Correction: Cingulate transcranial direct current stimulation in adults with HIV.

[This corrects the article DOI: 10.1371/journal.pone.0269491.].

Multiple treatment interruptions and protecting HIV-specific CD4 T cells enable durable CD8 T cell response and viral control.

Human Immunodeficiency Virus (HIV) remains a global health challenge, and novel approaches to improve HIV control are significantly important. The cell and gene therapy product AGT103-T was previously evaluated (NCT04561258) for safety, immunogenicity, and persistence in seven patients for up to 180 days post infusion. In this study, we sought to investigate the impact of AGT103-T treatment upon analytical treatment interruptions (ATIs). Six patients previously infused with AGT103-T were enrolled into an ATI study (NCT05540964), wherein they suspended their antiretroviral therapy (ART) until their viral load reached 100,000 copies/mL in two successive visits, or their CD4 count was reduced to below 300 cells/µL. During the ATI, all patients experienced viral rebound followed by a notable expansion in HIV specific immune responses. The participants demonstrated up to a five-fold increase in total CD8 counts over baseline approximately 1-2 weeks followed by the peak viremia. This coincided with a rise in HIV-specific CD8 T cells, which was attributed to the increase in antigen availability and memory recall. Thus, the protocol was amended to include a second ATI with the first ATI serving as an "auto-vaccination." Four patients participated in a second ATI. During the second ATI, the Gag-specific CD8 T cells were either maintained or rose in response to viral rebound and the peak viremia was substantially decreased. The patients reached a viral set point ranging from 7,000 copies/mL to 25,000 copies/mL. Upon resuming ART, all participants achieved viral control more rapidly than during the first ATI, with CD4 counts remaining within 10% of baseline measurements and without any serious adverse events or evidence of drug resistance. In summary, the rise in CD8 counts and the viral suppression observed in 100% of the study participants are novel observations demonstrating that AGT103-T gene therapy when combined with multiple ATIs, is a safe and effective approach for achieving viral control, with viral setpoints consistently below 25,000 copies/mL and relatively stable CD4 T cell counts. We conclude that HIV cure-oriented cell and gene therapy trials should include ATI and may benefit from designs that include multiple ATIs when induction of CD8 T cells is required to establish viral control.

Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

The Tenacious Treponema: A Retrospective Examination of Syphilis Treatment Disparities in Washington, DC.

BACKGROUND: Since 2000, there have been rising rates of syphilis infections nationally with higher incidence among minorities and persons living with human immunodeficiency virus (HIV) (PLWH). The purpose of this study was to determine syphilis treatment adequacy and factors associated with treatment delay. METHODS: This was a retrospective academic-public health collaboration with the District of Columbia Department of Public Health reviewing surveillance data of all primary, secondary, and early latent syphilis cases diagnosed between January 1, 2015, and December 31, 2019. Data were analyzed using multivariable logistic regression to identify factors associated with delayed treatment >14 days from diagnosis. RESULTS: Among 1852 individuals diagnosed with early syphilis, 93% (1730/1852) were male; 48% (893/1852) were coinfected with HIV; 43% (n = 796/1852) were African American/Black, 27% (n = 492/1852) were White, and race/ethnicity was unknown for 17% (n = 318/1852) of cases. Among 679 PLWH for whom viral load (VL) was known, 41% (278/679) had a VL < 20 copies/mL, and 18% (123/679) had VL >10,000 copies/mL. Treatment adequacy overall was 96.5%. Median time to syphilis treatment was 6 days (interquartile range = 4-7). Factors associated with delay of treatment included refused/unknown race (adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.00-3.79), and HIV VL > 10,000 copies/mL (aOR, 1.97; 95% CI, 1.08-3.58). CONCLUSIONS: The factors we identified associated with delayed treatment may reflect systemic factors contributing to the increased rates of infection among key populations. This highlights the importance of targeted public health efforts with the goal of reducing transmission of both HIV and syphilis.

Mixed Methods Analysis of Telehealth Experience, Satisfaction, and Quality of Care During the COVID Pandemic Among Persons with HIV in Washington, DC.

The purpose of this study is to describe telehealth experiences and quality of HIV care provided to an urban population of people with HIV (PWH) in Washington, DC. We used self-reported survey data from a cohort of PWH in the DC Cohort longitudinal study linked to medical records (October 26, 2020-December 31, 2021). Analyses followed a mixed-methods approach, including prevalence estimates and multivariable logistic regression of telehealth use by demographic and HIV characteristics. We measured primary motivation, modes of engagement, and telehealth satisfaction. Qualitative responses to open-ended questions were coded using collaborative coding. A framework developed by the National Quality Forum (NQF) was applied to the results. Among 978 participants, 69% reported using telehealth for HIV care during the pandemic. High school graduates were less likely to use telehealth compared to those with college education (aOR 0.69, 95% CI 0.48, 0.98). PWH with > 1 co-morbid condition were more likely to use telehealth compared to those without (aOR 1.42, 95% CI 1.02, 1.95). The majority reported satisfaction with telehealth (81%). Qualitative analysis of telehealth satisfaction found that most responses were related to access to care and technology, effectiveness, and patient experience. PWH using telehealth during the pandemic were satisfied with their experience though use differed demographically. Telehealth was used effectively to overcome barriers to care engagement, including transportation, costs, and time. As we transition away from the emergency pandemic responses, it will be important to determine how this technology can be used in the future in an equitable manner to further strengthen HIV care engagement.

Week 240 Efficacy and Safety of Fostemsavir Plus Optimized Background Therapy in Heavily Treatment-Experienced Adults with HIV-1.

INTRODUCTION: Efficacy and safety of the attachment inhibitor fostemsavir + optimized background therapy (OBT) were evaluated through 48 and 96 weeks in the phase 3 BRIGHTE trial in heavily treatment-experienced (HTE) adults failing their current antiretroviral regimen. Here, we report 240-week efficacy and safety of fostemsavir + OBT in adults with multidrug-resistant human immunodeficiency virus (HIV)-1 in BRIGHTE. METHODS: Heavily treatment-experienced adults failing their current regimen entered the randomized cohort (RC; 1-2 fully active antiretrovirals available) or non-randomized cohort (NRC; no fully active antiretrovirals available) and received open-label fostemsavir + OBT (starting Day 8 in RC and Day 1 in NRC). Endpoints included proportion with virologic response (HIV-1 RNA < 40 copies/mL, Snapshot), immunologic efficacy, and safety. RESULTS: At Week 240, 45% and 22% of the RC and NRC, respectively, had virologic response (Snapshot); 7% of the RC and 5% of the NRC had missing data due to coronavirus disease 2019 (COVID-19)-impacted visits. In the observed analysis, 82% of the RC and 66% of the NRC had virologic response. At Week 240, mean change from baseline in CD4+ T-cell count was 296 cells/mm3 (RC) and 240 cells/mm3 (NRC); mean CD4+/CD8+ ratio increased between Weeks 96 and 240 (RC 0.44 to 0.60; NRC 0.23 to 0.32). Between Weeks 96 and 240, four participants discontinued for adverse events, one additional participant experienced a drug-related serious adverse event, and six deaths occurred (median last available CD4+ T-cell count, 3 cells/mm3). COVID-19-related events occurred in 25 out of 371 participants; all resolved without incident. CONCLUSION: Through ~5 years, fostemsavir + OBT demonstrated durable virologic and immunologic responses with no new safety concerns between Weeks 96 and 240, supporting this regimen as a key therapeutic option for HTE people with multidrug-resistant HIV-1. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02362503.

Weight gain following switch to integrase inhibitors from non-nucleoside reverse transcriptase or protease inhibitors in people living with HIV in the United States: analyses of electronic medical records and prescription claims.

OBJECTIVES: Real-world data evaluating weight changes in people living with HIV (PLWH) following switch to integrase strand transfer inhibitor (INSTI), specifically bictegravir (BIC), are limited. This retrospective cohort study analyzed weight changes upon switching to INSTI from non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) in treatment-experienced PLWH. METHODS: Adult PLWH (≥18 years) treated with NNRTI or PI (non-switch cohorts) and those switching to INSTI (switch cohorts) between January 1, 2014 and August 31, 2019 were identified using IQVIA's Ambulatory Electronic Medical Records linked to a prescription drug claims database. The associations of switching to INSTI and individual INSTI agents with having ≥5% weight gain at 12 months of follow-up were evaluated, adjusting for demographics and baseline clinical characteristics. RESULTS: At 12 months of follow-up, PLWH in the NNRTI-INSTI switch cohort (n = 508) were more likely to have ≥5% weight gain over 12 months compared to the NNRTI non-switch cohort (n = 614; odds ratio, OR [95% CI], 1.7 [1.2-2.4]). Switching from NNRTI to dolutegravir (DTG: OR [95% CI], 2.1 [1.4-3.0]) or BIC (2.0 [1.0-4.2]) resulted in significantly higher odds of ≥5% weight gain. PI-INSTI switch (n = 295) and non-switch (n = 228) cohorts had similar proportions of PLWH with ≥5% (21.1-23.4%) or ≥10% (7.8-7.9%) weight gain, and no significant association was found between switching from PI to INSTI and weight gain. CONCLUSION: Weight gain and related metabolic health of PLWH switching from NNRTI to DTG or BIC should be closely monitored by clinicians. Further research is needed to assess other metabolic outcomes in PLWH remaining on PI and those who switch from PI to INSTI.

Weight gain after antiretroviral therapy initiation in people living with HIV in the United States: analyses of electronic medical records and prescription claims.

BACKGROUND: Treatment guidelines recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimens for treatment naïve people living with HIV (PLWH) in the United States (US). This retrospective database study compared weight changes following initiation of INSTI-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based ART in treatment-naïve PLWH. METHODS: Adult (≥18 years) PLWH initiated on INSTI, NNRTI, or PI plus ≥2 nucleoside reverse transcriptase inhibitors (NRTI) between 1 January 2014 to 31 August 2019 were identified in IQVIA's Ambulatory Electronic Medical Records (AEMR) linked to prescription drug claims (LRx). Weight changes over up to 36 months (M) of follow-up were compared among PLWH on INSTI- vs. NNRTI- and PI-based ART separately using non-linear mixed effect models, adjusting for demographics and baseline clinical characteristics. RESULTS: The INSTI, NNRTI, and PI cohorts included 931, 245, and 124 PLWH, respectively. For all three cohorts, the majority were male (78.2-81.2%) and overweight/obese (53.6-61.6%) at baseline; 40.8-45.2% of the groups were African American. The INSTI vs. NNRTI/PI cohorts were younger (median age: 38 years vs. 44 years/46 years), had lower weight at ART initiation (mean: 80.9 kg vs. 85.7 kg/85.0 kg), and had higher TAF usage during follow-up (55.6% vs. 24.1%/25.8%; all p < .05). Multivariate models showed higher weight gain among PLWH in INSTI vs. NNRTI and PI cohorts during treated follow-up (estimated weight gain after 36 M: 7.1 kg vs. 3.8 kg and 3.8 kg, both p < .05). CONCLUSION: Study findings highlight the need to monitor an increase in weight and potential metabolic complications among PLWH starting ART with INSTI.

Monkeypox-Associated Central Nervous System Disease: A Case Series and Review.

OBJECTIVE: Monkeypox virus (MPXV) disease has been declared a public health emergency by the World Health Organization, creating an urgent need for neurologists to be able to recognize, diagnosis, and treat MPXV-associated neurologic disease. METHODS: Three cases of MPXV-associated central nervous system (CNS) disease occurring during the 2022 outbreak, and their associated imaging findings are presented, with 2 cases previously published in a limited capacity in a public health bulletin. RESULTS: Three previously healthy immunocompetent gay men in their 30s developed a febrile illness followed by progressive neurologic symptoms with presence of a vesiculopustular rash. MPXV nucleic acid was detected by polymerase chain reaction (PCR) from skin lesions of 2 patients, with the third patient having indeterminate testing but an epidemiologic link to a confirmed MPXV disease case. Cerebrospinal fluid demonstrated a lymphocytic pleocytosis, elevated protein, and negative MPXV-specific PCR. In 2 patients, magnetic resonance imaging of the brain and spine demonstrated partially enhancing, longitudinally extensive central spinal cord lesions with multifocal subcortical, basal ganglia, thalamic, cerebellar, and/or brainstem lesions. The third patient had thalamic and basal ganglia lesions. All patients received 14 days of tecovirimat, and 2 patients also received multiple forms of immunotherapy, including intravenous immunoglobulin, pulsed high-dose steroids, plasmapheresis, and/or rituximab. Good neurologic recovery was observed in all cases. INTERPRETATION: MPXV can be associated with CNS disease. It is unclear whether this is from a parainfectious immune-mediated injury or direct CNS viral invasion. ANN NEUROL 2023;93:893-905.

Safety and durability of AGT103-T autologous T cell therapy for HIV infection in a Phase 1 trial.

The cell and gene therapy product AGT103-T was designed to restore the Gag-specific CD4+ T cell response in persons with chronic HIV disease who are receiving antiretroviral therapy. This autologous, genetically engineered cell product is under investigation in a Phase 1 clinical trial (NCT03215004). Trial participants were conditioned with cyclophosphamide approximately 1 week before receiving a one-time low (< 109 genetically modified CD4+ T cells) or high (≥109 genetically modified CD4+ T cells) dose of AGT103-T, delivering between 2 and 21 million genetically modified cells per kilogram (kg) body weight. There were no serious adverse events (SAEs) and all adverse events (AEs) were mild. Genetically modified AGT103-T cells were detected in most of the participant blood samples collected 6 months after infusion, which was the last scheduled monitoring visit. Peripheral blood mononuclear cells (PBMC) collected after cell product infusion were tested to determine the abundance of Gag-specific T cells as a measure of objective responses to therapy. Gag-specific CD4+ T cells were detected in all treated individuals and were substantially increased by 9 to 300-fold compared to baseline, by 14 days after cell product infusion. Gag-specific CD8+ T cells were increased by 1.7 to 10-fold relative to baseline, by 28 days after cell product infusion. Levels of Gag-specific CD4+ T cells remained high (~2 to 70-fold higher relative to baseline) throughout 3-6 months after infusion. AGT103-T at low or high doses was safe and effective for improving host T cell immunity to HIV. Further studies, including antiretroviral treatment interruption, are warranted to evaluate the product's efficacy in HIV disease. Clinical trial registration: www.clinicaltrials.gov, identifier: NCT03215004.

Two Cases of Monkeypox-Associated Encephalomyelitis - Colorado and the District of Columbia, July-August 2022.

Monkeypox virus (MPXV) is an orthopoxvirus in the Poxviridae family. The current multinational monkeypox outbreak has now spread to 96 countries that have not historically reported monkeypox, with most cases occurring among gay, bisexual, and other men who have sex with men (1,2). The first monkeypox case in the United States associated with this outbreak was identified in May 2022 in Massachusetts (1); monkeypox has now been reported in all 50 states, the District of Columbia (DC), and one U.S. territory. MPXV is transmitted by close contact with infected persons or animals; infection results in a febrile illness followed by a diffuse vesiculopustular rash and lymphadenopathy. However, illness in the MPXV current Clade II outbreak has differed: the febrile prodrome is frequently absent or mild, and the rash often involves genital, anal, or oral regions (3,4). Although neuroinvasive disease has been previously reported with MPXV infection (5,6), it appears to be rare. This report describes two cases of encephalomyelitis in patients with monkeypox disease that occurred during the current U.S. outbreak. Although neurologic complications of acute MPXV infections are rare, suspected cases should be reported to state, tribal, local, or territorial health departments to improve understanding of the range of clinical manifestations of and treatment options for MPXV infections during the current outbreak.

Cingulate transcranial direct current stimulation in adults with HIV.

BACKGROUND: Neuronal dysfunction plays an important role in the high prevalence of HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH). Transcranial direct current stimulation (tDCS)-with its capability to improve neuronal function-may have the potential to serve as an alternative therapeutic approach for HAND. Brain imaging and neurobehavioral studies provide converging evidence that injury to the anterior cingulate cortex (ACC) is highly prevalent and contributes to HAND in PWH, suggesting that ACC may serve as a potential neuromodulation target for HAND. Here we conducted a randomized, double-blind, placebo-controlled, partial crossover pilot study to test the safety, tolerability, and potential efficacy of anodal tDCS over cingulate cortex in adults with HIV, with a focus on the dorsal ACC (dACC). METHODS: Eleven PWH (47-69 years old, 2 females, 100% African Americans, disease duration 16-36 years) participated in the study, which had two phases, Phase 1 and Phase 2. During Phase 1, participants were randomized to receive ten sessions of sham (n = 4) or cingulate tDCS (n = 7) over the course of 2-3 weeks. Treatment assignments were unknown to the participants and the technicians. Neuropsychology and MRI data were collected from four additional study visits to assess treatment effects, including one baseline visit (BL, prior to treatment) and three follow-up visits (FU1, FU2, and FU3, approximately 1 week, 3 weeks, and 3 months after treatment, respectively). Treatment assignment was unblinded after FU3. Participants in the sham group repeated the study with open-label cingulate tDCS during Phase 2. Statistical analysis was limited to data from Phase 1. RESULTS: Compared to sham tDCS, cingulate tDCS led to a decrease in Perseverative Errors in Wisconsin Card Sorting Test (WCST), but not Non-Perseverative Errors, as well as a decrease in the ratio score of Trail Making Test-Part B (TMT-B) to TMT-Part A (TMT-A). Seed-to-voxel analysis with resting state functional MRI data revealed an increase in functional connectivity between the bilateral dACC and a cluster in the right dorsal striatum after cingulate tDCS. There were no differences in self-reported discomfort ratings between sham and cingulate tDCS. CONCLUSIONS: Cingulate tDCS is safe and well-tolerated in PWH, and may have the potential to improve cognitive performance and brain function. A future study with a larger sample is warranted.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. CLINICAL TRIALS REGISTRATION: NCT04363736.

Healthcare Worker With Large Vessel Acute Ischemic Stroke Likely Related to Mild SARS-CoV-2 Infection.

We report the case of a healthcare worker who presented with a large vessel acute ischemic stroke in setting of a mild SARS-CoV-2 infection and provide a review of the emerging literature on COVID-related stroke. A 43-year-old female presented with right-sided hemiparesis, aphasia and dysarthria. She had a nonproductive of cough for 1 week without fever, fatigue or dyspnea. A CT Head, CT angiography and CT perfusion imaging revealed a M1 segment occlusion of the left middle cerebral artery requiring transfer from a primary to a comprehensive stroke center. A nasopharyngeal swab confirmed SARS-CoV-2 infection prior to arrival at the accepting center. During the thrombectomy a 3 cm thrombus was removed. Thrombus was also evident in the 8 French short sheath during closure device placement so a hypercoagulable state was suspected. Stroke work-up revealed a glycosylated hemoglobin of 8.7%, elevation of inflammatory markers and an indeterminate level of lupus anticoagulant IgM. On discharge home, she had near complete neurological recovery. This case highlights suspected mechanisms of hypercoagulability in SARS-CoV-2 infection and the importance of optimizing stroke care systems during the COVID-19 pandemic.

Integrase Inhibitor Prescribing Disparities in the DC and Johns Hopkins HIV Cohorts.

Integrase inhibitors (INSTIs) are recommended by expert panels as initial therapy for people with HIV. Because there can be disparities in prescribing and uptake of novel and/or recommended therapies, this analysis assessed potential INSTI prescribing disparities using a combined data set from the Johns Hopkins HIV Clinical Cohort and the DC Cohort. We performed multivariable logistic regression to identify factors associated with ever being prescribed an INSTI. Disparities were noted, including clinic location, age, and being transgender. Identifying disparities may allow clinicians to focus their attention on these individuals and ensure that therapy decisions are grounded in valid clinical reasons.

Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1.

OBJECTIVES: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. DESIGN: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). METHODS: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4+ T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4+ T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). RESULTS: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4+ T-cell count increases were comparable across subgroups. Participants with baseline CD4+ T-cell counts less than 20 cells/µl had a mean increase of 240 cells/µl. In the safety population, more participants with baseline CD4+ T-cell counts less than 20 vs. at least 200 cells/µl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. CONCLUSION: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

The Cost-Effectiveness and Budget Impact of Ibalizumab-uiyk for Adults with Multidrug-Resistant HIV-1 Infection in the United States.

BACKGROUND: Ibalizumab-uiyk (ibalizumab) is a first-in-class, long-acting, postattachment HIV-1 inhibitor for adults with multidrug-resistant (MDR) HIV-1 infection. This analysis examines the cost-effectiveness and budget impact of ibalizumab treatment for this difficult-to-treat population in the United States. METHODS: A Markov model followed cohorts of adults with MDR HIV-1 infection through two final lines of antiretroviral therapy: ibalizumab + optimized background therapy (OBT) or OBT alone followed by nonsuppressive therapy. Model inputs were based on ibalizumab clinical trial data, market uptake projections, and published literature, with costs in 2019 dollars. The cost-effectiveness analysis assessed costs and health outcomes from a health care sector perspective for individuals receiving ibalizumab + OBT versus OBT alone over a lifetime time horizon. The budget-impact analysis estimated the impact on payer budgets of the introduction of ibalizumab over 3 years for a hypothetical commercial health plan. RESULTS: Compared with individuals receiving OBT alone, individuals receiving ibalizumab + OBT incurred higher costs but lived longer, healthier lives, with an incremental cost of $133,040 per QALY gained. For a hypothetical commercial health plan with 1 million members, the introduction of ibalizumab + OBT was estimated to increase budgets by $217,260, $385,245, and $560,310 ($0.018, $0.032, and $0.047 per member per month) in years 1, 2, and 3, respectively. These results were found to be robust in sensitivity and scenario analyses. CONCLUSIONS: Ibalizumab may represent a cost-effective and affordable option to improve health outcomes for individuals with MDR HIV-1 infection.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study.

BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.

Diffuse pneumonitis from coronavirus HKU1 on checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can produce specific immune-related adverse events including pneumonitis. The impact of ICI therapy on the severity of acute coronavirus infection symptomatology warrants further exploration. CASE PRESENTATION: We report a 65-year-old man diagnosed with stage IV melanoma who developed pulmonary and brain metastases and was treated with bilateral craniotomies followed by combined nivolumab and ipilimumab immunotherapy. He developed early-onset severe dyspnea associated with acute coronavirus HKU1 (non-COVID-19) infection, with diffuse pneumonitis evidenced by ground glass opacification on CT scan. He was treated with steroids leading to resolution of pneumonitis on repeat imaging, suggesting an exacerbated immune-mediated toxicity. CONCLUSION: We report the first case of a patient with melanoma with severe and reversible diffuse pneumonitis in association with coronavirus HKU1 following combined nivolumab and ipilimumab immunotherapy. Although we do not have data on the impact of ICI therapy on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) symptomatology, a possible interaction should be considered when deciding on dosing in patients with possible SARS-CoV-2 exposure or when evaluating patients with presumed ICI-related pneumonitis during the COVID-19 pandemic.