Perspectives on unhealthy alcohol use among men who have sex with men prescribed HIV pre-exposure prophylaxis: A qualitative study.

Unhealthy alcohol use is a common, often unaddressed behavior associated with increased risk for acquisition of HIV and may also be associated with decreased adherence to oral pre-exposure prophylaxis (PrEP) among gay, bisexual, and other men who have sex with men (MSM) living in the United States. To inform future alcohol-reduction interventions among individuals engaging in PrEP care, we sought to explore perspectives on alcohol use, PrEP adherence, and the acceptability of alcohol use treatment options for MSM prescribed oral formulations of PrEP in the Northeastern United States. Between February 2019 and July 2020, we conducted semi-structured interviews with 15 MSM without HIV who were prescribed PrEP and screened positive for unhealthy alcohol use with AUDIT-C ≥ 4 and were receiving care in Providence, Rhode Island or New Haven, Connecticut. Interviews were coded and analyzed using thematic analysis. Three themes emerged: 1) Consequences of fluctuations in drinking 2) Alcohol use negatively impacts health and relationships; and 3) Desire for a multimodal approach to treatment of unhealthy alcohol use. Our findings support the need to raise awareness of potential alcohol-related harms, address the spectrum of unhealthy alcohol use among MSM prescribed PrEP, and the acceptability and preferences for alcohol reduction interventions within PrEP programs.

Pharmacokinetic evaluation of sofosbuvir/velpatasvir for the treatment of Chronic Hepatitis C in pediatrics aged 3 and older.

INTRODUCTION: The World Health Organization proposed targets to eliminate hepatitis C virus (HCV) by 2030, aiming to treat ≥80% of people with HCV, decreasing new chronic infections by 90% and liver-related mortality by 65%. While children/adolescents represent a minority of cases, the true burden is underestimated. Advances in drug development have resulted in simplified treatments that are well-tolerated, effective, and pangenotypic in activity. Sofosbuvir/velpatasvir, a combined nucleotide analog NS5B polymerase inhibitor and NS5A inhibitor, respectively, is approved for HCV treatment for individuals ≥3 years, supported by safety data using lower-dose, novel formulations. AREAS COVERED: This review discusses chemistry, pharmacokinetics/pharmacodynamics, dosing, efficacy, and safety of sofosbuvir/velpatasvir highlighting pediatric data. Literature review included publications/conference abstracts from PubMed, Google, and Google Scholar. Information from key clinical trials/regulatory approvals is reviewed. EXPERT OPINION: Sofosbuvir/velpatasvir is a safe and effective therapy for the treatment of pangenotypic chronic HCV infection with limited cases of virologic relapse and adverse events among pediatric populations aged 3 years and older. However, the tolerability among children less than 6 years could be improved by alternative formulations, if not, shorter treatment durations. An aspirational role of direct-acting antivirals (DAAs) that should be explored is for the prevention of infection in exposed and at-risk pediatric populations.

Acute cytomegalovirus proctitis and epididymitis acquired via sexual transmission in an immunocompetent patient: a case report.

BACKGROUND: We present a case report of an immunocompetent host with presumed sexually transmitted cytomegalovirus proctitis and epididymitis, where there currently is a sparsity of published data. CASE PRESENTATION: A 21-year-old previously healthy Caucasian individual was admitted for severe rectal and testicular pain in the setting of proctitis and epididymitis. Serology and rectal pathology confirmed acute primary cytomegalovirus infection. CONCLUSIONS: This report details his diagnostic workup and highlights cytomegalovirus as a rare cause of sexually transmitted disease among immunocompetent persons.

Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.

A continent-wide effort and solidarity at curbing COVID-19 pandemic: the Africa task force for novel coronavirus (AFTCOR) infection prevention and control technical working group's experience.

A continent-wide Africa Task Force for Coronavirus with its six technical working groups was formed to prepare adequately and respond to the novel Coronavirus disease (COVID-19) outbreak in Africa. This research in practice article aimed to describe how the infection prevention and control (IPC) technical working group (TWG) supported Africa Centre for Disease Control and Prevention (Africa CDC) in preparedness and response to COVID-19 on the continent. To effectively address the multifaceted IPC TWG mandate of organizing training and implementing rigorous IPC measures at healthcare service delivery points, the working group was sub-divided into four sub-groups-Guidelines, Training, Research, and Logistics. The action framework was used to describe the experiences of each subgroup. The guidelines subgroup developed 14 guidance documents and two advisories; all of which were published in English. In addition, five of these documents were translated and published in Arabic, while three others were translated and published in French and Portuguese. Challenges faced in the guidelines subgroup included the primary development of the Africa CDC website in English, and the need to revise previously issued guidelines. The training subgroup engaged the Infection Control Africa Network as technical experts to carry out in-person training of IPC focal persons and port health personnel across the African continent. Challenges faced included the difficulty in conducting face-to-face IPC training and onsite technical support due to the lockdown. The research subgroup developed an interactive COVID-19 Research Tracker on the Africa CDC website and conducted a context-based operation and implementation research. The lack of understanding of Africa CDC's capacity to lead her own research was the major challenge faced by the research subgroup. The logistics subgroup assisted African Union (AU) member states to identify their IPC supply needs through capacity building for IPC quantification. A notable challenge faced by the logistics subgroup was the initial lack of experts on IPC logistics and quantifications, which was later addressed by the recruitment of professionals. In conclusion, IPC cannot be built overnight nor can it be promoted abruptly during outbreaks of diseases. Thus, the Africa CDC should build strong national IPC programmes and support such programmes with trained and competent professionals.

Outcomes of pregnant women exposed to Sotrovimab for the treatment of COVID-19 in the BA.1 Omicron predominant era (PRESTO).

BACKGROUND: Sotrovimab, a monoclonal antibody with efficacy against SARS-CoV-2 including certain Omicron variants, has been used in treatment of mild-moderate COVID-19. Limited data exists regarding its use in pregnant women. METHODS: Electronic medical record review of pregnant COVID-19 patients treated with sotrovimab from 12/30/21 - 1/31/22 (Yale New Haven Health Hospital System [YNHHS]) was performed. Included were pregnant individuals ≥ 12 years, weighing ≥ 40 kg, with positive SARS-CoV-2 test (within 10 days). Those receiving care outside YNHHS or receiving other SARS-CoV-2 treatment were excluded. We assessed demographics, medical history, and Monoclonal Antibody Screening Score (MASS). The primary composite clinical outcome assessed included emergency department (ED) visit < 24 h, hospitalization, intensive care unit (ICU) admission, and/or death within 29 days of sotrovimab. Secondarily, adverse feto-maternal outcomes and events for neonates were assessed at birth or through the end of the study period, which was 8/15/22. RESULTS: Among 22 subjects, median age was 32 years and body mass index was 27 kg/m2. 63% were Caucasian, 9% Hispanic, 14% African-American, and 9% Asian. 9% had diabetes and sickle cell disease. 5% had well-controlled HIV. 18%, 46%, and 36% received sotrovimab in trimester 1, 2, and 3, respectively. No infusion/allergic reactions occurred. MASS values were < 4. Only 12/22 (55%) received complete primary vaccination (46% mRNA-1273; 46% BNT162b2; 8% JNJ-78,436,735); none received a booster. CONCLUSIONS: Pregnant COVID-19 patients receiving sotrovimab at our center tolerated it well with good clinical outcomes. Pregnancy and neonatal complications did not appear sotrovimab-related. Though a limited sample, our data helps elucidate the safety and tolerability of sotrovimab in pregnant women.

Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant HIV infection and limited treatment options.

INTRODUCTION: Lenacapavir, the compound reviewed in this paper, is a novel, potent, and long-acting first-in-class HIV-1 capsid inhibitor that was granted a breakthrough therapy designation for HIV treatment by the U.S. Food and Drug Administration in May 2019. Lenacapavir was subsequently approved, in combination with other antiretroviral agents, for the treatment of multidrug-resistant HIV in people with HIV who have limited treatment options due to safety, intolerance, and resistance considerations, based on clinical trial data, which demonstrated its efficacy, tolerability, and safety for that population. AREAS COVERED: This review draws upon published and unpublished data of lenacapavir (GS-6207) to discuss its chemistry, mechanism of action, pharmacokinetic, and pharmacodynamic properties, as well as efficacy and safety observed in clinical trials; and an expert opinion section discusses its clinical uses, advantages, limitations, and potential future applications. EXPERT OPINION: Lenacapavir should be used in combination with at least one or two additional fully active agents, where possible, and adherence support is critical for selected companion drugs (particularly if self-administered) to optimize efficacy and prevent treatment-emergent resistance to lenacapavir. Providers should pay attention to drug-drug interactions when initiating lenacapavir.

Transforming medical education in Liberia through an international community of inquiry.

A critical component of building capacity in Liberia's physician workforce involves strengthening the country's only medical school, A.M. Dogliotti School of Medicine. Beginning in 2015, senior health sector stakeholders in Liberia invited faculty and staff from U.S. academic institutions and non-governmental organizations to partner with them on improving undergraduate medical education in Liberia. Over the subsequent six years, the members of this partnership came together through an iterative, mutual-learning process and created what William Torbert et al describe as a "community of inquiry," in which practitioners and researchers pair action and inquiry toward evidence-informed practice and organizational transformation. Incorporating faculty, practitioners, and students from Liberia and the U.S., the community of inquiry consistently focused on following the vision, goals, and priorities of leadership in Liberia, irrespective of funding source or institutional affiliation. The work of the community of inquiry has incorporated multiple mixed methods assessments, stakeholder discussions, strategic planning, and collaborative self-reflection, resulting in transformation of medical education in Liberia. We suggest that the community of inquiry approach reported here can serve as a model for others seeking to form sustainable global health partnerships focused on organizational transformation.

HIV risk profile and prevention needs of individuals seeking monkeypox (mpox) vaccination in an urban clinic in the U.S.: a brief report.

BACKGROUND: Our study survey assessed HIV risk profile and pre-exposure prophylaxis (PrEP) use among HIV-negative individuals seeking mpox vaccination, elucidating HIV prevention gaps and opportunities. METHODS: Anonymous cross-sectional surveys were self-administered at an urban academic center clinic in New Haven, CT, U.S. (August 18-November 18, 2022). Inclusion criteria included adults presenting for mpox vaccination who consented to the study. The study assessed STI risk (sexual practices, STI history, substance use). For HIV-negative participants, PrEP knowledge, attitudes, and preferences were assessed. RESULTS: Eighty-one of 210 individuals approached completed surveys (survey acceptance and completion rate 38.6%). Majority were cisgender-male (76/81; 93.8%), Caucasian (48/79; 60.8%), with median age 28 years (IQR-15). Nine of 81 (11.5%) self-reported HIV-positivity. Median sexual partner number (6 months prior) was 4 (IQR-5.8). Majority, 89.9% and 75.9%, reported insertive and receptive anal intercourse, respectively. 41% reported lifetime STI history, of whom 12.3% had an STI 6 months prior. Majority (55.8%) used ≥ 1 illicit substance; 87.7% moderate alcohol use. Among HIV-negative respondents, most (95.7%) were aware of PrEP, but only 48.4% used PrEP. CONCLUSION: Individuals seeking mpox vaccination engage in behaviors placing them at increased STI risk and would benefit from PrEP assessment.

Acute kidney injury due to myoglobin cast nephropathy in the setting of coronavirus disease 2019-mediated rhabdomyolysis: a case report.

BACKGROUND: We present this case of coronavirus disease 2019-associated acute kidney injury with rhabdomyolysis-with noteworthy renal biopsy findings demonstrating myoglobin cast nephropathy-to add to the limited literature on coronavirus disease 2019-related acute kidney injury and rhabdomyolysis. CASE PRESENTATION: A 67-year-old Caucasian man presented to our hospital with 3 weeks of malaise and decreased oral intake and several days of abnormal taste, poor appetite, decrease urine output, gastrointestinal symptoms, and myalgias, and was ultimately diagnosed with coronavirus disease 2019. His hospital course was complicated by acute kidney injury and, upon workup of his renal failure, was diagnosed with myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis. Ultimately, his renal function improved following hydration back to his baseline 6 weeks after his initial diagnosis of coronavirus disease 2019. CONCLUSIONS: Given our limited knowledge of manifestations of coronavirus disease 2019, it is important to have a more in-depth understanding of the spectrum of disease of coronavirus disease 2019, which can affect various organ systems, including the kidney, and the manifestations of end-organ damage associated with it. We present this case to highlight a rarely reported finding of myoglobin cast nephropathy due to coronavirus disease 2019-mediated rhabdomyolysis.

Long-term quantitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV (PWH).

BACKGROUND: The durability of immune responses to COVID-19 vaccines among older people living with HIV (PWH) is clinically important. METHODS: We aimed to assess vaccine-induced humoral immunity and durability in older PWH (≥ 55 years, n = 26) over 6 months (post-initial BNT162b2 series). A secondary and exploratory objective was to assess T-cell response and BNT162b2 booster reactogenicity, respectively. Our Visit 1 (3 weeks post-initial BNT162b2 dose) SARS-CoV-2 humoral immunity results are previously reported; these subjects were recruited for Visit 2 [2 weeks (+ 1 week window) post-second vaccination] and Visit 3 [6 months (± 2 week window) post-initial vaccination] in a single-center longitudinal observational study. Twelve participants had paired Visit 2/3 SARS-CoV-2 Anti-Spike IgG data. At Visit 3, SARS-CoV-2 Anti-Spike IgG testing occurred, and 5 subjects underwent T-cell immune response evaluation. Thereafter, subjects were offered BNT162b2 booster (concurrent day outside our study) per US FDA/CDC guidance; reactogenicity was assessed. The primary study outcome was presence of detectable Visit 3 SARS-CoV-2 Anti-Spike-1-RBD IgG levels. Secondary and exploratory outcomes were T-cell immune response and BNT162b2 booster reactogenicity, respectively. Wilcoxon signed-rank tests analyzed median SARS-CoV-2 Anti-Spike IgG 6-month trends. RESULTS: At Visit 3, 26 subjects underwent primary analysis with demographics noted: Median age 61 years; male n = 16 (62%), female n = 10 (38%); Black n = 13 (50%), White n = 13 (50%). Most subjects (n = 20, 77%) had suppressed HIV viremia on antiretroviral therapy, majority (n = 24, 92%) with CD4 > 200 cells/µL. At Visit 3, 26/26 (100%) had detectable Anti-Spike-1-RBD (≥ 0.8 U/mL). Among 12 subjects presenting to Visit 2/3, median SARS-CoV-2 Anti-Spike 1-RBD was 2087 U/mL at Visit 2, falling to 581.5 U/mL at Visit 3 (p = 0.0923), with a median 3.305-fold decrease over 6 months. Among subjects (n = 5) with 6-month T-cell responses measured, all had detectable cytokine-secreting anti-spike CD4 responses; 3 had detectable CD4 + Activation induced marker (AIM) + cells. Two had detectable cytokine-secreting CD8 responses, but all had positive CD8 + AIM + cells. CONCLUSIONS: Among older PWH, SARS-CoV-2 Anti-Spike IgG and virus-specific T-cell responses are present 6 months post-primary BNT162b2 vaccination, and although waning, suggest retention of some degree of long-term protective immunity.

Proactive strategies to optimize engagement of Black, Hispanic/Latinx, transgender, and nonbinary individuals in a trial of a novel agent for HIV pre-exposure prophylaxis (PrEP).

INTRODUCTION: Black and Hispanic/Latinx cisgender men who have sex with men (MSM), transgender women, transgender men, and gender nonbinary (TGNB) individuals have been historically underrepresented in HIV pre-exposure prophylaxis (PrEP) clinical trials. There is an urgent need for ongoing engagement with communities that have been the most impacted by HIV and diverse representation in clinical trials. Here we describe strategic approaches undertaken in the PURPOSE 2 trial to optimize engagement of underrepresented individuals. METHODS AND RESULTS: PURPOSE 2 is an ongoing Phase 3 trial evaluating the safety and efficacy of lenacapavir as PrEP in cisgender MSM and TGNB individuals. In PURPOSE 2, we used a multipronged approach aimed at enriching participation of underrepresented individuals. We conducted a review to identify evidence-informed recommendations from literature, engaged with stakeholders, and established the Global Community Advisory and Accountability Group (GCAG) to represent the needs of the community. Insights from stakeholders and GCAG members resulted in an expansion of the study population to include transgender men, gender nonbinary persons, and adolescents, and evaluation of population-specific outcomes. Feedback from stakeholders and GCAG members also informed investigator and site selection; these were selected based on prior experience working with persons from diverse racial, ethnic and gender identities, and estimates of local HIV incidence. Site selection was also expanded to include community-based clinics with services tailored towards Black, Hispanic/Latinx, and TGNB populations. We established a study-wide recruitment goal of 50% Black MSM and 20% Hispanic/Latinx MSM in US sites and 20% transgender women globally. Site-specific recruitment goals were also developed based on local demographics and HIV incidence. Mandatory trainings included Good Participatory Practice guidelines, gender inclusivity, and antiracism. CONCLUSION: While further work is needed to achieve equitable representation, the strategies we describe may serve as a framework for future clinical trials. TRIAL REGISTRATION: Clinical Trial Number: NCT04925752.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Qualitative assessment of anti-SARS-CoV-2 spike protein immunogenicity (QUASI) after COVID-19 vaccination in older people living with HIV.

OBJECTIVES: Effective and safe COVID-19 vaccines have been developed and have resulted in decreased incidence and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and can decrease secondary transmission. However, there are concerns about dampened immune responses to COVID-19 vaccination among immunocompromised patients, including people living with HIV (PLWH), which may blunt the vaccine's efficacy and durability of protection. This study aimed to assess the qualitative SARS-CoV-2 vaccine immunogenicity among PLWH after vaccination. METHODS: We conducted targeted COVID-19 vaccination (all received BNT162b2 vaccine) of PLWH (aged ≥ 55 years per state guidelines) at Yale New Haven Health System and established a longitudinal survey to assess their qualitative antibody responses at 3 weeks after the first vaccination (and prior to receipt of the second dose of the COVID-19 vaccine) (visit 1) and at 2-3 weeks after the second vaccination (visit 2) but excluded patients with prior COVID-19 infection. Our goal was to assess vaccine-induced immunity in the population we studied. Qualitative immunogenicity testing was performed using Healgen COVID-19 anti-Spike IgG/IgM rapid testing. Poisson regression with robust standard errors was used to determine factors associated with a positive IgG response. RESULTS: At visit 1, 45 of 78 subjects (57.7%) tested positive for SARS-CoV-2 anti-Spike IgG after the first dose of COVID-19 vaccine. Thirty-nine subjects returned for visit 2. Of these, 38 had positive IgG (97.5%), including 20 of 21 subjects (95.2%) with an initial negative anti-Spike IgG. Our bivariate analysis suggested that participants on an antiretroviral regimen containing integrase strand transfer inhibitors [relative risk (RR) = 1.81, 95% confidence interval (CI): 0.92-3.56, p = 0.085] were more likely to seroconvert after the first dose of the COVID-19 vaccine, while those with a CD4 count < 500 cells/µL (RR = 0.59, 95% CI: 0.33-1.05, p = 0.071), and those diagnosed with cancer or another immunosuppressive condition (RR = 0.49, 95% CI: 0.18-1.28, p = 0.15) may have been less likely to seroconvert after the first dose of the COVID-19 vaccine. The direction of these associations was similar in the multivariate model, although none of these findings reached statistical significance (RRintegrase inhibitor  = 1.71, 95% CI: 0.90-3.25, p = 0.10; RRCD4 count  = 0.68, 95% CI: 0.39-1.19, p = 0.18; RRcancer or another immunosuppressive condition  = 0.50, 95% CI: 0.19-1.33, p = 0.16). With regard to immunogenicity, we were able to record very high rates of new seroconversion following the second dose of the COVID-19 vaccine. CONCLUSIONS: Our study suggests that completing a two-dose series of BNT162b2 vaccine is critical for PLWH given suboptimal seroconversion rates after the first dose and subsequent improved seroconversion rates after the second dose.

Gaps and Opportunities in HIV Service Delivery in High Volume HIV Care Centers in Liberia: Lessons From the Field.

Background: Human Immunodeficiency Virus (HIV) infection continues to have a profound humanitarian and public health impact in western and central Africa, a region that risks being left behind in the global response to ending the AIDS epidemic. In Liberia, where the health system is being rebuilt following protracted civil wars and an Ebola virus disease outbreak, the Resilient and Responsive Health System (RRHS) is assisting with quality HIV services delivery through support from PEPFAR and HRSA but gaps remain across the cascade of care from diagnosis to viral load suppression. Objective: To highlight gaps in HIV service delivery in Liberia, identify opportunities and offer recommendations for improving the quality of service delivery. Methods: A narrative review of relevant literature was conducted following a search of all local and online databases known to the authors. Findings: Antiretroviral therapy (ART) has transformed the HIV response in Liberia by averting deaths, improving quality of life, and preventing new HIV infections but critical gaps remain. These include weak HIV prevention and testing strategies; suboptimal ART initiation and retention in care; low viral load testing volumes, commodity supply chain disruptions and a HIV workforce built on non-physician healthcare workers. In the context of the prevailing socioeconomic, heath system and programmatic challenges, these will impact achievement of the UNAIDS targets of 95-95-95 by 2030 and ending the epidemic. Conclusion: Combination prevention approaches are necessary to reach the most at risk populations, while a robust health workforce operating through facilities and communities will be needed to reach people with undiagnosed HIV earlier to provide efficient and effective services to ensure that people know their HIV status, receive and sustain ART to achieve viral suppression to maintain a long and healthy life within the framework of overall health system strengthening, achieving universal health coverage and the sustainable development goal.

High HIV Detection in a Tertiary Facility in Liberia: Implications and Opportunities.

Background: HIV/AIDS remains one of the world's most significant public health challenges; sub-Saharan Africa accounts for 71% of the global burden of HIV. Testing for HIV is pivotal to achieving UNAIDS 95-95-95 target towards bringing an end to the epidemic. Objective: The study assessed five-year HIV testing data from the largest tertiary hospital in Monrovia, Liberia and highlights risk groups that would benefit from targeted testing and prevention interventions. Methods: This was a single-center academic hospital-based retrospective analysis of HIV testing data from January 2014 to December 2018 obtained from all testing sites at John F. Kennedy Medical Center in Monrovia, Liberia. Pooled HIV testing data during the study period were analyzed using descriptive statistics and stratified by age, gender and pregnancy status. Annual diagnoses rates were reported as proportion of individuals tested within a specified category (age [<15 years, age 15-24 years and >=25 years], gender, and pregnancy status) that had a positive HIV test. Five-year trends were analyzed. Results: Over the study period, 41,343 non-pregnant individuals were screened for HIV. In addition, the antenatal clinic performed 24,913 tests. Of non-pregnant individuals tested, 4,066 (10%) were diagnosed with HIV ranging from 7% (909/12821) in 2018 to 13% (678/5079) in 2014. Case detection rates for individuals aged 15-24 were 7%, 5%, 4%, 6% and 3% for years 2014, 2015, 2016, 2017 and 2018 respectively. Annually, 2-3% of all pregnant women tested were diagnosed with HIV. While HIV detection rates decreased over time overall, children less than 15 years of age showed an annual increase from 6.7% in 2014 to 12.3% in 2018. Conclusion: A large five-year dataset from the largest tertiary facility in Liberia shows broad HIV detection rates that are much higher than national prevalence estimates. Ramping up HIV testing and prevention interventions including pre-exposure prophylaxis are sorely needed.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ∼6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.