Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is an underdiagnosed, progressive, and fatal multisystemic disease with a heterogenous clinical phenotype that is caused by TTR gene mutations that destabilize the TTR protein, resulting in its misfolding, aggregation, and deposition in tissues throughout the body. Areas covered: Inotersen, an antisense oligonucleotide inhibitor, was recently approved in the United States and Europe for the treatment of the polyneuropathy of ATTRv based on the positive results obtained in the pivotal phase 3 trial, NEURO-TTR. This review will discuss the mechanism of action of inotersen and its pharmacology, clinical efficacy, and safety and tolerability. A PubMed search using the terms 'inotersen,' 'AG10,' 'antisense oligonucleotide,' 'hereditary transthyretin amyloidosis,' 'familial amyloid polyneuropathy,' and 'familial amyloid cardiomyopathy' was performed, and the results were screened for the most relevant English language publications. The bibliographies of all retrieved articles were manually searched to identify additional studies of relevance. Expert opinion: Inotersen targets the disease-forming protein, TTR, and has been shown to improve quality of life and neuropathy progression in patients with stage 1 or 2 ATTRv with polyneuropathy. Inotersen is well tolerated, with a manageable safety profile through regular monitoring for the development of glomerulonephritis or thrombocytopenia

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands)

Assessment of a viral load result-triggered automated differentiated service delivery model for people taking ART in Lesotho (the VITAL study): study protocol of a cluster-randomized trial

INTRODUCTION: To sustainably provide good quality care to increasing numbers of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in resource-limited settings, care delivery must shift from a "one-size-fits-all" approach to differentiated service delivery models. Such models should reallocate resources from PLHIV who are doing well to groups of PLHIV who may need more attention, such as those with treatment failure. The VIral load Triggered ART care Lesotho (VITAL) trial assesses a viral load (VL)-, participant's preference-informed, electronic health (eHealth)-supported, automated differentiated service delivery model (VITAL model). With VITAL, we aim to assess if the VITAL model is at least non-inferior to the standard of care in the proportion of participants engaged in care with viral suppression at 24 months follow-up and if it is cost-saving. METHODS: The VITAL trial is a pragmatic, multicenter, cluster-randomized, non-blinded, non-inferiority trial with 1:1 allocation conducted at 18 nurse-led, rural health facilities in two districts of northern Lesotho, enrolling adult PLHIV taking ART. In intervention clinics, providers are trained to implement the VITAL model and are guided by a clinical decision support tool, the VITALapp. VITAL differentiates care according to VL results, clinical characteristics, sub-population and participants' and health care providers' preferences. EXPECTED OUTCOMES: Evidence on the effect of differentiated service delivery for PLHIV on treatment outcomes is still limited. This pragmatic cluster-randomized trial will assess if the VITAL model is at least non-inferior to the standard of care and if it is cost saving. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov (Registration number NCT04527874; August 27, 2020)