Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen with high antiviral potency, favourable safety and tolerability, and low propensity for resistance. We report week 48 results from a phase 3 trial evaluating switch from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·75 mg). METHODS: This phase 3, multicentre, randomised, active-controlled, open-label, non-inferiority trial was conducted at 77 research, community, and hospital-based clinics in 15 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation schedule to switch to doravirine (100 mg) and islatravir (0·75 mg) or to continue their baseline ART regimen. Block randomisation was based on a block size of four, and randomisation was stratified by baseline regimen (ie, protease inhibitor, integrase inhibitor, or other). Participants in the doravirine and islatravir group were instructed to take one tablet at approximately the same time each day, and participants in the baseline ART group continued to take the medication according to the locally approved label. HIV-1 RNA and safety evaluations were done at baseline and weeks 4, 12, 24, 36, and 48. CD4 cell counts were measured at baseline, week 24, and week 48. The primary endpoint was proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug) using the US Food and Drug Administration snapshot approach and prespecified non-inferiority margin of 4%. This study is registered with ClinicalTrials.gov (NCT04223778) and is completed. FINDINGS: Between Feb 18 and Oct 2, 2020, 740 individuals were screened for eligibility, of whom 672 (90·8%) participants (249 [37·1%] women and 423 [62·9%] men; median CD4 count of 678 cells per µL [IQR 496-868]) were randomly assigned to doravirine (100 mg) and islatravir (0·75 mg; n=336) or to continue baseline ART (n=336). The last follow-up visit occurred on Sept 8, 2021. At week 48, zero of 336 participants in the doravirine and islatravir group versus five (1·5%) of 336 participants in the baseline ART group had greater than or equal to 50 HIV-1 RNA copies per mL (difference -1·5, 95% CI -3·4 to -0·3). The per-protocol analysis showed consistent results. Headache was the most common adverse event in both groups (35 [10·4%] of 336 participants in the doravirine and islatravir group, 16 [4·8%] of 336 in the baseline ART group), infection rates were similar (113 [33·6%] in both groups), and discontinuations due to adverse events were low (seven [2·1%] vs one [0·3%]). 66 (19·6%) of 336 participants had treatment-related adverse events in the doravirine and islatravir group compared with 30 (8·9%) of 336 in the baseline ART group. In the islatravir and doravirine group, CD4 cell counts (mean change -30·3 cells per µL) and total lymphocyte counts (mean change -0·26 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to single-tablet doravirine (100 mg) and islatravir (0·75 mg) maintained viral suppression up to week 48 and was non-inferior to antiretroviral combinations used in clinical practice for adults with HIV-1; however, decreases in CD4 cell and total lymphocyte counts do not support further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Coronary artery stenosis in Japanese people living with HIV-1 with or without haemophilia.

An extremely high prevalence (12.2%) of moderate-to-severe coronary artery stenosis (CAS) was documented in asymptomatic Japanese haemophiliacs living with HIV-1 (JHLH) in our previous study. The cause of this phenomenon remains unknown. We conducted the CAS screening in people living with HIV-1 without haemophilia (PLWH without haemophilia) to compare the prevalence of CAS in JHLH and PLWH without haemophilia and to identify the risk factors including inflammation markers. Ninety-seven age-matched male PLWH without haemophilia who consulted our outpatient clinic between June and July 2021 were randomly selected, and 69 patients who provided informed consent were screened for CAS using coronary computed tomography angiography (CCTA). The number of JHLH cases was 62 in this study. The prevalence of moderate (> 50%) to severe (> 75%) CAS was significantly higher in JHLH [14/57 (24.6%) vs. 6/69 (8.7%), p = 0.015], and the ratio of CAS requiring urgent interventions was significantly higher [7 (12.3%) vs. 1 (1.4%), p = 0.013] in JHLH than in PLWH without haemophilia. Among the inflammatory markers, serum titres of intercellular adhesion molecule-1 (p < 0.05) and interleukin-6 (p < 0.05) in JHLH were significantly higher than those in PLWH without haemophilia. Although some patient demographics were different in the age-matched study, it might be possible to speculate that intravascular inflammation might promote CAS in JHLH.

Prevalence of transmitted drug resistance and phylogenetic analysis of HIV-1 among antiretroviral therapy-naïve patients in Northern Vietnam from 2019 to 2022.

Since the rapid expansion of antiretroviral therapy (ART) for HIV, transmitted drug resistance (TDR) has become a major concern in Vietnam. HIV services there are transitioning to be covered by social insurance. Access to pre-exposure prophylaxis (PrEP) is being expanded to tackle the growing HIV epidemic among men who have sex with men. Therefore, a cross-sectional study was conducted at 10 ART facilities in Northern Vietnam from 9th December 2019 to 9th June 2022 to investigate the prevalence and pattern of TDR among ART-naïve people living with HIV (PLWH). TDR mutations were defined according to the World Health Organization 2009 List of Mutations for Surveillance of Transmitted Drug Resistant HIV Strains. Mutation transmission dynamics and TDR clusters were investigated via phylogenetic analysis. We enrolled 391 ART-naïve PLWH. The overall TDR prevalence was 4.6%, with an annual prevalence of 6.0% in 2019/2020, 4.8% in 2021, and 1.3% in 2022. TDR mutations to non-nucleoside reverse transcriptase inhibitors (2.8%), including K103N were the most common. Less commonly, the protease inhibitor-associated mutation M46I and mutations to nucleoside reverse transcriptase inhibitors, including M184V/ I, were observed. CRF01_AE was the most common subtype (77.0%). CRF07_BC (14.3%), which had been rare in Vietnam, was also observed. No genetic association was observed between HIV-1 sequences with TDR mutations. In conclusion, the overall prevalence of TDR was stably low in this region. The phylogenetic tree suggests that TDR clusters have not formed. Continuous monitoring of HIV TDR and strains is crucial to maintaining ART and PrEP efficacy.

Prevalence, characteristics, and virologic correlations of hepatitis delta (D) among patients with hepatitis B surface antigen in Mongolia.

Clinical and biochemical features of hepatitis delta virus (HDV) infections in Mongolia remain largely unknown. We aimed to investigate the clinical characteristics of HDV patients in Mongolia using several markers. The 143 hepatitis B surface antigen (HBsAg)-positive patients were divided into 122 HDV-positive and 21 HDV-negative patients by HDV RNA positivity. Subgroup analysis was performed between hepatitis B e antigen (HBeAg)-positive and -negative HDV-positive patients. Liver function, quantitative HBsAg (qHBsAg), anti-HDV Immunoglobulin (Ig) M, Mac-2 binding protein glycosylation isomer (M2BPGi), hepatitis B virus (HBV) DNA level, and HDV RNA level were tested. HDV RNA was positive in 85.3% (122/143) of patients showing anti-HDV IgG. Liver disease activity was higher in HDV-positive patients than in HDV-negative patients. The HDV-positive group included a higher proportion of patients with high qHBsAg and M2BPGi levels (p < 0.001). The positivity rate for anti-HDV IgM was significantly higher in the HDV-positive group (p < 0.001). HDV RNA levels showed an inverse correlation with qHBsAg levels in HBeAg-positive-HDV-positive patients (r = -0.49, p = 0.034), and a positive correlation with qHBsAg levels in HBeAg-negative patients (r = 0.35, p < 0.001). Hepatitis B virus (HBV) DNA and HDV RNA levels did not show any correlation. M2BPGi levels likewise did not correlate with HDV RNA levels. A high positivity rate for HDV RNA was observed for HBV patients in Mongolia using the highly sensitive HDV RNA assay. The positivity rate for anti-HDV IgM was high in HDV RNA-positive patients. Severity of liver disease and M2BPGi levels were both high in the HDV RNA-positive group.

Identification of New Circulating Recombinant Form of HIV-1 CRF127_07109 in Northern Vietnam.

Some candidates of a new circulating recombinant form (CRF) of HIV-1 were found in northern Vietnam in our previous study. We succeeded in near full-length sequencing using MinION with plasma samples from 12 people living with HIV. Three of the samples were CRF109_0107, which was recently reported in China. Three others were the newly identified CRF127_07109, while six of them were considered to be CRF127_07109-related unique recombinant forms (URFs). The time to the most recent common ancestor of CRF127_07109 was estimated to be between 2015 and 2019. Our findings showed that CRF127_07109 and related URFs were generated recently in northern Vietnam, rather than migrated independently to northern Vietnam.

Determination of intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations in dried blood spots for pre-exposure prophylaxis adherence.

OBJECTIVES: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 µL of 50% methanol and 400 µL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 µm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 µL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch. RESULTS: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration. CONCLUSIONS: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP.

Identification of viral protein R of human immunodeficiency virus-1 (HIV) and interleukin-6 as risk factors for malignancies in HIV-infected individuals: A cohort study.

BACKGROUND: Despite effective antiretroviral therapy, patients with human immunodeficiency virus type-1 (HIV) suffer from a high frequency of malignancies, but related risk factors remain elusive. Here, we focused on blood-circulating viral protein R (Vpr) of HIV, which induces proinflammatory cytokine production and genotoxicity by exogenous functions. METHODS AND FINDINGS: A total 404 blood samples of HIV patients comprising of 126 patients with malignancies (tumor group) and 278 patients without malignancies (non-tumor group), each of 96 samples was first selected by one-to-one propensity score matching. By a detergent-free enzyme-linked immunosorbent assays (detection limit, 3.9 ng/mL), we detected Vpr at a higher frequency in the matched tumor group (56.3%) than in the matched non-tumor group (39.6%) (P = 0.030), although there was no different distribution of Vpr levels (P = 0.372). We also detected anti-Vpr immunoglobulin (IgG), less frequently in the tumor group compared with the tumor group (22.9% for tumor group vs. 44.8% for non-tumor group, P = 0.002), and the proportion of patients positive for Vpr but negative of anti-Vpr IgG was significantly higher in the tumor group than in the non-tumor group (38.6% vs. 15.6%, respectively, P < 0.001). Additionally, Interleukin-6 (IL-6), the levels of which were high in HIV-1 infected patients (P < 0.001) compared to non-HIV-infected individuals, was significantly higher in advanced cases of tumors (P < 0.001), and IL-6 level was correlated with Vpr in the non-tumor group (P = 0.010). Finally, multivariate logistic regression analysis suggested a positive link of Vpr with tumor occurrence in HIV patients (P = 0.002). CONCLUSION: Vpr and IL-6 could be risk factors of HIV-1 associated malignancies, and it would be importance to monitor these molecules for well managing people living with HIV-1.

Rehabilitation facilitates functional improvement following intravenous infusion of mesenchymal stem cells in the chronic phase of cerebral ischemia in rats.

The primary objective of this study was to investigate the potential facilitating effects of daily rehabilitation for chronic cerebral ischemia following the intravenous infusion of mesenchymal stem cells (MSC) in rats. The middle cerebral artery (MCA) was occluded by intraluminal occlusion using a microfilament (MCAO). Eight weeks after MCAO induction, the rats were used as a chronic cerebral ischemia model. Four experimental groups were studied: Vehicle group (medium only, no cells); Rehab group (vehicle + rehabilitation), MSC group (MSC only); and Combined group (MSC + rehabilitation). Rat MSCs were intravenously infused eight weeks after MCAO induction, and the rats received daily rehabilitation through treadmill exercise for 20 min. Behavioral testing, lesion volume assessment using magnetic resonance imaging (MRI), and histological analysis were performed during the observation period until 16 weeks after MCAO induction. All treated animals showed functional improvement compared with the Vehicle group; however, the therapeutic efficacy was greatest in the Combined group. The combination therapy is associated with enhanced neural plasticity shown with histological analysis and MRI diffusion tensor imaging. These findings provide behavioral evidence for enhanced recovery by combined therapy with rehabilitation and intravenous infusion of MSCs, and may form the basis for the development of clinical protocols in the future.

Asian participants' experience in phase 3/3b studies of long-acting cabotegravir and rilpivirine: Efficacy, safety, pharmacokinetic, and virological outcomes through week 96.

OBJECTIVES: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96. METHODS: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS-2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV-1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV-1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed. RESULTS: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV-1 RNA <50 copies/mL, none had HIV-1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug-related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein-adjusted 90% inhibitory concentrations (CAB, 0.166 µg/mL; RPV, 12 ng/mL) through week 96. CONCLUSIONS: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV-1 virological suppression in Asian individuals.

Sitafloxacin- Versus Moxifloxacin-Based Sequential Treatment for Mycoplasma Genitalium Infections: Protocol for a Multicenter, Open-Label Randomized Controlled Trial.

BACKGROUND: Mycoplasma genitalium is an emerging sexually transmitted pathogen associated with increasing antibiotic resistance. The current treatment guidelines recommend moxifloxacin-sequential therapy for macrolide-resistant Mgenitalium or strains with unknown resistance profiles. However, it is unclear whether sitafloxacin, a 4th-generation fluoroquinolone antibiotic, is effective against resistant strains. OBJECTIVE: This study aims to assess and compare the efficacy and safety of sitafloxacin- and moxifloxacin-based treatment regimens for managing Mgenitalium infections. METHODS: We will conduct this randomized controlled trial at multiple centers in Japan. Eligible participants include adults aged 18 years or older with a confirmed Mgenitalium infection, as determined through the nucleic acid amplification test. Patients will be randomly assigned using a stratified approach based on the treatment facility and infection site. The interventions comprise oral sitafloxacin (200 mg) daily for 7 days (with optional pretreatment of oral doxycycline, 200 mg, daily for up to 7 days), with a control group receiving oral doxycycline (200 mg) daily for 7 days followed by moxifloxacin (400 mg) daily for another 7 days. The primary outcome is the treatment success rate with a superiority margin of 10%, as confirmed through the nucleic acid amplification test. Secondary outcomes encompass changes in the bacterial load at the urogenital or rectal sites and the emergence of posttreatment-resistant mutant strains. RESULTS: Enrollment commenced in June 2023 and will conclude in December 2024, with findings anticipated by 2025. The expected success rates fall within the range of 80% for sitafloxacin and 42% for moxifloxacin against Mgenitalium carrying the G248T (S83I) mutation, based on previous studies. Accordingly, with a 5% significance level (2-sided) and 80% statistical power, we aim to recruit 50 participants per group, factoring in a 10% expected dropout rate. CONCLUSIONS: This study will provide valuable insights into the efficacy and safety of sitafloxacin- versus moxifloxacin-based sequential therapy in treating Mgenitalium infections. These findings have the potential to influence clinical guidelines, favoring more effective therapeutic choices. The multicenter approach enhances the robustness of this study. However, a limitation is the potential insufficiency of statistical power to detect posttreatment-resistant mutant strains in each group, rendering posttreatment-resistance mutations a notable concern. In the future, we may need to increase the sample size to enhance power. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031230111); https://jrct.niph.go.jp/en-latest-detail/jRCTs031230111. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52565.

Efficacy and Safety of Pre-Exposure Prophylaxis to Control HIV and Sexually Transmitted Infection Among Men Who Have Sex With Men: Protocol for a Single-Arm Interventional Study.

BACKGROUND: Pre-exposure prophylaxis (PrEP) against HIV infection is a new approach that involves the prophylactic use of the anti-HIV drug Truvada (tenofovir disoproxil fumarate [TDF] and emtricitabine [FTC]) by people not infected with HIV. OBJECTIVE: The objective of this investigator-initiated clinical study of PrEP was to evaluate the incidence of HIV and sexually transmitted infection (STI), safety and efficacy of PrEP in PrEP users, and their compliance with PrEP medication. The social, medical, and economic benefits of PrEP in Japan was assessed. METHODS: This single-center feasibility study of PrEP was conducted at the National Center for Global Health and Medicine, Tokyo, Japan, where a cohort of men who have sex with men without HIV was established in January 2017. This single-arm interventional study compared the efficacy and safety of PrEP in a single group of men who have sex with men who participated in PrEP cohort studies. For reference, the cohort study participants who did not participate in the PrEP study were included for comparison. Blood samples were collected for storage at baseline and clinic visits at 1, 3, and 6 months after starting PrEP and every 3 months thereafter. The participants were administered with 1 tablet of Truvada once daily as PrEP. They underwent blood and anal swab tests 1 and 3 months after starting PrEP and then HIV and STI infection assessments at 3-month intervals. Blood samples were centrifuged at the AIDS Clinical Center Laboratory. PrEP safety was evaluated by monitoring serum creatinine levels for symptoms of renal function disorders. The primary end point was the incidence of HIV in PrEP users (100 person-years). The secondary end points were the incidence of STI in PrEP users (100 person-years), incidence of adverse events caused by Truvada, frequency of high-risk sexual activity, and adherence to periodic visits and medication. RESULTS: The study protocol was reviewed and approved by the certified review board of the National Center for Global Health and Medicine (NCGM-C-003129-03) on April 20, 2020. Changes to the study plan were submitted for review by the certified review board and approved before implementation. Recruitment was completed on March 28, 2019, and the study was completed (last adult participant and last time point) on March 31, 2021. The data were analyzed, and the main results of the study have been published in a peer-reviewed journal. CONCLUSIONS: The findings indicated that PrEP is a highly effective and feasible strategy against HIV infection in terms of prophylactic response, retention, and compliance. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000031040; https://tinyurl.com/3msdkeb8 and Japan Registry of Clinical Trials jRCTs031180134; https://tinyurl.com/2p88mhyr. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/50919.

Multicenter observational survey on psychosocial and behavioral impacts of COVID-19 in people living with HIV in Northern Vietnam.

Socially marginalized groups, including people living with HIV/AIDS (PLHIV), could be disproportionately affected by Coronavirus disease 2019 (COVID-19). Following an initial single-center survey conducted in 2020, we conducted a second survey of 11 antiretroviral therapy (ART) sites in Northern Vietnam between June 2021 and January 2022. We tested anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) nucleocapsid IgG antibodies and assessed prevention against COVID-19 and impacts of COVID-19 on access to ART, economic security, risky health behaviors, and mental health using self-reported questionnaires. In total, 7808 PLHIV on ART participated in the second survey. The overall prevalence of SARS-CoV-2 antibody was as low as 1.2%. There was no clear upward trend in COVID-19 infection among PLHIV compared with the rate of infection among the general population. HIV treatment was generally maintained and no increase in risky health behaviors was observed. The economic impacts were significant, with high unemployment rate, poorer economic security, and binge drinking strongly associated with depression. However, the prevalence of depression decreased by 11.2% compared with pre-COVID-19 levels. Social support, including for patients to continue HIV treatment and effective employment/financial assistance, may help to alleviate the negative socioeconomic impacts of COVID-19 and improve mental health among PLHIV.

HIV-1 protective epitope-specific CD8+ T cells in HIV-1-exposed seronegative individuals.

Although previous studies have reported HIV-1-specific T cell responses in HIV-1-exposed seronegative (HESN) individuals, there has been no detailed analysis of these T cells against HIV-1 infection. We investigated HIV-1-specific CD8+ T cell responses in 200 Japanese HESN men who have sex with men (MSM). T cell responses to 143 well-characterized HIV-1 epitope peptides were analyzed by intracellular cytokine staining assay consisting of 3-week cultures of PBMCs stimulated with peptides. HLA-B∗51:01-restricted Pol TI8-specific and HLA-A∗02:06-restricted Pol SV9-specific CD8+ T cells were identified in two and one individuals, respectively, whereas CD8+ T cells specific for other HLA-A∗02:06-restricted or HLA-B∗51:01 epitopes were not present in these individuals. These epitope-specific T cells recognized HIV-1-infected cells. Because these two epitopes were previously reported to be protective in HIV-1-infected individuals, these protective epitope-specific T cells might suppress HIV-1 replication in HESN-MSM individuals. The present study suggests the contribution of protective epitope-specific T cells to protection against HIV-1 infection.

Epitope-dependent effect of long-term cART on maintenance and recovery of HIV-1-specific CD8+ T cells.

IMPORTANCE: HIV-1-specific CD8+ T cells are anticipated to become effector cells for curative treatment using the "shock and kill" approach in people living with HIV-1 (PLWH) under combined antiretroviral therapy (cART). Previous studies demonstrated that the frequency of HIV-1-specific CD8+ T cells is reduced under cART and their functional ability remains impaired. These studies analyzed T-cell responses to a small number of HIV-1 epitopes or overlapping HIV-1 peptides. Therefore, the features of CD8+ T cells specific for HIV-1 epitopes under cART remain only partially clarified. Here, we analyzed CD8+ T cells specific for 63 well-characterized epitopes in 90 PLWH. We demonstrated that CD8+ T cells specific for large numbers of HIV-1 epitopes were maintained in an epitope-dependent fashion under long-term cART and that long-term cART enhanced or restored the ability of HIV-1-specific T cells to proliferate in vitro. This study implies that some HIV-1-specific T cells would be useful as effector cells for curative treatment.

Preinfection Neutralizing Antibodies, Omicron BA.5 Breakthrough Infection, and Long COVID: A Propensity Score-Matched Analysis.

BACKGROUND: Data are limited on the role of preinfection humoral immunity protection against Omicron BA.5 infection and long coronavirus disease (COVID) development. METHODS: We conducted nested case-control analysis among tertiary hospital staff in Tokyo who donated blood samples in June 2022 (1 month before Omicron BA.5 wave), approximately 6 months after receiving a third dose of COVID-19 mRNA vaccine. We measured live virus-neutralizing antibody titers against wild type and Omicron BA.5, and anti-receptor-binding domain (RBD) antibody titers at preinfection, and compared them between cases and propensity-matched controls. Among the breakthrough cases, we examined association between preinfection antibody titers and incidence of long COVID. RESULTS: Preinfection anti-RBD and neutralizing antibody titers were lower in cases than controls. Neutralizing titers against wild type and Omicron BA.5 were 64% (95% confidence interval [CI], 42%-77%) and 72% (95% CI, 53%-83%) lower, respectively, in cases than controls. Individuals with previous Omicron BA.1/BA.2 infections were more frequent among controls than cases (10.3% vs 0.8%), and their Omicron BA.5 neutralizing titers were 12.8-fold higher than infection-naive individuals. Among cases, preinfection antibody titers were not associated with incidence of long COVID. CONCLUSIONS: Preinfection immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may play a role in protecting against the Omicron BA.5 infection but not preventing long COVID.

Steady-state pharmacokinetics of plasma tenofovir alafenamide (TAF), tenofovir (TFV) and emtricitabine (FTC), and intracellular TFV-diphosphate and FTC-triphosphate in HIV-1 infected old Japanese patients treated with bictegravir/FTC/TAF.

Emtricitabine (FTC) plus tenofovir alafenamide (TAF) has demonstrated efficacy and safety for pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection. We measured the plasma PK of FTC, tenofovir (TFV), and TAF in a steady-state pharmacokinetic (PK) study of bictegravir/FTC/TAF in HIV-1-infected patients. Furthermore, validated liquid chromatography-tandem mass spectrometry was used to measure intracellular TFV-diphosphate (DP) and FTC-triphosphate (TP), the active metabolites of TFV and FTC, respectively. Plasma and dried blood spot samples were collected from 10 male patients aged ≥ 50 years at various time intervals: 0 (trough), 1, 2, 3, 4, 6, 8, 12, and 24 h after drug administration. The mean ± standard deviation of plasma PK parameters were as follows: The maximum concentrations of TAF, TFV, and FTC were 104.0 ± 72.5, 27.9 ± 5.2, and 3,976.0 ± 683.6 ng/mL, respectively. Additionally, their terminal elimination half-lives were 0.6 ± 0.5, 31.6 ± 10.4, and 6.9 ± 1.4 h, respectively. These results were consistent with previously reported data. The intracellular levels of TFV-DP and FTC-TP varied widely among individuals; however, they remained stable over 24 h in each individual at approximately 1,000-1,500 and 2,000-3,000 fmol/punch, respectively, indicating that plasma concentrations did not affect the intracellular concentrations of their active metabolites. These results demonstrated that measuring intracellular TFV-DP and FTC-TP could be useful for monitoring adherence to PrEP in clients on this regimen.

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

BACKGROUND: Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS: SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS: 837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION: These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING: ViiV Healthcare.

Effect of unintended short-term 3.0 g/day amoxicillin and probenecid treatment for early syphilis on patients with HIV-1 infection.

Background: Standard therapy for early syphilis involves intramuscular injections of penicillin G, which frequently faces shortages in several countries. Fourteen-day amoxicillin therapy has been suggested as an alternative to benzathine penicillin G, but the optimal duration of amoxicillin therapy remains unclear and could theoretically be shortened to less than 14 days. The aim of this study was to explore the effectiveness of short-term amoxicillin therapy for early syphilis. Methods: We retrospectively explored the effectiveness of short-term amoxicillin therapy for early syphilis. The treatment data of patients who had received amoxicillin therapy for less than 14 days for unintended reasons were reviewed. Diagnosis was confirmed based on either the physician's description or clinical presentation. Successful treatment was defined as a fourfold or greater decline in the rapid plasma reagin titer or sero-reversion to negative within 12 months. Results: Of 295 patients, 8 received short-term amoxicillin treatment. All were men who had sex with men and people living with human immunodeficiency virus. Their median age, CD4 count, and treatment duration were 34 years (range, 26-40), 258/mL (range, 112-930), and 9.5 days (range, 5-11), respectively. One patient had primary syphilis, six had secondary syphilis, and one had early latent syphilis. All patients, except one who showed reinfection, demonstrated a serological response within 4 months. The median time for serological response was 112 days. Conclusion: The results indicate that early syphilis could potentially be treated with 5-11 days of amoxicillin therapy combined with probenecid. This suggests that short-term amoxicillin therapy might be a sufficient treatment for early syphilis instead of the standard 14-day course.