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Porcine deltacoronavirus (PDCoV) poses a significant threat to both the pig industry and public safety, and has recently been identified in humans. Currently, there are no commercially available vaccines or antiviral treatments for PDCoV. In this study, recombinant porcine interferon δ8 (rINF-δ8) expressed by the HEK 293F expression system was used to evaluated its antiviral activity against PDCoV both in vitro and in vivo. Results demonstrated that rIFN-δ8 displayed non-toxic to ST cells and primary PAMs, and effectively inhibited PDCoV replication in a dose-dependent manner in vitro, with complete suppression of virus replication at a concentration of 2 μg/ml. Treatment of piglets with two doses of 25 μg/kg of rIFN-δ8 reduced clinical symptoms, decreased virus shedding, alleviated intestinal damage, and lowered the viral load in the jejunum and ileum. Furthermore, the levels of interferon-stimulated genes (ISGs) such as Viper, Mx1, ISG15, IFIT1, OSA, and IFITM1 were significantly increased both in vitro and in vivo, with elevated ISG levels sustained for at least 3 days in vivo. These findings suggest that rIFN-δ8 has the potential to serve as an effective antiviral agent for preventing PDCoV in pigs in the future., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Psoriasis, a chronic inflammatory skin disease, presents unique challenges when co-occurring with HIV. Tildrakizumab, an IL-23p19 inhibitor, has demonstrated efficacy in treating moderate-to-severe psoriasis. This retrospective case series reports three individuals living with HIV and psoriasis treated with tildrakizumab. Clinical outcomes, including Psoriasis Area and Severity Index (PASI) and HIV viral load, were recorded over a year. All three patients achieved significant clinical improvements with tildrakizumab, with PASI scores improving by over 95%. No adverse effects were reported, and HIV viral loads remained undetectable. Tildrakizumab appears to be a safe and effective treatment option for psoriasis in individuals living with HIV, providing significant benefits without compromising HIV control., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To date, the effectiveness of direct-acting antivirals (DAAs) discontinued before 4 weeks has not been analysed in routine clinical practice. The study aimed to determine whether such a short therapy will enable achieving a sustained virological response under real-world experience. The study population of 97 patients who discontinued DAA therapy and had data enabling analysis of patient and disease characteristics, and assessment of treatment effectiveness was selected from 16,815 patients registered in the EpiTer-2 database. The most common reason for discontinuation was hepatic decompensation (20.6%) or the patient's personal decision (18.6%). Patients who discontinued treatment were significantly older, more frequently therapy-experienced, more likely to have cirrhosis, a history of decompensation and a Child-Pugh B or C classification than those who completed treatment. SVR was achieved by 93.5% of patients who discontinued treatment after 4 weeks, 60.9% if discontinued at 3 or 4 week and 33.3% at Week 1 or 2. Patients receiving pangenotypic but not genotype-specific treatment who discontinued after 4 weeks were as likely to achieve SVR as those who completed therapy. Patients who responded to treatment that lasted no longer than 2 weeks had a low baseline viral load (<400,000 IU/mL). Despite discontinuation of therapy after Week 4, the chances of SVR are high. Very early discontinuation does not preclude therapeutic success, especially in patients with low baseline viral load., (© 2024 John Wiley & Sons Ltd.)

Background & Aims: Genetic polymorphisms in the sodium taurocholate cotransporting peptide (NTCP encoded by SLC10A1) have been described, but their role in untreated and treated patients with chronic hepatitis delta (CHD) remains unknown. Virological response (VR) to the NTCP inhibitor bulevirtide (BLV) was achieved at week 48 by >70% of patients with CHD, but nearly 15% experienced virological non-response (VNR) or partial response (PR). This study aimed to evaluate whether NTCP genetic polymorphisms affect baseline HDV RNA load and response to BLV in patients with CHD., Methods: BLV-untreated and -treated patients were enrolled in a retrospective cross-sectional and longitudinal study. Clinical and virological characteristics were collected at baseline and up to 96 weeks in the BLV-treated patients. NTCP genetic polymorphisms were identified by Sanger sequencing., Results: Of the six NTCP polymorphisms studied in 209 untreated patients with CHD, carriers of the rs17556915 TT/CC (n = 142) compared to CT (n = 67) genotype presented with higher median HDV RNA levels (5.39 vs. 4.75 log 10  IU/ml, p = 0.004). Of 209 patients receiving BLV monotherapy at 2 mg/day, 76 were evaluated at week 24 and 40 up to week 96. Higher mean baseline HDV RNA levels were confirmed in TT/CC (n = 43) compared to CT (n = 33) carriers (5.38 vs. 4.72 log 10  IU/ml, p = 0.010). Although 24-week VR was comparable between TT/CC and CT carriers (25/43 vs. 17/33, p = 0.565), the former group presented VNR more often than PR (9/11 vs. 9/23, p = 0.02) at week 24. 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment., Conclusions: The NTCP rs17556915 C>T genetic polymorphisms may influence baseline HDV RNA load both in BLV-untreated and -treated patients with CHD and may contribute to identifying patients with different early virological responses to BLV., Impact and Implications: Although several sodium taurocholate cotransporting polypeptide (NTCP) genetic polymorphisms have been described, no data are available on their potential role in modifying HDV RNA load or treatment response to bulevirtide (BLV) in patients with chronic hepatitis delta (CHD). In this study, we demonstrated that patients with CHD, either treated or untreated, carrying NTCP rs17556915 TT/CC, presented higher baseline HDV RNA levels compared to those with the CT genotype. Higher HDV RNA levels in TT/CC carriers compared to CT carriers were also confirmed in patients with CHD treated with BLV monotherapy up to 96 weeks. Furthermore, carriers of TT/CC, compared to CT genotype, more frequently showed viral non-response (VNR) than partial response (PR) at week 24 of BLV treatment, and 7/9 TT/CC genotype carriers remained VNR at week 48 of BLV treatment. This is the first study demonstrating a potential role of NTCP genetic polymorphisms in influencing HDV viral load and early virological response to BLV monotherapy. Since no direct HDV resistance to BLV has been described so far, if confirmed in larger studies, the genetic polymorphisms in NTCP may help identify patients with different patterns of early virological response to BLV., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n = 6) or IFNα (n = 7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ., Competing Interests: Declaration of competing interest Kazuaki Chayama has received honoraria from Bristol-Myers Squibb and MSD K.K., AbbVie, Gilead Science, Dainippon Sumitomo Pharma and Mitsubishi Tanabe Pharma and research funding from Gilead Science, Dainippon Sumitomo Pharma, MSD K.K., AbbVie, Eisai, TORAY, Otsuka Pharma, Chugai Pharma, Takeda Pharma and Roche. Jeffrey Glenn, director, and equity holder of Eiger Biopharmaceuticals. Ohad Etzion has received consulting fees from Eiger Biopharmaceuticals. The other authors declare no conflicts of interest that pertain to this work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Lizhong decoction (LZD) is a frequently utilized traditional Chinese remedy for diarrhea. It is unknown how effective it is as an antiviral against PEDV infection., Aim of the Study: In vitro and in vivo PEDV infection models were used to evaluate the anti-PEDV potential of LZD extract., Materials and Methods: LC-MS was used for qualitative analysis of LZD. The antiviral effect of LZD against PEDV using flow cytometry (FC), Quantitative real-time polymerase chain reaction (QPCR), immunofluorescence assay (IFA) analysis in Vero and IPEC-J2 cells. Additionally, we measured the survival rate, clinical symptoms, body weights, fecal scores, temperature, histological analysis, and viral load in a model of newborn piglets infected with PEDV in order to assess the antiviral impact of LZD in vivo., Results: In total, 648 compounds were identified, including 144 Alkaloids, 128 Terpenoids, etc. LZD effectively suppressed PEDV replication in vitro. According to time of addition experiments, LZD mostly inhibited PEDV during the viral life cycle's replication stages. During PEDV infection, LZD can Significantly decrease the apoptotic rate of IPEC-J2 cells and Vero cells. In comparison to the model group, LZD was able to decrease the viral titers in the infected piglets' intestinal and visceral tissues, ameliorate their intestinal pathology, cause a significant increase in body weight growth and increase the piglet survival rate., Conclusion: Our findings indicate that the aqueous solution derived from LZD suppressed PEDV replication both in vitro and in vivo, indicating its potential as a candidate for pharmaceutical development., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Two-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States., Methods: Virologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA ® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined., Results: A total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC (n = 1,450), BIC/FTC/TAF (n = 5,691), or a DTG-based 3DR (n = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%)., Conclusions: Among virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH., (© 2024. The Author(s).)

Background: Protease inhibitor (PI)-based Antiretroviral Therapy (ART) regimens are key drugs in HIV management, especially when used as second line drugs. However, some PI-based ART have high adherence demands or tolerable adverse effects which may affect adherence and subsequently viral suppression. We assessed the extent of viral suppression, its determinants, and the experiences of clients on PI-based ART undergoing intensive adherence counselling (IAC) in a public HIV clinic., Methods: Mixed methods sequential explanatory study involving a quantitative retrospective chart review for clients on PI-based ART who had received IAC from Dec 2016 to May 2023 and qualitative interviews for clients on PI-based ART who had received IAC in the past six months at an urban public HIV clinic in Uganda., Results: In this study, a total of 189 client charts were included. The median number of IAC sessions received was three (interquartile range, IQR, of 3 to 4) with median time of receiving IAC of three ( IQR, of 2 to 4). One half (51%, 95/186) of the clients had achieved viral suppression and the odds of suppression increased by 30% for every additional month on IAC. Respondents perceived the effectiveness of PI-based ART and IAC in achieving and supporting viral suppression, respectively., Conclusion: Despite the perceived effectiveness of PI-based ART and IAC, suboptimal levels of viral suppression were observed among clients on PI-based ART who had received IAC. Therefore, it is important to provide IAC for optimal duration as it increases the chances of viral suppression. Further investigation of the barriers of viral suppression for clients on PI-based ART undergoing IAC is needed., (© 2024. The Author(s).)

Observational studies suggest a reduction in fatal or severe COVID-19 disease with the use of ACE2 inhibitors and statins. We implemented a randomized controlled tree-arm open label trial evaluating the benefits of adding telmisartan (TLM) or atorvastatin (ATV) to lopinavir boosted ritonavir (LPVr) on the SARS-CoV-2 nasopharyngeal viral load in patients with mild / moderate COVID-19 infection in Côte d'Ivoire. RT-PCR positive COVID-19 patients ≥ 18 years, with general or respiratory symptoms for less than 7 days were randomized (1:1:1) to receive LPVr (400 mg/100 mg twice daily), LPVr + TLM (10 mg once daily) or LPVr + ATV (20 mg once daily) for 10 days. The primary endpoint was viro-inflammatory success defined as a composite variable at day 11: Ct ≥ 40 and C-reactive protein < 27 mg/L. We randomized 294 patients: 96 to LPVr, 100 to LPVr + TLM, 98 to LPVr + ATV arms. Baseline characteristics were well balanced between arms. In the primary analysis (missing = failure), 46% patients in the LPVr arm reached viro-inflammatory success at day 11 vs 43% in the LPVr + TLM arm (p = 0.69) and 43% in the LPVr + ATV arm (p = 0.68). The median time from baseline to resolution of COVID-19 related symptoms was not different between arms. Nine patients were hospitalized: 2 in the LPVr arm, 5 in the LPVr + TLM arm and 2 in the LPVr + ATV arm and 4 patients died. Among adults with mild to moderate COVID-19 infection, the addition of telmisartan or atorvastatin, to the standard LPVr treatment is not associated with a better virological or clinical outcome.Trial registration: NCT04466241, registered on 10/07/2020., (© 2024. The Author(s).)

Objective: HIV-1 management has advanced significantly with antiretroviral therapy (ART), yet challenges persist, including low-level HIV-1 viraemia (LLV). LLV presents a complex scenario, with varied definitions in the literature, reflecting uncertainties in its clinical interpretation. Questions arise regarding the underlying mechanisms of LLV, whether it signifies ongoing viral replication or stems from other factors. This study aimed to systematically review strategies for LLV management, providing insights into optimal clinical approaches., Methods: MEDLINE, EMBASE, Cochrane Library, Web of Science and Canadian Agency for Drugs and Technologies in Health were searched for relevant literature on LLV management. We included studies published between 2004 and 2024, assessing interventions such as ART modification, genotypic resistance testing, adherence assessment, performing therapeutic drug monitoring, testing for chronic coinfections and assessing the viral reservoir via HIV DNA quantification. Meta-analyses were conducted where feasible., Results: The systematic review identified 48 eligible records. Findings indicated limited evidence supporting the effectiveness of ART regimen modification in achieving virological suppression among individuals with LLV. However, studies assessing genotypic resistance testing revealed a significant association between resistance-associated mutations and virological suppression during LLV. Adherence to ART emerged as a critical determinant of treatment efficacy, with interventions showing promise in achieving viral suppression. The clinical utility of therapeutic drug monitoring in managing LLV remained inconclusive. Gaps in the literature were identified regarding follow-up scheduling, managing concurrent chronic infections and assessing inflammatory markers in LLV management., Conclusions: While ART modification may not consistently achieve virological suppression, genotypic resistance testing may offer insights into treatment outcomes. Adherence to ART emerged as a crucial factor, necessitating tailored interventions. However, further research is needed to elucidate the clinical utility of therapeutic drug monitoring and other management strategies. The study highlights the importance of ongoing research to refine therapeutic approaches and improve patient outcomes in LLV management., Prospero Registration Number: CRD42024511492., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

5-Aminolevulinic acid (5-ALA), a non-proteinogenic amino acid, is an intermediate in the biosynthesis of heme and exerts antiviral effects against feline coronavirus (FCoV); however, the underlying mechanisms remain unclear. In the biosynthesis of heme, 5-ALA is condensed and converted to protoporphyrin IX (PpIX), which is then transformed into heme by the insertion of ferrous iron. Previous research has suggested that the metabolites generated during heme biosynthesis contribute to the antiviral effects of 5-ALA. Therefore, the present study investigated the in vitro mechanisms responsible for the antiviral effects of 5-ALA. The results obtained revealed that 5-ALA and PpIX both effectively reduced the viral titer in the supernatant of FCoV-infected fcwf-4 cells. Moreover, PpIX exerted virucidal effects against FCoV. We also confirmed that 5-ALA increased PpIX levels in cells. While hemin induced heme oxygenase-1 gene expression, it did not reduce the viral titer in the supernatant. Sodium ferrous citrate decreased PpIX levels and suppressed the antiviral effects of 5-ALA. Collectively, these results suggest that the antiviral effects of 5-ALA against FCoV are dependent on PpIX.

Adherence to antiretroviral therapy (ART) is essential for the effective management of HIV, which includes keeping the HIV viral load undetectable. This study aimed to determine whether certain ART medications are more "forgiving" of poor adherence in achieving viral suppression. We identified subgroups of ART medication usage and determined the extent to which ART adherence is associated with viral suppression across those subgroups. Data came from claims and clinical records (2017-2019) of 3,552 HIV-positive adult members of a Medicaid managed care plan. Pharmacy fill data were examined to characterize ART medications using latent class analysis (LCA), which captures the complexity of real-world ART usage (i.e., multiple medications, ART switching). LCA yielded five ART medication patterns over three years, mostly characterized by recent medications and formulations of ART, though they varied in number of tablets and in medication class. Mixed effects logistic regression models were estimated to determine whether odds of viral suppression differed by ART adherence level. After adjusting for covariates, those with at least 90% adherence (i.e., 90 to < 95%) did not significantly differ from those with 95% adherence or greater in terms of viral suppression, which corroborates existing clinical recommendations. These findings can inform provider-patient communication for people with HIV, especially those who have difficulty maintaining adherence. This includes those experiencing unstable housing, mental health conditions, or substance use., (© 2024. The Author(s).)

BRAAVE (NCT03631732), a Phase 3b, multicenter, open-label US study, demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among Black individuals with suppressed HIV through 48 weeks. Here, 72-week resistance, adherence, and virologic outcomes are presented. Enrollment criteria permitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistance (R), protease inhibitor (PI)-R, and certain nucleos(t)ide reverse transcriptase inhibitor (NRTI)-R (M184V/I allowed; ≥3 thymidine analog mutations [TAMs] excluded); but excluded primary integrase strand transfer inhibitor (INSTI)-R. Pre-existing resistance was determined using historical genotypes and retrospective baseline proviral DNA genotyping. Adherence, virologic outcomes, and viral blips were assessed. Of 489 participants receiving B/F/TAF with ≥1 post-switch HIV-1 RNA measurement: pre-existing NRTI-R (15% of participants), M184V/I (11%), ≥1 TAMs (8%), NNRTI-R (22%), and PI-R (13%) were observed; pre-existing INSTI-R substitutions (2%) were detected post-randomization; mean viral blip frequency was 0.9% across all timepoints (unassociated with virologic failure); 24% of participants had <95% adherence (98% of whom had HIV-1 RNA <50 copies/mL at last visit); none had treatment-emergent study-drug resistance. Overall, 99% of participants, including all with baseline NRTI-R/INSTI-R, had HIV-1 RNA <50 copies/mL at the last visit, demonstrating that B/F/TAF maintained virologic suppression through 72 weeks regardless of pre-existing resistance, viral blips, and suboptimal adherence., (© 2024 Gilead Sciences, Inc. and The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Lenacapavir is a novel, first-in-class, capsid inhibitor, which has been approved as an adjunctive therapy for multidrug-resistant human immunodeficiency virus (HIV)-1 virus in combination with optimized background regimen (OBR). Lenacapavir has demonstrated a significant decrease in viral load and high rate of virologic suppression in patients with multidrug-resistant HIV-1 infection with limited treatment options. Here, we report a case of 43-year-old male who was diagnosed with HIV-1 infection in 2005 but failed to achieve viral suppression due to multiclass resistance. After lenacapavir use with OBR, viral suppression was achieved, and recovery of CD4 + T-cell count was observed for 8 months. This case report shows the first lenacapavir experience in Asia in a heavily treatment-experienced HIV patient with limited treatment options., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Objective: To describe the efficacy of intermittent nucleoside analogue-based (NA) regimen to maintain HBV virological suppression in HBV/HIV-1 patients., Methods: Conducted between 2014 and 2023, this observational retrospective study included all HBV (positive AgHbs)/HIV-1 coinfected patients with HIV RNA ≤ 50 cp/mL and HBV DNA ≤ 25 UI/mL who were switched to an intermittent (<7/7 days(D)) TDF or TAF-containing antiretroviral (ART) regimen. The primary outcome was the HBV virological success rate (SR) (proportion of patients with HBV pVL < 25 UI/mL) at W48., Results: Among 501 HBV/HIV-1 patients, 19(3.7 %) had switched to an intermittent NA-containing regimen that included TDF/FTC or TDF/3TC or TAF/FTC or TDF alone administered 5D-a-week(n = 7), 4D-a-week(n = 7) or 3D-a-week(n = 5). HBV virological success rates were 100 % [95 %CI 82.3-100] and 100 %[95 %CI 80.5-100] at W48 and W96(n = 17), respectively; with no viral HBV or HIV rebound (61.8 months (32.4-70.3) of follow-up)., Conclusion: This case series shows the potential for intermittent NA-containing regimens to maintain long-term control of HBV replication among suppressed HBV/HIV-1 patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: This in vitro study aimed to investigate the effect of several phenolic compounds, including doxorubicin, quercetin, and resveratrol, on HSV-1 infection., Methods: The cytotoxicity of the drugs was assessed on Vero cells using the MTT assay. HSV-1 was treated with the drugs, and the supernatants were collected at various time points. TCID50% and qPCR tests were conducted on the supernatants to determine viral titration post-inoculation., Results: The TCID50% assay showed significant changes in viral titration for acyclovir, doxorubicin, and quercetin at most concentrations ( p -value < .05), while no significant changes were observed for resveratrol. The qPCR results demonstrated that drug-treated HSV-1 exhibited a significant reduction in DNA titers at various time points compared to non-treated HSV-1 infected Vero cells, except doxorubicin (0.2 µM) and acyclovir (5 µm). However, over time, DNA virus levels gradually increased in the drug-treated groups. Notably, at certain concentrations of doxorubicin and quercetin-treated groups, virus titer significantly declined, similar to acyclovir., Conclusions: Our findings suggest that quercetin at concentrations of 62 and 125 µM significantly reduced HSV-1 infectivity, as well as these two concentrations of quercetin showed a significant difference in virus reduction compared with acyclovir (10 µM) at certain time points. The anti-inflammatory properties of quercetin, in contrast to acyclovir, make it a potential candidate for anti HSV-1 treatment in life-threatening conditions such as Herpes encephalitis. Additionally, doxorubicin, an anticancer drug, showed meaningful inhibition of HSV-1 at non-toxic concentrations of 2 and 8 µM, suggesting its potential interference with HSV-1 in viral-oncolytic therapy in cancer treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/aim: Tenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB)., Methods: We retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF ( n = 58) or TAF ( n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed., Results: Baseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF ( p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF ( p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively ( p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups., Conclusion: TMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID-19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS-CoV-2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose-dependent antiviral effect against the SARS-CoV-2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS-CoV-2 Omicron or HPIV3, indicating a virus-specific effect. At high concentrations, CsA was associated with an increase of IL-8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug-virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Long-acting injectable cabotegravir and rilpivirine is licensed for individualised treatment of HIV-1 infection in resource-rich settings. Additional evidence is required to support use in African treatment programmes where demographic factors, viral subtypes, previous treatment, and delivery and monitoring approaches differ. The aim of this study was to determine whether switching to long-acting therapy with injections every 8 weeks is non-inferior to daily oral therapy in Africa., Methods: CARES is a randomised, open-label, non-inferiority trial being conducted at eight sites in Uganda, Kenya, and South Africa. Participants with HIV viral load below 50 copies per mL on oral antiretroviral therapy and no history of virological failure were randomly assigned (1:1; web-based, permuted blocks) to receive cabotegravir (600 mg) and rilpivirine (900 mg) by intramuscular injection every 8 weeks, or to continue oral therapy. Viral load was monitored every 24 weeks. The primary outcome was week 48 viral load below 50 copies per mL, assessed with the Food and Drug Administration snapshot algorithm (non-inferiority margin 10 percentage points) in the intention-to-treat exposed population. This trial is registered with the Pan African Clinical Trials Registry (202104874490818) and is ongoing up to 96 weeks., Findings: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 512 participants (295 [58%] female; 380 [74%] previous non-nucleoside reverse transcriptase inhibitor exposure). Week 48 viral load was below 50 copies per mL in 246 (96%) of 255 participants in the long-acting therapy group and 250 (97%) of 257 in the oral therapy group (difference -0·8 percentage points; 95% CI -3·7 to 2·3), demonstrating non-inferiority (confirmed in per-protocol analysis). Two participants had virological failure in the long-acting therapy group, both with drug resistance; none had virological failure in the oral therapy group. Adverse events of grade 3 or greater severity occurred in 24 (9%) participants on long-acting therapy and ten (4%) on oral therapy; one participant discontinued long-acting therapy (for injection-site reaction)., Interpretation: Long-acting therapy had non-inferior efficacy compared with oral therapy, with a good safety profile, and can be considered for African treatment programmes., Funding: Janssen., Competing Interests: Declaration of interests CK reports funding paid to institution and donation of drugs to institution from Janssen for the work reported in this manuscript. SS reports funding paid to institution and personal fees for speaking at symposia from Janssen and donation of drugs to institution from ViiV, all outside the work reported in this manuscript. FC reports funding paid to institution and donation of drugs to institution from Janssen and funding paid to institution from ViiV, Gilead, Wellcome Trust, and the National Institute of Health Research UK outside the work reported in this manuscript; and unpaid role as Chair of Steering Committee for an investigator-initiated long-acting implementation trial. KM reports personal fees for speaking at symposia from Janssen outside of the work reported in this manuscript. VVE is an employee of Johnson & Johnson and holds stock options in Johnson & Johnson; and a patent related to rilpivirine. PM was an employee of Janssen at the time of trial design, and then an employee of ViiV during the time of trial conduct, manuscript submission, and publication; and holds stock from GSK as an employee of ViiV. FAB is an employee of Johnson & Johnson and holds stock options of Johnson & Johnson. NIP reports grants paid to institution, donation of drugs to institution, and personal fees for speaking at symposia from Janssen outside the work reported in this manuscript; and is the Chief Investigator on a trial with funding paid to institution by the EU for testing anti-tuberculosis drug combinations based on the drug ganfeborole, owned by GSK. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Herpes simplex virus type 1 (HSV-1) is responsible for a wide range of human infections, including skin and mucosal ulcers, encephalitis, and keratitis. The gold standard for treating HSV-1 infections is acyclovir. However, the use of this drug is associated with several limitations such as toxic reactions and the development of drug-resistant strains. So, there is an urgent need to discover and develop novel and effective agents against this virus. For the first time, this study aimed to investigate the antiviral effects of the Thermally Expanded Graphite (TEG)-copper oxide (CuO) nanocomposite against HSV-1 and compare results with its constituent components. After microwave (MW)-assisted synthesis of TEG and CuO nanosheets as well as MW-CuO/TEG nanocomposite and characterization of all these nanomaterials, an MTT assay was used to determine their cytotoxicity. The quantitative real-time PCR was then used to investigate the effects of these nanomaterials on viral load. Three-hour incubation of HSV-1 with TEG nanosheets (500 μg/mL), MW-CuO nanosheets (15 μg/mL), and MW-CuO/TEG nanocomposite (35 μg/mL) resulted in a decrease in viral load with an inhibition rate of 31.4 %, 49.2 %, and 74.4 %, respectively. The results from the post-treatment assay also showed that TEG nanosheets (600 μg/mL), MW-CuO nanosheets (15 μg/mL), and MW-CuO/TEG nanocomposite (10 μg/mL) led to a remarkable decrease in viral load with an inhibition rate of 56.9 %, 63 %, and 99.9 %, respectively. The combination of TEG and MW-CuO nanosheets together and the formation of a nanocomposite structure display strong synergy in their ability to inhibit HSV-1 infection. MW-CuO/TEG nanocomposites can be considered a suitable candidate for the treatment of HSV-1 infection., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ahmad Tavakoli reports financial support was provided by Iran University of Medical Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure-response (E-R) from five studies in treatment-experienced and integrase-resistant (INI-r) patients infected with HIV-1. Importantly, model-based simulations of the E-R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub-population with Q148-driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation-containing products) factors expected to influence the DTG E-R relationship. Model-based post hoc exposure metrics (C min and C avg ) were incorporated into a mechanistic population viral dynamic model describing the short-term effect of DTG on log10 HIV-1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24-week HIV RNA response was also assessed using logistic regression. There was good concordance between model-based predictions and observed virologic response on day 10 and week 24. The E-R model-based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor-resistant (INI-r) population., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: Tenofovir-containing antiretroviral therapy regimens may have long-term toxicity-related side effects. This study aimed to compare the virological efficacy of co-formulated darunavir/ritonavir plus lamivudine with darunavir/ritonavir plus tenofovir and emtricitabine or lamivudine., Methods: The ANDES study was a 48-week, phase 4, randomized, open-label, non-inferiority trial in treatment-naïve adults living with human immunodeficiency virus (HIV). Patients were randomized on a 1:1 basis to receive a daily oral regimen of either dual therapy based on a generic co-formulation of darunavir/ritonavir (800/100 mg) plus a generic lamivudine 300 mg pill, or triple therapy with darunavir/ritonavir plus tenofovir/emtricitabine (300/200 mg) or tenofovir/lamivudine (300/300 mg). The primary endpoint was the proportion of patients with a viral load of <50 copies/mL at week 48 in the intention-to-treat population. The US Food and Drug Administration snapshot algorithm and a non-inferiority margin of -12% were used. The secondary objective was to analyse safety in the per-protocol population. This study has been registered at ClinicalTrials.gov (NCT02770508)., Results: Between November 2015 and 31 October 2020, 336 participants were assigned at random to the triple therapy arm (n=165) or the dual therapy arm (n=171). After 48 weeks, 153 patients in the triple therapy group (93%) and 155 patients in the dual therapy group (91%) achieved virological suppression (difference -2.1%, 95% confidence interval -7.0 to 2.9). Drug-related adverse events were more common in the triple therapy group (P=0.04). Two toxicity-related events led to discontinuation in each group., Interpretation: Co-formulated darunavir/ritonavir plus lamivudine showed non-inferiority and a safer toxicity profile compared with the standard-of-care triple therapy regimen including tenofovir in treatment-naïve patients., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Analytical treatment interruption (ATI) is widely acknowledged as an essential component of studies to advance our understanding of HIV cure, but discussion has largely been focused on adults. To address this gap, we reviewed evidence related to the safety and utility of ATI in paediatric populations. Three randomised ATI trials using CD4 T-cell and clinical criteria to guide restart of antiretroviral therapy (ART) have been conducted. These trials found low risks associated with ATI in children, including reassuring findings pertaining to neurocognitive outcomes. Similar to adults treated during acute infection, infants treated early in life have shifts in virological and immunological parameters that increase their likelihood of achieving ART-free viral control. Early ART limits the size and diversity of the viral reservoir and shapes effective innate and HIV-specific humoral and cellular responses. Several cases of durable ART-free viral control in early treated children have been reported. We recommend that, where appropriate for the study question and where adequate monitoring is available, ATI should be integrated into ART-free viral control research in children living with HIV. Paediatric participants have the greatest likelihood of benefiting and potentially the most years to prospectively realise those benefits. Excluding children from ATI trials limits the evidence base and delays access to interventions., Competing Interests: Declaration of interests DP reports support from the National Institutes of Health (NIH), being the recipient of the 2023 Jonathan Lax Lectureship sponsored by the BEAT Martin Delaney Collaboratory and Wistar Institute in Philadelphia, and being on the scientific advisory board of ViiV Healthcare and the Elizabeth Glaser Pediatric AIDS Foundation. PP reports grant support from the NIH-Pediatric Adolescent Virus Elimination project (May, 2020, to May, 2025) and the National Institute of Allergy and Infectious Diseases ([NIAID] grant U01AI135941, Targeting HIV reservoirs in children with HIVIS-DNA and MVA-CMDR vaccines) and being a founder of Probiomics (Tor Vergata University of Rome). PRos reports consulting fees from Achilles Vaccines and being on the board of directors of the PENTA Foundation. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The ongoing, observational BICSTaR (BICtegravir Single Tablet Regimen) cohort study is evaluating real-world effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV across 14 countries over 24 months. We present 12-month data from the BICSTaR Asia cohort., Methods: Data were pooled from retrospective and prospective cohorts of antiretroviral therapy (ART)-naïve (hereafter, TN) and ART-experienced (hereafter, TE) people with HIV (aged ≥21 years) receiving B/F/TAF in routine clinical care in the Republic of Korea, Singapore, and Taiwan. Analyses included effectiveness (primary endpoint: HIV-1 RNA <50 copies/ml, missing = excluded analysis), CD4 count, CD4/CD8 ratio, safety, treatment persistence, and patient-reported outcomes (prospective group)., Results: The analysis population included 328 participants (80 retrospective, 248 prospective; 65 TN, 263 TE). Participants were predominantly male (96.9% TN, 93.2% TE) with ≥1 comorbidity (52.3% TN, 57.8% TE); median age (years) was 31 (TN) and 42 (TE). Following 12 months of B/F/TAF, HIV-1 RNA was <50 copies/ml in 98.2% (54/55) of TN and 97.0% (227/234) of TE participants. Median (Q1, Q3) CD4 cell count increased by +187 (119, 291) cells/μl in the TN group (p < 0.001) and remained stable (+8 [-91, 110] cells/μl) in the TE group. B/F/TAF persistence was high in the prospective group, with 1/34 (2.9%) TN and 5/214 (2.3%) TE participants discontinuing treatment within 12 months. Drug-related adverse events occurred in 5.8% (19/328) of participants, leading to treatment discontinuation in 0.6% (2/328)., Conclusions: Real-world evidence from BICSTaR supports the effectiveness, safety and tolerability of B/F/TAF in people with HIV in Asia., Competing Interests: Declaration of competing interest CSW has received advisory board and speaking fees from Gilead Sciences, Janssen, and ViiV Healthcare, and research funding from Gilead Sciences. K-YL, J-aL, JC, and AM are employees of Gilead Sciences and own shares in Gilead Sciences. RH was an employee of Gilead Sciences and owned shares in Gilead Sciences at the time of writing. C-CH has received research support and speaker honoraria from Gilead Sciences, and has served on advisory boards for Gilead Sciences. SHL has received speaker honoraria from and served on advisory boards for Gilead Sciences Korea and GSK Korea. Y-TT, C-JY, Y-SK and JYC declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24., Methods: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log 10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA., Results: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV., Conclusions: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96., Impact and Implications: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96., Gov Identifier: NCT03852719., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The Porcine reproductive and respiratory syndrome (PRRS) causes severe financial losses to the global swine industry. Due to continuous virus evolution, the protection against the PRRS provided by current vaccines is limited. In order to find new antiviral strategies, this study investigated the antiviral potential of antimicrobial peptides (AMPs) against PRRSV. Given the diversity of PRRSV strains and the limited effectiveness of existing vaccines in controlling PRRSV, this study evaluated the inhibitory effects of KLAK, Cecropin B, Piscidin1, and Caerin1.1 on 3 strains of PRRSV (lineage 5 classical strain, lineage 8 highly pathogenic strain, and lineage 1 NADC30-like strain). Caerin1.1 exhibited significant dose-dependent antiviral activity, with an effective concentration (EC 50 ) of 7.5 μM. Caerin1.1 effectively inhibited PRRSV replication when added before or in early infection but showed reduced effectiveness when added in late infection, indicating its potential involvement in targeting early transcription mechanisms of viral RNA polymerase and significantly upregulating cytokine gene expression. In the NADC30 strain-based animal infection model, Caerin1.1 treatment significantly reduced lung viral loads and inflammation in the lungs of PRRSV-infected pigs, with a mortality rate of 0 % (0/5) in the treated group compared to 66.67 % (4/6) in the untreated group, indicating a reduction in the mortality rate. Additionally, compared with the untreated group, the Caerin1.1-treated group showed significant improvements, such as lighter fever, more daily weight gain, less clinical symptoms, less viral load in blood, and less virus oral shedding (P < 0.05). These findings reveal the potential of antimicrobial peptides as PRRSV therapeutic agents and suggest that Caerin1.1 is a promising candidate for a novel anti-PRRSV drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences., (© 2024. The Author(s).)

Background: HIV/AIDS has left a profound impact, leading to significant mortality, morbidity, economic strain, and disability on a global scale. The introduction of antiretroviral therapy (ART) has played a pivotal role in mitigating the economic burden of HIV and enhancing overall productivity. However, the emergence of virological failure presents a critical contemporary challenge within global health, reflecting the complexity of effectively managing HIV treatment outcomes in the 21st century., Methods: An institutional based, cross-sectional study was conducted. Data were collected using a pretested, structured checklist. Data were edited and cleaned using Microsoft Excel 2016 and analyzed using SPSS version 25. Baseline demographic and clinical data were summarized using descriptive statistics. Multiple logistic regression analysis was run to identify association between dependent and independent variables, by computing odds ratio and 95% confidence interval. A p-value < 0.05 was considered significant., Results: The study delved into the health profile of 117 individuals who were receiving treatment with a third-line antiretroviral therapy (ART) regimen. The findings revealed that the median age of the participants stood at 44 (IQR = ± 17) years and male accounted 53%. The median duration of after HIV diagnosis was found to be 14.25 (± IQR = 5.71) years. Overall virological suppression after third line ART was 76.9% at 6 months. Following adjustment with multiple variable logistic regression, good adherence to medication showed statistical significance in achieving virologic suppression (AOR = 8.48(95% CI: 2.3-30.8), p = 0.001). In contrast, the absence of a change in the second line regimen (AOR = 3.0(95% CI: 0.36-24.8), p = 0.31) and receiving second-line medication for less than three years (AOR = 1.07(95% CI: 0.39-2.95), p = 0.89), and baseline viral load above 100,000 (AOR = 1.74(0.64-2.95), p = 0.27) shows statistically non-significant association with virologic suppression., Clinical Trial Number: Not applicable., Conclusion: This multicenter study provides strong evidence on virological suppression following the use of third-line antiretroviral therapy drugs in Ethiopia. The results of the study indicate rate of Virological suppression after starting third-line ART drugs is significantly linked to good adherence., (© 2024. The Author(s).)

Background: In Uganda, 20% (19,073/94,579) of children and adolescents (0-19 years) living with HIV (CALHIV) were receiving second-line antiretroviral therapy (ART) by the end of March 2020. Data on incidence and predictors of virological failure among these CALHIV on second-line ART is limited. Lack of this information and limited access to HIV drug resistance testing prevents early identification of CALHIV at risk of virological failure on second-line ART. The aim of this study was to determine the incidence and predictors of virological failure among CALHIV on second-line ART in Uganda., Methodology: This was a retrospective cohort study of all CALHIV aged 0-19 years who were switched to second-line ART regimen between June 2010 and June 2019 at the Baylor Uganda Centre of Excellence clinic. Data was analysed using STATA 14. Cumulative incidence curves were used to assess incidence of virological failure. Factors associated with virological failure were identified using sub-distributional hazard regression analysis for competing risks considering death, transfer out and loss to follow-up as competing risks., Results: Of 1104 CALHIV, 53% were male. At switch to Protease Inhibitor (PI) based second-line ART, majority (47.7%) were aged 5 - 9 years,56.2% had no/mild immune suppression for age while 77% had viral load copies < 100,000 copies/mL. The incidence of virological failure on second-line ART regimen among CALHIV was 3.9 per 100 person-years (PY) with a 10-year cumulative incidence rate of 32%. Factors significantly associated with virological failure were age 10 - 19 years (HR 3.2, 95% 1.6 - 6.2, p < 0.01) and HIV viral load count > 100,000 copies/mL (HR 2.2, 95% CI 1.5 - 3.1), p < 0.01) prior to second-line ART switch., Conclusion: Treatment outcomes for children and adolescents on second-line ART are favourable with one third of them developing virological failure at 10 years of follow up. Adolescent age group and high HIV viral load at the start of second-line ART were significantly associated with virological failure on second-line ART. There is need to determine optimal strategies to improve ART treatment outcomes among adolescents with high viral load counts at second-line ART switch., (© 2024. The Author(s).)

This case-control study explored cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatis B virus (HIV/HBV) coinfection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were ∼3-fold lower among patients with incomplete HBV viral suppression (n = 4) compared to those with complete suppression (n = 5) (516 vs 1456 fmol/punch)., Competing Interests: Potential conflicts of interest . S. N.: Research funding to institution from Gilead Sciences; Scientific Advisory Board for Vir Bio and stock options/vesting. P. L. A.: Research funding from Gilead Sciences paid to institution. J.J.K. was employed by the University of Colorado at the time this work was performed; she is now an employee of Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood., Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset. The statistical analysis used a generalized linear mixed-effects model., Results: A total of 139 sequences were obtained from 37 out of the 44 (84%) enrolled participants. The genotyping success varied across respiratory compartments, which ranged from 42% with oropharyngeal specimens to 67% with nasopharyngeal specimens and showed improvement with higher viral loads. No RdRp mutations known to be associated with RDV resistance were identified, and for 34 detected mutations at 32 amino acid positions that are not known as RDV-associated, there was no evidence of any associations with the RDV exposure, respiratory compartment, or time. At least 1 of these 34 mutations were detected in all participants, and some differed from the larger sequence dataset., Conclusions: This study highlighted the SARS-CoV-2 short-term genomic stability within hosts and across upper respiratory compartments, which suggests a lack of evolution of RDV resistance over time. This contributes to our understanding of SARS-CoV-2 genomic dynamics.

Background: Tenofovir/lamivudine/dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen for people with HIV (PWH), including those who were previously virologically suppressed on nonnucleoside reverse transcriptase inhibitors (NNRTIs). We sought to estimate the real-world effectiveness of the TLD transition in Ugandan public-sector clinics., Methods: We conducted a prospective cohort study of PWH aged ≥18 years who were transitioned from NNRTI-based ART to TLD. Study visits were conducted on the day of TLD transition and 24 and 48 weeks later. The primary end point was viral suppression (<200 copies/mL) at 48 weeks. We collected blood for retrospective viral load (VL) assessment and conducted genotypic resistance tests for specimens with VL >500 copies/mL., Results: We enrolled 500 participants (median age 47 years; 41% women). At 48 weeks after TLD transition, 94% of participants were in care with a VL <200 copies/mL (n = 469/500); 2% (n = 11/500) were lost from care or died; and only 2% (n = 9/500) had a VL >500 copies/mL. No incident resistance to DTG was identified. Few participants (2%, n = 9/500) discontinued TLD due to adverse events., Conclusions: High rates of viral suppression, high tolerability, and lack of emergent drug resistance support use of TLD as the preferred first-line regimen in the region., Clinical Trials Registration: NCT04066036., Competing Interests: Potential conflicts of interest. V. C. M. received investigator-initiated research grants and consultation fees from Eli Lilly, Bayer, Gilead Sciences, Merck, and ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Evaluate the real-world effectiveness and safety of different treatment regimens for treatment-naïve high viral load chronic hepatitis B (CHB) patients. Between January 2021 and August 2022, CHB patients with HBV DNA ≥ 10 7 IU/mL were collected from four medical centers in Shenzhen. Patients treated with mono or combine antiviral therapy. The primary endpoint was the cumulative incidence of virological response at 48 weeks, and other endpoints included changes in HBsAg, HBeAg, ALT, and eGFR at 48 weeks. We used propensity score-based inverse probability of treatment weighting (IPTW) to balance the bias. Weighted logistics regression was used to estimate the factors affecting virological response. A total of 391 patients were included in the study, with 296 patients undergoing statistical analysis after IPTW. The patients were distributed into four groups: ETV (n = 62), TDF (n = 89), TAF (n = 36), TDF + LdT/ETV (n = 109). The 48-week cumulative incidence of virological response was significantly lower in ETV group (52.3%) compared to TDF (71.7%), TAF (74.2%), and TDF + LdT/ETV groups (77.9%) (P < 0.05). There were no significant differences in HBsAg loss among the four groups, but the HBeAg seroconversion rate was significantly higher in the TAF group. The ALT normalization rate was significantly higher in the TAF group (72.2%) compared to the others at 48 weeks (P < 0.05). In treatment-naïve CHB patients with high viral load, combination therapy was not superior to TDF or TAF monotherapy in virological response. Patients treated with TDF or TAF showed superior virological response compared to those treated with ETV. The TAF group demonstrated superiority in terms of ALT normalization and HBeAg seroconversion., (© 2024. The Author(s).)

Immunocompromised people are at high risk of prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and progression to severe coronavirus disease 2019 (COVID-19). However, the efficacy of late-onset direct-acting antiviral (DAA) therapy with therapeutics in clinical use and experimental drugs to mitigate persistent viral replication is unclear. In this study, we employed an immunocompromised mouse model, which supports prolonged replication of SARS-CoV-2 to explore late-onset treatment options. Tandem immuno-depletion of CD4 + and CD8 + T cells in C57BL/6 mice followed by infection with SARS-CoV-2 variant of concern (VOC) beta B.1.351 resulted in prolonged infection with virus replication for 5 weeks after inoculation. Early-onset treatment with nirmatrelvir/ritonavir (paxlovid) or molnupiravir was only moderately efficacious, whereas the experimental therapeutic 4'-fluorouridine (4'-FlU, EIDD-2749) significantly reduced virus load in the upper and lower respiratory compartments 4 days postinfection (dpi). All antivirals significantly lowered virus burden in a 7-day treatment regimen initiated 14 dpi, but paxlovid-treated animals experienced rebound virus replication in the upper respiratory tract 7 days after treatment end. Viral RNA was detectable 28 dpi in paxlovid-treated animals, albeit not in the molnupiravir or 4'-FlU groups, when treatment was initiated 14 dpi and continued for 14 days. Low-level virus replication continued 35 dpi in animals receiving vehicle but had ceased in all treatment groups. These data indicate that late-onset DAA therapy significantly shortens the duration of persistent virus replication in an immunocompromised host, which may have implications for clinical use of antiviral therapeutics to alleviate the risk of progression to severe disease in highly vulnerable patients., Importance: Four years after the onset of the global coronavirus disease 2019 (COVID-19) pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4 + and CD8 + T cell-depleted immunocompromised mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-fluorouridine (4'-FlU). Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals (DAAs) for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group., Competing Interests: M.G.N. and A.A.K. receive licensing fees and royalties based on Emory's sublicense of the molnupiravir technology to Ridgeback Biotherapeutics. This technology is part of the research described in this paper. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. M.G.N. is a co-inventor on patent WO 2019/1736002 covering composition of matter and use of 4'-FlU (EIDD-2749) and its analogs as an antiviral treatment. This study could affect his personal financial status. R.K.P. reports contract testing from Enanta Pharmaceuticals, Atea Pharmaceuticals, and Icosagen Biosciences, and research support from Gilead Sciences, outside of the described work. A.L.G. reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen, and Hologic, and research support from Gilead, outside of the described work. All other authors declare that they have no competing interests.

Background: Antiretroviral therapy (ART) for HIV infection has evolved substantially. The development of long-acting drugs, such as cabotegravir (CAB) and rilpivirine (RPV) might improve treatment satisfaction among people living with HIV (PLWH). The real-world effectiveness of long-acting ART and its effect on patient satisfaction needs to be assessed. This study investigated antiviral effectiveness and treatment satisfaction in PLWH who switched from conventional to long-acting ART (CAB + RPV)., Methods: This prospective cohort study included PLWH aged 18 years and older who switched to CAB + RPV and received the injections every 8 weeks between June 2022 and May 2023, after a 4-week oral lead-in phase. The eligibility criteria included viral suppression, absence of hepatitis B virus (HBV) DNA, and no prior RPV resistance mutations. Clinical data, including renal, lipid, and glucose biomarker levels, were monitored from the baseline to 44 weeks after switching. Treatment satisfaction was assessed using the HIV Treatment Satisfaction Questionnaire. A linear mixed-effects model was used to estimate changes in clinical data from baseline., Results: Thirty-eight male participants were enrolled. Some participants had detectable levels of viral replication; however, all participants maintained viral suppression (HIV-RNA < 50 copies/mL) at 44 weeks and no cases of virological failure were detected. The creatinine level decreased by - 0.04 mg/dL (95% confidence interval [CI]: - 0.07 to - 0.01), lipid and glucose profiles remained stable, and treatment satisfaction increased by 6.6 points (95% CI: 2.4 to 10.8) after switching to CAB + RPV., Conclusions: Long-acting ART provides effective viral suppression and enhances treatment satisfaction in PLWH switching from conventional ART. Long-acting ART can improve patient well-being; however, patient selection and monitoring to prevent HBV-related complications are important., (© 2024. The Author(s).)

Exceptional elite controllers represent an extremely rare group of people with HIV-1 (PWH) who exhibit spontaneous, high-level control of viral replication below the limits of detection in sensitive clinical monitoring assays and without disease progression in the absence of antiretroviral therapy for prolonged periods, frequently exceeding 25 years. Here, we discuss the different cases that have been reported in the scientific literature, their unique genetic, virological, and immunological characteristics, and their relevance as the best model for the functional cure of HIV-1., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an ex vivo model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4 + cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our in vivo findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an ex vivo model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our in vivo study indicates that in contrast to in vitro observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency., Competing Interests: The authors declare no conflict of interest.

Rituximab occasionally induces reactivation of hepatitis C virus (HCV) in patients with resolved HCV infection, sometimes with fatal consequences. As rituximab has become one of the first-line therapies for the treatment of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) and is more widely used, there is a lack of studies reporting the effectiveness and safety of rituximab in patients with PLA2R-associated MN and resolved HCV infection. A single-center retrospective study was conducted on PLA2R-associated membranous nephropathy (MN) patients who were HCVAb positive but HCV-RNA negative and treated with rituximab. A total of 598 adult patients with PLA2R-associated MN who underwent rituximab therapy were screened. General clinical information, including gender, age, pathological data, and previous treatment plans, was collected from medical records. Routine blood tests, liver and kidney function assessments, blood lipid profiles, 24-h urine protein levels, anti-PLA2R antibody titers, circulating B-cell counts, and HCV viral loads were measured at the time of rituximab infusion and repeated at intervals of 1-3 months post-rituximab administration. A total of 8 patients were enrolled, with a median follow-up period of 19.00 (range: 16.00-25.25) months. Among the 8 patients, 5 were male, and the mean age was 50.13 ± 4.29 years. Histological findings indicated that tubuloreticular inclusions, mesangial deposits, intramembranous deposits, and subendothelial deposits were not observed in any of the 8 patients. The overall 1-year remission rate for these patients was 75%, accompanied by a significant reduction in proteinuria. Additionally, blood albumin levels increased significantly, and renal function remained stable. No increase in HCV viral load and stable liver function tests were observed throughout the entire follow-up period. This study suggested that on the basis of successful eradication of HCV virus with antiviral drugs, rituximab can effectively induce clinical remission of patients with PLA2R associated MN and resolved HCV infection, and does not lead to a significant increase in HCV virus load. However, this finding is based on a very small sample size and should be confirmed in larger clinical trials., (© 2024. The Author(s).)

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8 + T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4 + and CD8 + T cells (T EM ) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8 + T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific T EM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption., (© 2024. The Author(s).)

Background: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment., Methods: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used., Results: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation., Conclusion: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Luwaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity., (© 2024. The Author(s).)

Introduction: Rapid initiation of ART after HIV diagnosis is recommended for individual and public health benefits. However, certain clinical and ART-related considerations hinder immediate initiation of therapy., Methods: An open-label, single-arm, single-centre 48-week prospective clinical trial involving ART-naïve HIV-diagnosed adults who started bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) within a week from the first hospital visit, before the availability of baseline laboratory and genotype results. The primary aim was to determine the proportion of people with at least one condition that would hinder immediate initiation of any recommended ART regimen other than BIC/FTC/TAF. Clinicaltrials.gov: NCT04416906., Results: We included 100 participants: 79% men, 64% from Latin America, median age 32 years. According to European AIDS Clinical Society (EACS) and US Department of Health and Human Services 2023 guidelines, 11% (95%CI 6; 19) of participants had at least one condition that made any ART different from BIC/FTC/TAF less appropriate for a rapid ART strategy. Seventy-nine percent of the people started BIC/FTC/TAF within the first 48 hours of their first hospital visit. There were 16 early discontinuations (11 lost to follow-up). By week 48, 92% (95%CI 86; 98) of the participants of the ITT population with observed data achieved viral suppression. Eight grade 3-4 adverse events (AEs), five serious AEs and six ART-related AEs were identified. Adherence remained high., Conclusions: BIC/FTC/TAF is an optimal treatment for rapid initiation of ART. However, additional strategies to improve retention in care must be implemented., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and two groups treated for 20-30 days with low- (10 mg/kg/day) or high- (30 mg/kg/day) dose BLZ945. With the high-dose BLZ945 treatment, there was a significant reduction in cells expressing CD163 and CD206 across all four brain areas examined, compared with the low-dose treatment and control groups. In 9 of 11 tested regions, tissue viral DNA (vDNA) loads were reduced by 95%-99% following at least one of the two doses, and even to undetectable levels in some instances. Decreased numbers of CD163+ and CD206+ cells correlated significantly with lower levels of vDNA in all four corresponding brain areas. In contrast, BLZ945 treatment did not significantly affect the number of microglia. Our results indicate that doses as low as 10 mg/kg/day of BLZ945 are sufficient to reduce the tissue vDNA loads in the brain with no apparent adverse effect. This study provides evidence that infected PVMs are highly sensitive to CSF1R inhibition, opening new possibilities to achieve viral clearance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Coinfections with human pegivirus 1 (HPgV-1) are common in chronic hepatitis C virus (HCV) patients. However, little is known about whether HPgV-1 is affected by direct-acting antivirals during HCV treatment. Metagenomic analysis and reverse transcriptase-quantitative PCR (RT-qPCR) were performed on RNA from the plasma of 88 selected chronic HCV patients undergoing medical treatment. Twenty (23%) of these HCV patients had HPgV-1 coinfections and were followed by RT-qPCR during treatment and follow-up to investigate HPgV-1 RNA titers. Recovered sequences could be assembled to complete HPgV-1 genomes, and most formed a genotype 2 subclade. All HPgV-1 viral genomic regions were under negative purifying selection. Glecaprevir/pibrentasvir treatment in five patients did not consistently lower the genome titers of HPgV-1. In contrast, a one log 10 drop of HPgV-1 titers at week 2 was observed in 10 patients during treatment with sofosbuvir-containing regimens, sustained to the end of treatment (EOT) and in two cases decreasing to below the detection limit of the assay. For the five patients treated with ledipasvir/sofosbuvir with the inclusion of pegylated interferon, titers decreased to below the detection limit at week 2 and remained undetectable to EOT. Subsequently, the HPgV-1 titer rebounded to pretreatment levels for all patients. In conclusion, we found that HCV treatment regimens that included the polymerase inhibitor sofosbuvir resulted in decreases in HPgV-1 titers, and the addition of pegylated interferon increased the effect on patients with coinfections. This points to the high specificity of protease and NS5A inhibitors toward HCV and the more broad-spectrum activity of sofosbuvir and especially pegylated interferon., Importance: Human pegivirus 1 coinfections are common in hepatitis C virus (HCV) patients, persisting for years. However, little is known about how pegivirus coinfections are affected by treatment with pangenotypic direct-acting antivirals (DAAs) against HCV. We identified human pegivirus by metagenomic analysis of chronic HCV patients undergoing protease, NS5A, and polymerase inhibitor treatment, in some patients with the addition of pegylated interferon, and followed viral kinetics of both viruses to investigate treatment effects. Only during HCV DAA treatment regimens that included the more broad-spectrum drug sofosbuvir could we detect a consistent decline in pegivirus titers that, however, rebounded to pretreatment levels after treatment cessation. The addition of pegylated interferon gave the highest effect with pegivirus titers decreasing to below the assay detection limit, but without clearance. These results reveal the limited effect of frontline HCV drugs on the closest related human virus, but sofosbuvir appeared to have the potential to be repurposed for other viral diseases.

The aim of this study was to determine the antiviral activity of cannabidiol (CBD) against SARS-CoV-2 infection. CBD is the second most studied cannabinoid obtained from Cannabis plants. We investigated the potential use of CBD, which has so far proven to have a positive effect on different diseases, in the SARS-CoV-2 infection. To test this, in vivo studies were carried out using K18-hACE2 transgenic mice. To reveal the potential therapeutic effect of the CBD at the histopathological and molecular level challenge experiments were performed. The study was designed with two groups (n = 10) and in the treatment group animals were infected with SARS-CoV-2 virus strain B.1.1.7 alpha before the administration of CBD. While the disease progressed and resulted in death in the control group that was infected by the virus alone, it was observed that the infection slowed down and the survival rate increased in the mice treated with CBD along with the virus. In this study, K18-hACE2 transgenic mice infected with the wild SARS-CoV-2 virus were used to investigate and prove the antiviral activity of CBD., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The mortality and hospitalization rate by COVID-19 dropped significantly currently, but its seasonal outbreaks make antiviral treatment still vital. The mortality and hospitazation rate by COVID-19 dropped significantly currently, but its seasonal ourbreaks make antiviral treatment still vital. In our study, syrian golden hamsters were treated with molnupiravir and interferons (IFNs) after SARS-CoV-2 infection. Their weight changes, pathological changes, virus replication and inflammation levels were evaluated. In the IFNs single treatment, only IFN-α group reduced viral load (p < 0.05) and virus titer in hamster lungs. The TNF-α expression decreased significantly in both IFNs treatment at 2dpi. Histological and immunofluorescence results showed lung damage in the IFNs groups were milder at 4dpi. In the molnupiravir/IFN-α combination treatment, weight loss and virus replication in lung were significantly decreased in the mono-molnupiravir group and combination group (p < 0.05), the expression of IL-6, TNF-α, IL-1β and MIP-1α also decreased significantly (p < 0.05), but the combination treatment was not more effective than the mono-molnupiravir treatment. Histological and immunofluorescence results showed the lung damage and inflammation in mono-molnupiravir and combination groups were milder. In summary, IFNs treatment had anti-inflammatory effect against SARS-CoV-2, only IFN-α showed a weak antiviral effect. Molnupiravir/IFN-α combination treatment was effective against SARS-CoV-2 but was not superior to mono-molnupiravir treatment. IFN-α could be considered for immunocompromised patients to stimulate and activate early immune responses., (© 2024 Wiley Periodicals LLC.)

Background: Currently, real-world data on doravirine are scarce. In a national prospective cohort, we assessed the effectiveness and tolerability of switching to doravirine-based antiretroviral therapy (ART) in people with HIV., Methods: We did a nationwide, matched, prospective cohort study of people with HIV without previous virological failure and stable for at least 12 months on non-doravirine-containing triple or dual ART switching to doravirine before Sept 1, 2020 (exposed group). Participants in the exposed group were matched 1:2 to individuals continuing stable non-doravirine-containing ART, on age, sex, HIV acquisition category, time since ART initiation, calendar time, pre-ART CD4-count, pre-ART plasma viral load (PVL) and anchor drug class before switching. The primary outcome was protocol-defined virological failure (PDVF; PVL of ≥200 copies per mL) in the intention-to-treat (ITT) population at week 104, with participants modifying their regimen or becoming lost to follow-up considered as PDVF (non-inferiority margin +5%). In contrast, in the on-treatment population, those who modified their regimen or became lost to follow-up were censored from that moment onwards. Tolerability was a secondary outcome., Findings: In total, 590 participants in the exposed group and 1180 participants in the unexposed group (of whom 55·3% used integrase strand transfer inhibitor-based regimens) were included. In the ITT analysis, PDVF occurred in 135 (22·9%) exposed participants and in 295 (25·0%) unexposed participants (risk difference -2·12%, upper limit of the one-sided 95% CI +1·40%). In the on-treatment analysis, 10 (2·2%) of 455 non-censored exposed participants and 26 (2·9%) of 885 non-censored unexposed participants had PDVF (risk difference -0·70%, upper limit of the one-sided 95% CI +0·73%). All exposed participants with a PVL of 200 copies or more per mL resuppressed without regimen modification: no confirmed virological failure (two consecutive PVLs of ≥200 copies per mL) was observed. 104 (17·6%) exposed participants and 211 (17·9%) unexposed participants modified their regimen. 73 (12.4%) exposed participants discontinued doravirine due to adverse events: abnormal dreams (1·7%) and insomnia (1·5%) were most common., Interpretation: Switching to doravirine in well suppressed people with HIV without previous virological failure was non-inferior compared with continuing non-doravirine-containing regimens after 2 years in a real-world setting., Funding: None., Competing Interests: Declaration of interests FWNMW has received consultancy fees from ViiV Healthcare, all paid to his institution. BJvW has received a research grant and speaker fees from Gilead Health Sciences, and speaker and advisory board fees from ViiV Healthcare, all paid to his institution. MvdV has received research and consultancy fees from ViiV Healthcare, Gilead Health Sciences, and MSD, all paid to his institution. KB has received research grants and consultancy fees from ViiV Healthcare, Gilead Health Sciences, and MSD. TM has received research grants and consultancy fees from ViiV Healthcare, Gilead Health Sciences, and MSD, all paid to her institution. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)