A Structured Telephone Interview for collecting Geriatric health domains in Older People with HIV during COVID era (preprint)

Background Elderly people living with HIV show a significant prevalence of multimorbidity, polypharmacy and frailty that increase the risk of disability. Telehealth has been suggested as a new tool to monitor people living with HIV in the COVID era, but its effectiveness in elderly is unknown. The aim of this study was two-fold: to explore feasibility of a telephone interview and its capability to collect relevant geriatric outcomes. Methods Assessed health domains included comorbidities, falls, urinary incontinence, antiretroviral drugs exposure and comedications (polypharmacy), and the following patient reported outcomes: quality of life, intrinsic capacity, and resilience. Results 214 (70.6%) answered and completed the interview. During confinement period, 57 (26.7%) of people switched antiretroviral therapy : 119 (55.4%) to dual therapy regimens and 95 (44.6%) to triple regimens. Prevalence of geriatric syndromes were falls in 31 cases (14.7%), urinary incontinence in 48 cases (22.7%) and polypharmacy 122 cases (57.2%). Mean Health-related Quality of Life score was mildly impaired (0,88%) with good concordance of Helath-related Quality of Life self-perception in a visual analogue scale (8/10) (r=+0.348; p <0.01). Intrinsic capacity depicted impaired functional ability in multiple domains (0.737 ) and Resilience (CD-RISC) was suboptimal (0.6). Conclusions A structured telephone call was feasible in elderly people living with HIV and allowed to collect clinically meaningful geriatric health domains when face-to-face visits are not needed or discouraged.

Transient Plasma Viral Rebound After Sars-cov-2 Vaccination in an Exceptional Hiv-1 Elite Controller Woman (preprint)

Background Elite controllers are able to control viral replication without antiretroviral therapy. Exceptional elite controllers do not show disease progression for more than 25 years. Different mechanisms have been proposed and several elements of both innate and adaptive immunity are implicated. Vaccines are immune stimulating agents that can promote HIV-RNA transcription; transient plasma HIV-RNA detectability has been described within 7-14 days after different vaccinations. The most reliable mechanism involved in virosuppressed people living with HIV is a generalized inflammatory response that activates bystander cells harboring latent HIV. So far no data about viral load increase in elite controllers after SARS-CoV-2 vaccination are reported in literature. Case Presentation We report the case of a 65-year-old woman of European ancestry, diagnosed with HIV-1/HCV co-infection more than 25 years ago. Since then, HIV-RNA remained undetectable and she never received ARV therapy. In 2021 she was vaccinated with mRNA-BNT162b2 vaccine (Pfizer-BioNTech®). She was administered with three doses in June, July and October 2021, respectively. The last available viral load was undetectable in March 2021. We observed an increase of VL at 32 cp/ml and 124 cp/mL, two and seven months after the first vaccine dose, respectively. During monthly follow-up, HIV-RNA gradually and spontaneously dropped becoming undetectable without ARV intervention. COVID-19 serology was positive with IgG 535 BAU/mL, showing response to vaccination. We measured total HIV-DNA at different time-points and we found it detectable both at the time of the higher plasma HIV-RNA (30 cp/10^6 PBMCs) and when it was undetectable (13 cp/10^6 PBMCs), in reduction. Conclusions This case is the first report, to our knowledge, describing a rebound of plasma HIV-RNA in an elite controller after three doses of mRNA-BNT162b2 vaccine for SARS-CoV-2. Concomitantly with a spontaneous reduction of plasma HIV-RNA ten months after the third dose of mRNA-BNT162b2 vaccine (Pfizer-BioNTech®) without antiretroviral therapy intervention, we observed a reduction of total HIV-DNA in peripheral mononuclear cells. The potential role of vaccinations in altering HIV reservoir, even in elite controllers population when plasma HIV-RNA is undetectable, could be a valuable aspect to take into account for the future HIV eradication interventions.

GRAd-COV2 vaccine provides potent and durable immunity in a randomised placebo-controlled phase 2 trial (COVITAR) (preprint)

Background. SARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method. 917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. Results. The safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. Conclusion. GRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses.

Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Pneumonia (preprint)

Rationale There are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation. Objective Evaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia. Methods A randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days. Main Outcome Measurements Primary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days. Main Results Pre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2 levels at or below the median value ([≤]60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with [≤]60% FIO2 at baseline that no longer required supplemental oxygen (at least 24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed. Conclusions Post-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen ([≤]60% FiO2). Further studies are warranted.

Diagnostic SARS-CoV-2 Cycle Threshold Value Predicts Disease Severity, Survival and 6-month Sequelae in COVID-19 Symptomatic Patients (preprint)

Background: No pathogen-specific prognostic biomarkers are yet available for SARS-CoV-2. We sought to assess whether SARS-CoV-2 cycle threshold value (Ct) at diagnosis may predict COVID-19 severity, clinical manifestations and 6-month sequelae. Methods: Hospitalised and outpatient cases were randomly sampled from the diagnoses of March and data collected after 6 months by interview and from the regional database for COVID-19 emergency. Patients were stratified according to their RNA-dependent-RNA-polymerase Ct in the nasal-pharyngeal swab at diagnosis: group A≤20.0, 20.028.0. Disease severity was classified according to a composite scale evaluating hospital admission, worst oxygen support required and survival. Results: One-hundred sixty-eight survivors and thirty-two deceased patients were included: 27.5% in A and B both, 45.0% in C. 90% of patients were symptomatic and 63.7% were hospitalised. Median time from COVID-19 onset to swab collection was 5 days. Lethality, number of comorbidities, disease severity, type and amount of signs and symptoms, as well as 6-month sequelae inversely distributed among the groups with respect to SARS-CoV-2 Ct. After adjusting for confounding, SARS-CoV-2 Ct at diagnosis was still associated with COVID-19-related death (p=0.023), disease severity (p=0.023), amount of signs and symptoms (p<0.01) and presence of sequelae (p<0.01). Conclusions: Early quantification of SARS-CoV-2 along the course of the disease may be a useful predictive marker to inform differential strategies of clinical management and resource allocation.

The longest persistence of viable SARS-CoV-2 with recurrence of viremia and relapsing symptomatic COVID-19 in an immunocompromised patient - a case study (preprint)

BackgroundImmunocompromised patients show prolonged shedding of SARS-CoV-2 in nasopharyngeal swabs. We report a case of a prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of COVID-19 in a lymphoma patient. MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by Real time-PCR (RT-PCR). On five positive nasopharyngeal swabs, we performed viral culture and next generation sequencing. We analysed the patients adaptive and innate immunity to characterize T and NK cell subsets. FindingsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive with cycle threshold mean values of 22 {+/-} 1{middle dot}3 for over 8 months. All five performed viral cultures were positive and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in three out of four COVID-19 clinical relapses and cleared each time after remdesivir treatment. T and NK cells dynamic was different in aviremic and viremic samples and no SARS-CoV-2 specific antibodies were detected throughout the disease course. InterpretationIn our patient, SARS-CoV-2 persisted with proven infectivity for over eight months. Viremia was associated with COVID-19 relapses and remdesivir treatment was effective in viremia clearance and symptoms remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood that are probably recruited in inflammatory tissue for viral eradication. In addition we found a high level of NK cells repertoire perturbation with a relevant involvement during SARS-CoV-2 viremia. FundingNone.