crucial for HIV-2 reactivation and viral production. Proviral LTRs from 66 antiretroviral-naive HIV-2-infected patients included in the French ANRS HIV-2 CO5 Cohort were sequenced. High genetic variability within the HIV-2 LTR was observed, notably in the U3 subregion, the subregion encompassing most known TF binding sites. Genetic variability was significantly higher in HIV-2 group B than in group A viruses. Notably, all group B viruses lacked the peri-ETS binding site, and 4 group B sequences (11%) also presented a complete deletion of the first Sp1 binding site. The lack of a peri-ETS binding site was responsible for lower transcriptional activity in activated T lymphocytes, while deletion of the first Sp1 binding site lowered basal or Tat-mediated transcriptional activities, depending on the cell line. Interestingly, the HIV-2 cellular reservoir was less frequently quantifiable in patients infected by group B viruses and, when quantifiable, the reservoirs were significantly smaller than in patients infected by group A viruses. Our findings suggest that mutations observed in vivo in HIV-2 LTR sequences are associated with differences in transcriptional activity and may explain the small cellular reservoirs in patients infected by HIV-2 group B, providing new insight into the reduced pathogenicity of HIV-2 infection. IMPORTANCE Over 1 million patients are infected with HIV-2, which is often described as an attenuated retroviral infection. Patients frequently have undetectable viremia and evolve at more slowly toward AIDS than HIV-1-infected patients. Several studies have reported a smaller viral reservoir in peripheral blood mononuclear cells in HIV-2-infected patients than in HIV-1-infected patients, while others have found similar sizes of reservoirs but a reduced amount of cell-associated RNA, suggesting a block in HIV-2 transcription. Recent studies have found associations between mutations within the HIV-1 LTR and reduced transcriptional activities. Until now, mutations within the HIV-2 LTR region have scarcely been studied. We conducted this research to discover if such mutations exist in the HIV-2 LTR and their potential association with the viral reservoir and transcriptional activity. Our study indicates that transcription of HIV-2 group B proviruses may be impaired, which might explain the small viral reservoir observed in patients

A New Mechanism of Resistance of Human Immunodeficiency Virus Type 2 to Integrase Inhibitors: A 5-Amino-Acid Insertion in the Integrase C-Terminal Domain

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2. METHODS: We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations. RESULTS: Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change). CONCLUSIONS: Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen

Feasibility of an Intervention to Support Hearing and Vision in Dementia: The SENSE-Cog Field Trial

Objectives: People with dementia (PwD) frequently experience hearing and vision impairment that is underrecognized and undertreated, resulting in reduced quality of life. Managing these impairments may be an important strategy to improve outcomes in PwD. Our objective was to field-trial a multifaceted sensory intervention (SI) to enhance hearing and vision in PwD. Design: An international single-arm open-label feasibility, acceptability, and tolerability study. Setting: Home-based setting in the United Kingdom, France, and Cyprus. Participants: Adults aged 60 years and older with mild-to-moderate dementia and uncorrected or suboptimally corrected hearing and/or vision impairment, and their study partners (n = 19 dyads). Intervention: A sensory intervention (SI), comprising assessment of hearing and vision, fitting of corrective devices (glasses, hearing aids), and home-based support from a sensory support therapist for device adherence and maintenance, communication training, referral to support services, environmental sensory modification, and optimization of social inclusion. Measurements: Ratings of study procedure feasibility, and intervention acceptability/tolerability, ascertained through questionnaires, participant diaries, therapist logbooks, and semistructured interviews. Results: We successfully delivered all intervention components, and these were received and enacted as intended in all those who completed the intervention. No serious adverse events were reported. Acceptability (ie, understanding, motivation, sense of achievement) and tolerability (ie, effort, fatigue) ratings of the intervention were within a priori target ranges. We met recruitment and retention (93.8%) targets in two of the three sites. Participants completed more than 95% of diary entries, representing minimal missing data. Delays in the logistics circuit for the assessment and delivery of hearing aids and glasses were identified, requiring modification. The need for minor modifications to some outcome measures and the inclusion criteria were identified. Conclusion: This is the first study combining home-based hearing and vision remediation in PwD. The positive feasibility, acceptability, and tolerability findings suggest that a full-scale efficacy trial, with certain modifications, is achievable

Individualised sensory intervention to improve quality of life in people with dementia and their companions (SENSE-Cog trial): study protocol for a randomised controlled trial

BackgroundHearing and vision impairments are highly prevalent in people with dementia and may have a negative impact on quality of life and other dementia-related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia-related outcomes. The SENSE-Cog trial will test whether a home-based multi-part sensory intervention is effective in improving quality of life and other key outcomes in people with dementia and hearing or vision problems (or both) and their companions.MethodsThis is anEuropean, multi-centre, observer-blind, pragmatic, randomised controlled trial. Three hundred fifty four people with dementia and hearing or vision impairment (or both) and their companions will be randomly assigned to receive either care as usual or a multi-component sensory intervention including assessment and correction of hearing or vision impairments (or both), home-based (maximum 10 visits over 18weeks), therapist-delivered sensory support (that is, adherence to devices; improving the sensory environment (that is, lighting), communication training, and sign-posting to other support agencies). Change from baseline to intervention end (18weeks) and post-intervention (36weeks) will be compared between the two arms in the following outcomes: quality of life (primary endpoint), sensory and cognitive functional ability, relationships, mental well-being, health resource utilisation and cost-effectiveness.DiscussionThis is one of two articles outlining the SENSE-Cog trial. Here, we describe the protocol for the effectiveness of the SENSE-Cog intervention. A parallel and complementary process evaluation will be described elsewhere. If the SENSE-Cog trial demonstrates that the sensory intervention improves outcomes in dementia, we will make a toolkit of training materials, resources and information available to health and social care providers to implement the intervention in routine practice. This will be a significant contribution to the therapeutic management of people with dementia and sensory impairment.Trial registrationISRCTN (Trial ID: ISRCTN17056211) on 19 February 2018

Clin Infect Dis

Background: New options for first-line treatment of HIV-2 infection are needed. We evaluated an integrase inhibitor (raltegravir)-containing regimen. Methods: ART-naive adults infected with HIV-2 only and history of CDC group B or C event, or a CD4 count 50 cells/muL/year over the past 3 years, or a confirmed plasma HIV-2 RNA (pVL) >/=100 copies (cp)/mL were eligible for this non-comparative trial. The composite primary endpoint was survival at 48 weeks (W48) without any of the following: CD4 gain from baseline /=40 cp/mL from W24, raltegravir permanent discontinuation, incident B or C event. HIV-2 ultrasensitive pVL (uspVL) and total DNA were assessed using "in-house" PCR assays. Results: Baseline median CD4 count of 30 enrolled individuals (67% women) was 436 cells/microL (InterQuartile Range[IQR] 314- 507); pVL was >/=40 cp/mL in 20/30 (67%); uspVL was >/=5 cp/mL in 23/25 (92%); total DNA was >6 cp/PCR in 8/25 (32%). At W48, the composite endpoint of success was reached in 12/30 (40%; 95% Confidence Interval 22.7 to 59.4). Failure was mainly due to CD4 gain 6 cp/PCR in 3/26 (12%). Median CD4 gain was +87 cells/microL (IQR +38- +213, n=28). No serious adverse reaction was reported. Conclusion: Raltegravir-containing cART is a safe option for first line treatment of HIV-2 infection, yielding a comparable success rate to protease inhibitors. UspVL and total DNA were undetectable in the vast majority of participants