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Background: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50-mg dose of dolutegravir (TLD+50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD+50 in individuals with TB/human immunodeficiency virus (HIV)., Methods: We performed a prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. The primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment., Results: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naive participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naive participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz-lamivudine-tenofovir. Median age was 37 years, 35% were female, the median CD4 count was 120 cells/mm3 (interquartile range, 50-295), and 87% had HIV-1 RNA >1000 copies/mL. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. The primary virologic outcome was assessed in 73 participants, 69 of whom (95%; 95% confidence interval, 89%-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among 4 participants with HIV-1 RNA >1000 copies/mL., Conclusions: In programmatic settings, concurrent rifampin-containing TB treatment and TLD+50 was feasible, well tolerated, and achieved high viral suppression rates in a cohort of predominantly ART-naive people with TB/HIV., (© 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: Reducing the number of active compounds for lifelong human immunodeficiency virus (HIV) treatment is of interest, especially to reduce potential long-term side effects. So far, available data assessing viral control support the robustness and safety of 2DR (2-drug regimen) antiretroviral therapy compared to 3DR. However, further in-depth investigations of the viral reservoirs are mandatory to guarantee long-term safety of these regimens regarding stable intact HIV-1 DNA copies, HIV-1 RNA transcripts, and sustained immunological control., Methods: The RUMBA study is the first prospective randomized controlled trial evaluating the impact of switch from 3DR to 2DR on the viral reservoir. Participants on any stable second-generation integrase strand transfer inhibitor-based 3DR regimen with HIV-1 RNA < 50 copies/mL plasma for at least 3 months were randomized to switch to dolutegravir/lamivudine (DTG/3TC, n = 89) or to switch or stay on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, n = 45). After 48 weeks, virological, immunological, and metabolic parameters were evaluated., Results: We did not observe a significant difference in change over time in the mean number of intact HIV-1 DNA copies/million CD4+ T cells with DTG/3TC compared to B/F/TAF. There was no evidence in this study that switching to DTG/3TC increased the active reservoir by HIV-1 transcription. No significant changes in proinflammatory cytokines or major immune cell subsets were observed. Changes in exhaustion and activation of specific cellular subsets were small and bidirectional. Metabolic outcomes are similar between the treatment regimens., Conclusions: This study confirms the safety of DTG/3TC compared to B/F/TAF through viral control after in-depth investigations of the intact HIV-1 reservoir, HIV-1 transcription, and inflammatory markers., Clinical Trials Registration: NCT04553081., Competing Interests: Potential conflicts of interest. M. D. S. has been granted speakers fees from Gilead Sciences, ViiV Healthcare, and MSD; and has received grants from MSD, ViiV Healthcare, and Gilead Sciences to conduct independent investigator-initiated research in the HIV field. L. V. has been granted speaker fees and support for research projects by ViiV Healthcare, Gilead Sciences, and Johnson and Johnson over the past 5 years. 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.)

Background: Dolutegravir plus lamivudine has emerged as a preferred treatment for HIV; however, initiating this regimen without baseline resistance testing raises concerns about the potential presence of pretreatment lamivudine resistance. We aimed to evaluate the efficacy of dolutegravir plus lamivudine in the absence of information on baseline resistance testing in treatment-naive people with HIV., Methods: We did an open-label, non-inferiority, single-centre, phase 4, randomised controlled study (D2ARLING), designed to assess the efficacy and safety of dolutegravir plus lamivudine in treatment-naive people with HIV with no available baseline resistance testing. We included participants aged 18 years or older with HIV-1 diagnosis who were naive to antiretroviral therapy and had no baseline genotypic resistance testing result available. We randomly assigned (1:1) participants to receive dolutegravir 50 mg plus lamivudine 300 mg or a three-drug regimen including dolutegravir 50 mg plus tenofovir disoproxil fumarate 300 mg and either emtricitabine 200 mg or lamivudine 300 mg. Randomisation was stratified by baseline HIV-1 RNA (≤100 000 vs >100 000 copies per mL) and CD4 cell count (<200 vs ≥200 cells per μL). Per protocol, we performed genotypic drug-resistance testing on day 1 and it remained double-masked throughout the study, simulating a scenario of inaccessibility of baseline resistance testing. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48 (intention-to-treat exposed analysis via the Snapshot algorithm) with prespecified non-inferiority margin of 10%. This trial is registered with ClinicalTrials.gov (NCT04549467)., Findings: Between Nov 17, 2020, and Aug 31, 2022, 214 participants were randomly assigned to and treated with dolutegravir plus lamivudine (n=106) or dolutegravir plus tenofovir disoproxil fumarate and either emtricitabine or lamivudine (n=108). Median age of participants was 31 years (IQR 26-39) and 49 (23%) were female. At baseline, 66 (31%) of participants had an HIV-1 RNA viral load of more than 100 000 copies per mL, and 44 (21%) had a CD4 T-cell count of less than 200 cells per μL. At week 48, 97 (92%) of 106 participants in the dolutegravir plus lamivudine group and 96 (89%) of 108 participants in the dolutegravir plus tenofovir disoproxil fumarate with either emtricitabine or lamivudine group had HIV-1 RNA of less than 50 copies per mL (difference 2·62%; 95% CI -5·3 to 10·6), showing non-inferiority of dolutegravir plus lamivudine to the three-drug regimen. None of the participants in the dolutegravir plus lamivudine group and two in the control group had protocol-defined virological failure, and none developed treatment-emergent resistance mutations to any of the study drugs. Overall adverse event rates were similar between arms. Less than 1% of participants in both groups were discontinued due to adverse events., Interpretation: This study provides evidence supporting the non-inferiority of dolutegravir plus lamivudine compared with a preferred three-drug regimen in treatment-naive individuals without baseline resistance testing. These findings suggest that baseline resistance testing might not be a requirement for initiating treatment with dolutegravir plus lamivudine in settings with low frequency or suspicion of transmitted drug resistance to these drugs., Funding: ViiV Healthcare., Competing Interests: Declaration of interests EC has served on advisory boards for GlaxoSmithKline, ViiV Healthcare, and Janssen; served as an investigator for ViiV Healthcare and Merck; and has received honoraria for his speaking from GlaxoSmithKline, Janssen, Merck, and ViiV Healthcare. NP has served on advisory boards for GlaxoSmithKline, ViiV Healthcare, and Janssen; served as an investigator for ViiV Healthcare and Merck; and has received honoraria for his speaking from GlaxoSmithKline and ViiV Healthcare. VM served as an investigator for ViiV Healthcare; and has received honoraria for his speaking from Janssen. JHR, PM, GAC, SS, and JB declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Rationale: Current research on antiviral treatment in children is relatively limited, especially in children under 1 year old., Patient Concerns: Liu XX, an 8-month-old infant (case number: 3001120473), presented to the hospital in August 2016 with a chief complaint of being "hepatitis B surface antigen positive for 8 months and experiencing abnormal liver function for 5 months.", Diagnoses: The patient was diagnosed as chronic hepatitis B cirrhosis (G3S3-4) with active compensatory phase., Interventions: The treatment regimen commenced with lamivudine (LAM) for the initial 8 weeks, followed by the addition of interferon α (IFNα) after 1 year of age. At 2 years old, LAM was substituted with entecavir, and at 3 years old, IFNα was replaced with pegylated interferon α (PEG IFNα)., Outcomes: After 8 weeks of LAM monotherapy, Liu XX experienced hepatitis B e antigen loss. Subsequently, after 36 weeks of IFNα add-on therapy, hepatitis B virus DNA became undetectable, and after 48 weeks of switching to PEG IFNα treatment, hepatitis B surface antigen loss was observed. Remarkably, following 50 weeks of drug discontinuation, the child remained functionally cured., Lessons: Chronic hepatitis B virus-infected infants and young children can achieve durable functional cure with PEG IFNα-based individualized therapy. This case provides a valuable reference for the diagnosis and treatment of such patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: We compared the effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) and dolutegravir plus lamivudine (DTG + 3TC) in our cohort of treatment-naive people with HIV (PWH)., Methods: In a multicentre cohort of treatment-naive PWH starting a first-line regimen with either dolutegravir plus lamivudine or BIC/FTC/TAF, Kaplan-Meier survival analysis was used to estimate time to virological failure (VF) and time to treatment discontinuation (TD), whereas Cox regression was used to evaluate predictors of VF and TD. Changes in CD4+ cell count were assessed via non-parametric tests, and linear regression analyses were performed to explore predictors of CD4+ cell count changes., Results: One hundred and seventy individuals were included: 66 started dolutegravir plus lamivudine (DTG group) and 104 started BIC/FTC/TAF (BIC group). During follow-up, we observed two VFs in the DTG group [1.7 per 100 person-years of follow-up (PYFU)] and two in the BIC group (1.7 per 100 PYFU). Estimated probability of remaining free from VF at Week 144 was 95.9% in the DTG group and 95.2% in the BIC group (log-rank P = 0.955). Four TDs were observed in the DTG group (3.4 per 100 PYFU) and 21 in the BIC group (17.6 per 100 PYFU). Estimated probability of maintaining the study regimen at Week 144 was 90.3% in the DTG group and 70.0% in the BIC group; individuals in the BIC group had a higher probability of TD (log-rank P = 0.003). In both groups, the CD4+ count improved significantly during follow-up., Conclusions: Our study shows that both strategies are effective and safe, with few VFs and TDs due to tolerability issues., (© 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.)

Patient-reported outcomes (PROs) facilitate communication between patients and providers, enhancing patient-centered care. We report PROs for virologically suppressed people living with HIV-1 who switched to dolutegravir/lamivudine (DTG/3TC) or continued their 3- or 4-drug current antiretroviral regimen (CAR) in the phase 3 SALSA study. Secondary endpoints included change from baseline in HIV Treatment Satisfaction Questionnaire (status version; HIVTSQs) and HIV Symptom Distress Module (HIV-SDM) at Weeks 4, 24, and 48. A post hoc analysis assessed change in HIVTSQs and HIV-SDM by age (≥ 50 and < 50 years). Higher HIVTSQs scores represent greater treatment satisfaction (range, 0-60); lower HIV-SDM scores indicate less symptom bother (range, 0-80). Participants in the DTG/3TC (n = 246) and CAR (n = 247) groups reported comparable baseline HIVTSQs total scores (mean [SD], 55.2 [6.5] and 55.8 [5.5], respectively). Beginning at Week 4, mean HIVTSQs scores in the DTG/3TC group further increased vs. CAR and were sustained through Week 48. Baseline mean (SD) HIV-SDM symptom bother scores were comparable between the DTG/3TC (9.0 [9.9]) and CAR (7.9 [9.3]) groups. Small improvements in HIV-SDM scores favoring DTG/3TC were observed at Weeks 4 and 24 and sustained through Week 48 (though not significant between groups). Participants aged ≥ 50 and < 50 years who switched to DTG/3TC reported higher satisfaction and less symptom distress vs. CAR; these results were generally comparable between age groups. Participants who switched to DTG/3TC reported rapid and sustained improvements in treatment satisfaction compared with those who continued CAR, reinforcing the benefits of DTG/3TC beyond virologic suppression (NCT04021290; registration date, 7/11/2019)., Competing Interests: Declarations. Ethical Approval: This study was designed in agreement with the International Conference on Harmonization Good Clinical Practice and adhered to the principles of the Declaration of Helsinki. Study documents were reviewed and approved by national, regional, or investigational center ethics committees or institutional review boards. Consent to Participate: Written informed consent was obtained before participant screening. Consent to Publish: Not applicable. Competing Interests: PK has received grants from Gilead, Merck, Theratechnologies, and ViiV Healthcare/GSK (paid to institution); has received consulting fees from and participated in data safety monitoring/advisory boards for Gilead, Merck, and ViiV Healthcare/GSK; and holds stock/stock options in Gilead, GSK, Johnson & Johnson, Merck, Moderna, and Pfizer. AEC has received grants from Gilead, GSK, MSD, and ViiV Healthcare (paid to institution); speaker fees from MSD; travel/meeting support from Gilead and ViiV Healthcare; and has participated in advisory boards for MSD, Theratechnologies, and ViiV Healthcare. CJ-O has received consulting fees from GSK and ViiV Healthcare; honoraria from AbbVie, CCO, Gilead, GSK, Janssen-Cilag, and ViiV Healthcare; payment for expert testimony from GSK and ViiV Healthcare; travel/meeting support from CCO, Gilead, GSK, Janssen-Cilag, MSD, and ViiV Healthcare; has participated in data safety monitoring/advisory boards for Gilead, GSK, Janssen-Cilag, MSD, and ViiV Healthcare; and holds a leadership role with BAGNAE. MGD has received grants and honoraria from and participated in data safety monitoring/advisory boards for AbbVie, Gilead, Janssen, MSD, and ViiV Healthcare; has received meeting/travel support from Gilead and Janssen; and has received equipment/materials from Gilead. SDG has no competing interests. CB has received research grants from GSK and Pfizer and received speaker fees from and participated in advisory boards for Gilead, GSK, and Merck. LH has received honoraria and meeting/travel support from Gilead, MSD, and ViiV Healthcare. P-LL has no competing interests. JO, AO, BW, BJ, LAE, DF, MK, and JP are employees of GSK or ViiV Healthcare and may own stock in GSK., (© 2024. The Author(s).)

Introduction. Lamivudine plus dolutegravir (3TC/DTG) and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) regimens are commonly used as first-line treatments for people living with human immunodeficiency virus (HIV) (PLWH) worldwide. Gap Statement. There are limited comparative data on the antiviral activity and safety between these regimens in ART-naive PLWH, particularly in China, where the 3TC/DTG regimen was integrated into first-line therapy in 2021 and gained broader adoption after its inclusion in the National Health Insurance in 2022. Aims. This study aims to provide real-world evidence comparing the 3TC/DTG regimen to the B/F/TAF regimen in ART-naive PLWH in China. Methodology. This retrospective study enrolled PLWH initiating ART with either 3TC/DTG or B/F/TAF in Shanghai from January 2020 to January 2023. Demographic characteristics and clinical information were collected and compared for each patient. Results. A total of 380 eligible, ART-naive PLWH were included, with 190 patients in the 3TC/DTG group and 190 patients in the B/F/TAF group. Following the initiation of ART, most patients (94.1 and 89.3% for 3TC/DTG and B/F/TAF groups, respectively) achieved viral suppression (<50 copies of HIV RNA per millilitre) at week 24. The CD4 cell count significantly increased from a baseline of 301.3±185.8 cells per microlitre to 479.5±229.3 cells per microlitre at week 36 for the 3TC/DTG group and from 289.2±188.8 cells per microlitre at baseline to 487.8±234.2 cells per microlitre at week 36 for the B/F/TAF group. Both groups experienced an increase in blood lipid levels after initiating ART, with higher levels of high-density lipoprotein cholesterol (HDL-C) observed in the 3TC/DTG group compared with the B/F/TAF group. Renal and hepatic function indicators remained stable in both groups. Conclusions. 3TC/DTG demonstrates similar antiviral efficacy to B/F/TAF and does not significantly impact liver and kidney functions. Patients receiving 3TC/DTG showed higher plasma HDL-C levels compared with those on B/F/TAF, which confer long-term clinical benefits in reducing cardiovascular risk.

Background: Ainuovirine, as a third-generation non-nucleoside reverse transcriptase inhibitor against HIV-1, is widely used in China. To evaluate its therapeutic efficacy and disadvantages, a comparative study based on Ainuovirine had been conducted., Method: We investigated 199 people living with HIV-1 who received Ainuovirine (ANV)/lamivudine/tenofovir and 202 people living with HIV-1 who received Efavirenz (EFV)/lamivudine/tenofovir., Results: After 48 weeks of therapy, ANV and EFV showed similar viral inhibitory effects. However, in the ANV group, more participants had CD4/CD8 ratios restored to the normal range, lower levels of triglycerides and low-density lipoprotein, relatively normal liver alanine aminotransferase, and fewer adverse events., Conclusion: Therefore, due to its role in immune reconstitution, dyslipidemia, and safety, ANV may be a recommended option for people living with HIV-1., 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 reduce the risk of side effects and enhance therapeutic efficiency, drug delivery systems that offer precise control over active ingredient release while minimizing burst effects are considered advantageous. In this study, a novel approach for the controlled release of lamivudine (LV) was explored through the fabrication of polyelectrolyte-coated microparticles. LV was covalently attached to poly(ε-caprolactone) via ring-opening polymerization, resulting in a macromolecular prodrug (LV-PCL) with a hydrolytic release mechanism. The LV-PCL particles were subsequently coated using the layer-by-layer (LbL) technique, with polyelectrolyte multilayers assembled to potentially modify the carrier's properties. The LbL assembly process was comprehensively analyzed, including assessments of shell thickness, changes in ζ-potential, and thermodynamic properties, to provide insights into the multilayer structure and interactions. The sustained LV release over 7 weeks was observed, following zero-order kinetics (R 2 > 0.99), indicating a controlled and predictable release mechanism. Carriers coated with polyethylene imine/heparin and chitosan/heparin tetralayers exhibited a distinct increase in the release rate after 6 weeks and 10 weeks, respectively, suggesting that this coating can facilitate the autocatalytic degradation of the polyester microparticles. These findings indicate the potential of this system for long-term, localized drug delivery applications, requiring sustained release with minimal burst effects.

Around 1.2 million women living with HIV give birth annually, majority of whom will breastfeed their infants while receiving antiretroviral therapy (ART). Lamivudine, a component of first-line ART regimens crosses from maternal plasma to breast milk, with measurable concentrations in some breastfed infants. Wide variability in plasma-to-breast milk transfer has been reported within- or across studies, probably due to differences in sampling framework. This work sought to characterize the milk-to-plasma transfer of lamivudine, quantify inter-patient variability and associated factors, and predict exposure of a breastfed infant. We explored data from an observational pharmacokinetic study that included 35 Ugandan mothers and their infants. Mothers received lamivudine doses of 150 mg twice daily or 300 mg once daily as part of their antiretroviral regimen. Pharmacokinetic sampling was undertaken across two visits approximately 8 weeks apart, providing 248 maternal plasma, 256 breast milk-, and 151 infant blood concentrations, measured across a 24-h sampling interval. A one-compartmental model best described the plasma disposition of lamivudine, with first-order absorption, interindividual variability on clearance and volume of distribution, and a proportional residual error model. A lag in time of plasma-to-breast milk drug accumulation was described using an effect compartment model with a milk-to-plasma ratio of 1.77. An estimated daily infant dose of 179.3 μg/kg (range: 125.8, 282.3) closely predicted the observed infant steady-state concentrations and translated into 3.34% (2.13, 7.20) and 3.35% (1.10, 7.15) of the standard daily maternal dose in visits 1 and 2, respectively. The established modeling framework can be extended to other drugs., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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: 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.)

Objectives: To develop a pragmatic twice daily lamivudine dosing strategy for preterm infants from 24 to 37 completed weeks of gestation., Methods: Data were combined from eight pharmacokinetic studies in neonates and infants receiving lamivudine oral solution. A population pharmacokinetic model was developed using non-linear mixed effects regression. Different lamivudine dosing strategies, stratified by gestational age at birth (GA) bands, were simulated in a virtual population of preterm infants, aimed at maintaining lamivudine drug exposures (AUC0-12) within a reference target range of 2.95 to 13.25 µg·h/mL, prior to switching to WHO-weight band doses when ≥4 weeks of age and weighing ≥3 kg., Results: A total of 154 infants (59% female) contributed 858 lamivudine plasma concentrations. Median (range) GA at birth was 38 (27-41) weeks. At the time of first pharmacokinetic sampling infants were older with median postnatal age (PNA) of 6.3 (0.52-26.6) weeks. Lamivudine concentrations were described by a one-compartment model, with CL/F and V/F allometrically scaled to weight. Maturation of CL/F was described using an Emax model based on PNA. CL/F was also adjusted on GA to allow extrapolation for extreme prematurity. Simulations predicted an optimal lamivudine dosing for infants GA ≥24 to <30 weeks of 2 mg/kg twice daily from birth until weighing 3 kg; and for GA ≥30 to <37 weeks, 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily until weighing 3 kg., Conclusions: Model-based predictions support twice daily pragmatic GA band dosing of lamivudine for preterm infants, but clinical validation is warranted., (© 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.)

Background: The efficacy and safety of dolutegravir+lamivudine (DTG +3TC) and bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) have been demonstrated in clinical trials of treatment-naïve therapy. However, real-life data are lacking. We investigated and compared the virological outcomes and safety of DTG + 3TC with BIC/FTC/TAF in an adult cohort of people living with HIV (PLWH)., Research Design and Methods: We performed a retrospective cohort analysis of PLWH who were naïve to antiretroviral therapy and initiated the antiretroviral regimen of DTG + 3TC or BIC/FTC/TAF from January 2020 to March 2022. Treatment effectiveness, defined as the capability of treatment to achieve viral suppression (viral load < 50 copies/mL), was analyzed. Changes in immunology, metabolism, liver and renal function after 48 weeks of treatment were evaluated., Results: At 48 weeks, both groups showed high viral suppression, with 82.4% (108/131) and 89% (129/145) of the patients in the BIC/FTC/TAF and DTG + 3TC groups, respectively, having viral suppression (OR = 0.58, 95% CI: 0.29-1.15, P  = 0.3). No differences existed in immunology, metabolism, liver and renal function; however, BIC/FTC/TAF led to greater weight gain., Conclusions: Both optimization strategies showed high tolerability in antiretroviral therapy-naïve patients, with no differences in virological efficacy; however, BIC/FTC/TAF may be related to the risk of weight gain risk. Further research is required to evaluate this problem.

We characterized population pharmacokinetics in 42 African children receiving once-daily 25 mg (14 to <20 kg) or 50 mg (>20 kg) dolutegravir. Coadministration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95% confidence interval: 8.13%-30.8%) compared with zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background: Mother-to-child transmission of HIV during breastfeeding remains a challenge in low- and middle-income countries (LMIC). A prevention package was initiated during the highly attended 2nd visit of the Expanded Program of Immunisation (EPI-2) to identify the undiagnosed infants living with HIV and reduce the postnatal transmission of infant exposed to HIV., Methods: PREVENIR-PEV is a non-randomized phase II clinical trial conducted at two health centres in Bobo Dioulasso (Burkina Faso). The study recruited mothers living with HIV aged 15 years and older with their singleton breastfed infants. During EPI-2 (at 8 weeks) and upon signature of the informed consent, a point-of-care early infant diagnosis (EID) was performed. HIV exposed uninfected (HEU) infants were followed-up until 12 months of age. High risk HEU infants (i.e., whose maternal viral load ≥ 1000 cp/mL at EPI-2 or M6) received an extended postnatal prophylaxis (PNP) with lamivudine until end of follow-up or the end of breastfeeding., Results: Between 4 December 2019 and 4 December 2020, 118 mothers living with HIV-1 were identified, and 102 eligible mother/infant pairs had their infants tested for HIV EID. Six infants were newly diagnosed with HIV, and 96 HEU infants were followed-up for 10 months. Among the participants followed-up, all mothers were prescribed antiretrovirals. All 18 infants eligible for PNP at either EPI-2 or 6 months (M6) were initiated on lamivudine. No HIV transmission occurred, and no serious adverse events were reported in infants receiving lamivudine., Conclusions: The PREVENIR-PEV prevention package integrated into existing care is safe and its implementation is feasible in a LMIC with a low HIV prevalence. More research is needed to target mother/infant pairs not adhering to the intervention proposed in this trial., Trial Registration: NCT03869944; first registered on 11/03/2019., (© 2024. The Author(s).)

Objectives: To assess the efficacy and safety of a two-drug regimen (2DR) with dolutegravir (DTG) and lamivudine (3TC) in maintaining viral suppression during pregnancy and breastfeeding, and to evaluate its potential as an alternative to the recommended three-drug regimen (3DR) in preventing mother-to-child transmission (MTCT) of HIV., Methods: We present a case of a 34-year-old pregnant woman who, after discontinuing 3DR due to side effects and poor adherence, was switched to DTG/3TC at gestational week 23. Maternal viral load (VL) and infant HIV status were monitored throughout pregnancy and a ten-month breastfeeding period. Data on pharmacokinetic changes in pregnancy and the risks associated with 2DR were reviewed., Results: The patient's VL remained suppressed (<20 copies/mL) from gestational week 23 until the end of the breastfeeding period. A healthy HIV-negative baby was born at 39 weeks, and the child remained HIV-negative after ten months of breastfeeding. The 2DR was well-tolerated, improved adherence, and reduced fetal drug exposure. Despite limited experience with 2DR in pregnancy, no viral rebound occurred, and no adverse effects were observed., Conclusions: Although 3DR remains the preferred therapy during pregnancy and breastfeeding, this case indicates that DTG/3TC may be an effective alternative for patients experiencing intolerance or poor adherence to 3DR. Further studies are needed to explore the impact of pharmacokinetic changes in pregnancy on 2DR efficacy and to confirm its safety and role in preventing MTCT., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) ( n = 109) or tenofovir/emtricitabine (TFV/3TC) ( n = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI 95 , 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); P = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI 95 , 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens., Competing Interests: L.F.L.-C. has received unrestricted research funding outside the submitted work from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; consultancy fees and lecture fees from Gilead Sciences and ViiV Healthcare. N.E. has received fees as a consultant and speaker from ViiV Healthcare, Merck Sharp & Dohme, Gilead Sciences, and travel grants from Gilead Sciences and Merck Sharp for attending conferences. C.S., M.H. and A.G.-V. have received travel grants for attending conferences from Gilead Sciences.

Background: Antiretroviral therapy (ART) has transformed HIV management, with various regimens available. Dolutegravir (DTG) plus lamivudine (3TC) dual therapy is now the one of the first line regimens., Methods: A retrospective, observational study included treatment naïve people living with HIV (PLWH) with baseline HIV RNA viral load (VL) greater than 500,000 copies/mL from March 2020 to June 2022. PLWH on DTG + 3TC were included in the 2DR group, while others on INSTI-based three-drug regimens were divided in the 3DR group. Viral suppression, immunological recovery, and safety were assessed., Results: The study included 52 PLWH, with no significant baseline differences. Virologic suppression rates at weeks 24 and 48 were similar in both groups, even with baseline HIV RNA VL greater than 1,000,000 copies/mL. CD4 + T cell counts improved rapidly. No serious adverse effects were reported., Conclusions: DTG + 3TC dual therapy demonstrates effectiveness in treatment naïve PLWH with high baseline HIV RNA VL, suggesting its potential as a first line regimen for all treatment naïve PLWH., (© 2024. The Author(s).)

Background: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV., Methods: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV (400 mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/mL) at 48 weeks per US Food and Drug Administration Snapshot analysis., Results: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression, and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (P < .001), respectively, discontinued treatment because of adverse effects, death, or lost to follow-up. The median increase of CD4 count was 181 and 223 cells/μL (P = .020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < .001)., Conclusions: BIC/FTC/TAF was more efficacious and safer than EFV (400 mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China., Competing Interests: Potential conflicts of interest. L. D. served on the advisory boards of Gilead Sciences and ViiV. 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 permissions, please e-mail: journals.permissions@oup.com.)

Background: Renally adjusted lamivudine dosages are effective. However, some of the kidney failure patients managed with lamivudine-containing regimens are failing to suppress HIV in peritoneal dialysis (CAPD) effluent. The steady-state lamivudine pharmacokinetics among these patients was evaluated., Methods: This overnight open-label pharmacokinetic study enrolled participants living with HIV and managed with CAPD. Lamivudine levels in blood serum and CAPD effluent samples were quantified using liquid chromatography coupled with a mass spectrometer. Pharmacokinetic measures were obtained through non-compartmental analysis., Results: Twenty-eight participants were recruited with a median antiretroviral (ARV) drug duration of 8 (IQR,4.5-10.5) years and a CAPD duration of 13.3 (IQR,3.3-31.9) months. 14.3% (4/28) had detectable unsuppressed HIV-1 viral load in CAPD effluents. The majority (78,6%,22/28) of participants received a 50 mg dose, while 10.7% (3/28), and another 10.7% (3/28) received 75 mg and 300 mg dosages, respectively. Among those treated with 75 and 300 mg, 66.7% (2/3) and 33.3% (1/3) had detectable HIV-VL in CAPD, respectively. The peritoneal membrane characteristics and CAPD system strengths were variable across the entire study population. Lamivudine exposure was increased in blood serum (50 mg-AUC 0-24 h , 651.3 ng/mL; 75 mg-AUC 0-24 h , 677.84 ng/mL; 300 mg-AUC 0-24 h , 3135.89 ng/mL) compared to CAPD effluents (50 mg-AUC 0-24 h , 384.91 ng/mL; 75 mg-AUC 0-24 h , 383.24 ng/mL; 300 mg-AUC 0-24 h , 2001.60 ng/mL) among the entire study population. The C max (50 mg, 41.5 ng/mL; 75 mg, 53.2 ng/mL; 300 mg, 199.1 ng/mL) and C min (50 mg, 17.8 ng/mL; 75 mg, 16.4 ng/mL; 300 mg, 76.4 ng/mL) measured in serum were within the therapeutic levels., Conclusions: Steady-state lamivudine pharmacokinetic measures were variable among the entire study population. However, the total lamivudine exposure was within the therapeutic levels., (© 2024. The Author(s).)

Antiretroviral regimens for human immunodeficiency virus (HIV) infection have continuously evolved; however, antiretrovirals can cause severe adverse reactions. Two-drug regimen therapy can decrease lifetime cumulative drug exposure and long-term toxicities associated with multiple antiretrovirals. The preferred 2-drug regimen constitutes dolutegravir (DTG) and lamivudine (3TC). This study determined the rate of virological suppression and incidence of adverse events at week 48 in treatment-naïve people living with HIV initiated on DTG + 3TC. This was a single-center, retrospective, observational study. Treatment-naïve people aged ≥18 years who received at least 1 DTG + 3TC dose between May 2020 and May 2022 were included. Eighty-nine people living with HIV were enrolled. Twenty-five (28.1%) patients with a DTG + 3TC regimen at baseline were analyzed because of comorbidities, and 48% because of concomitant tuberculosis (TB). Viral suppression at 48 weeks was achieved in 91.67% of patients, and TB was well controlled. At week 48, 84 (94.38%) patients had viral loads < 50 copies/mL, and 21 (91.31%) of the 23 participants with a baseline HIV-1-RNA level ≥ 1 × 105 copies/mL achieved virological success. Fifteen (88.23%) of the 17 participants with a baseline CD4 + cell count of <200 cells/µL achieved virological suppression. The median CD4 + cell count change from baseline was 539.5 cells/µL. No significant changes in triglycerides, low-density lipoprotein cholesterol, weight, or creatinine were observed from baseline to 48 weeks. One patient had severe insomnia at 4 weeks. Our findings support the real-world effectiveness and low metabolic impact of DTG + 3TC. Using DTG + 3TC in patients coinfected with TB and HIV has favorable therapeutic outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Although dolutegravir (DTG) is deemed stable, safe, cost-effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG-based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE-to-TLD switchers) in three large primary care facilities in South Africa METHODS: We conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE-to-TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed-effect models among TEE-to-TLD switchers to consider repeated measures., Results: Of 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow-up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m 2 (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m 2 , and CD4 counts <200 cells/μL. Of 298 TEE-to-TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE-to-TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/μL were independent risk factors for lower weight gain after TLD switch., Conclusions: We report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE-to-TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG-based regimen., (© 2024 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing., Methods: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm., Discussion: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial., Trial Registration: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57., Clinicaltrials: gov: NCT04337450., 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 © 2023. Published by Elsevier Inc.)

Introduction: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities., Methods: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively., Results: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available., Conclusions: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning., (© 2024 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV., Methods: D 2 EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872., Findings: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects., Interpretation: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines., Funding: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen., Competing Interests: Declaration of interests GVM, AK, SE, MNP, and MHL received support for the present manuscript from Janssen and ViiV Healthcare, paid to their institution. GVM, AK, and SE received support for the present manuscript from Unitaid, paid to their institution. GVM received support for the present manuscript from the US National Institutes of Health (NIH) and the Australian National Health and Medical Research Council (NHMRC), paid to their institution. MHL received support for the present manuscript from Gilead, paid to their institution. AK received grants or contracts from the Medical Research Future Fund, NHMRC, NIH, and Biotron, paid to their institution; consulting fees from Merck, paid to their institution; support for attending meetings or travel from the HIV Netherlands Australia Thailand Research Collaboration, Keystone conferences, the New South Wales (NSW) Government, and NSW Office for Health and Medical Research, paid to their institution; patent planned issues or pending (PCT/AU2023/050918), with no renumeration; has acted as Chair of the ASCOT data and safety monitoring board, with no renumeration; and is the Director and Chair of Scientia Clinical Research Phase I Unit Board, with no renumeration. ML received fees from Certa Therapeutics for participation on a data safety monitoring board. GVM and MHL have participated on an advisory board for ViiV Healthcare and Gilead. NK received research grants from NIH, WHO, Indian Council of Medical Research, University of New South Wales, Unitaid, Massachusetts General Hospital—Harvard University, and TREAT Asia–The Foundation for AIDS Research for the conduct of research. DB is an employee of ViiV Healthcare and holds GSK stock options. 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.)

Objectives: Dolutegravir + lamivudine (DTG + 3TC) is a first-line regimen for people with HIV. However, there are still concerns about its efficacy in people with tuberculosis (TB)/HIV due to the lack of available evidence and drug-drug interaction with rifampicin., Methods: A single-centre retrospective observational case series was conducted in Guangxi Zhuang Autonomous Region, China. We included all people with TB/HIV on combined use of once-daily (q.d.) dosing DTG + 3TC and rifampicin (RIF)-containing anti-TB regimens between 2020 and 2022. HIV-RNA, CD4 cell counts were collected and analysed., Results: In all, 21 people with HIV (PWH) were included in this study. All the PWH were treatment-naïve and told to take DTG + 3TC q.d. with food. The median age was 53 years, and 71.43% were male. A total of 71.43% PWH had baseline viral load (VL) > 100 000 copies/mL, and 33.33% had baseline VL greater than 500 000 copies/mL. Only one PWH had CD4 cell count greater than 200 cells/μL, and the median CD4 count was 20 cells/μL. A total of 16 PWH started DTG + 3TC after initiation of the RIF-based anti-TB regimen, and the other five PWH initiated DTG + 3TC before the treatment of TB. All the PWH had at least 24 weeks of follow-up visits and all of the TB treatments were successful. A total of 20 PWH (95.24%) achieved viral suppression (VL <50 copies/mL). All detected viral loads between weeks 24 and 48 were less than 200 copies/mL. Among the PWH who started DTG + 3TC after the initiation of RIF-based anti-TB regimen, all achieved viral suppression by week 24 except the non-suppressed PWH. CD4 counts were greatly improved after antiretroviral treatment: the median CD4 counts were raised from 20 to 171 cells/μL at week 48. No serious adverse events were reported., Conclusions: This case series preliminarily validates the efficacy of DTG + 3TC q.d. with food when combined with RIF-based anti-TB regimens in people with TB/HIV., (© 2024 British HIV Association.)

Objectives: The availability of doravirine (DOR) allowed clinicians to prescribe a dolutegravir (DTG)-based two-drug regimen (2DR) in individuals not eligible to receive lamivudine (3TC) or rilpivirine (RPV). The aims of this study were to describe the durability of DTG + DOR compared with DTG/3TC and DTG/RPV and the rate of virological failure and target not-detected maintenance over time., Methods: This retrospective, monocentric analysis included all subjects who started a DTG-based 2DR from 2018 to 2022 as a simplification. Descriptive statistics and non-parametric tests to describe and compare the groups were applied. Kaplan-Meier probability curves and Cox regression models for regimens durability were used., Results: The study enrolled 710 individuals: 499 treated with DTG/3TC, 140 with DTG/RPV, and 71 with DTG + DOR. A 2DR with DOR was prescribed to older subjects who had a longer infection, greater exposure to different antiretroviral regimens, a higher proportion of resistance-associated mutations, and a worse immune-virologic status. Over a cumulative follow-up of 68 152 weeks, 42 discontinuations were registered (5.9%). DTG + DOR had a risk of treatment interruption of 7.8% at 48 weeks and 9.8% at 96 weeks, significantly higher than the other 2DRs. In the multivariate Cox model, DTG + DOR and DTG/RPV were significantly associated with discontinuation. The maintenance of target not detected during follow-up was similar among groups. The rate of virological failure was higher for DTG + DOR through different event definitions., Conclusions: DTG + DOR durability was high over a long follow-up albeit lower than for other 2DRs. This combination might be an effective option in people with HIV that has proven difficult to treat., (© 2024 British HIV Association.)

Background: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches., Methods: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants., Findings: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group., Interpretation: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen., Funding: ANRS MIE., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Two-drug regimens for the treatment of HIV are increasingly available. The oral regimen of dolutegravir plus lamivudine is recommended as a preferred option in multiple national guidelines but is not currently included in WHO HIV treatment guidelines nor widely used in Africa. Long-acting injectable cabotegravir and rilpivirine is being rolled out in the USA, Europe, and Australia but its use in sub-Saharan Africa is currently restricted to clinical trials. Given the increasing life expectancy, rising prevalence of non-communicable diseases, and resulting polypharmacy among people living with HIV, there are potential advantages to the use of two-drug regimens, particularly in African women, adolescents, and older adults. This Viewpoint reviews existing evidence and highlights the risks, benefits, and key knowledge gaps for the use of two-drug regimens in settings using the public health approach in Africa. We suggest that a two-drug regimen of dolutegravir and lamivudine can be safely used as a switch option for virologically suppressed individuals in settings using the public health approach once chronic hepatitis B has been excluded. Individuals with HIV who are switched to two-drug regimens should receive a full course of hepatitis B vaccinations. More efficacy data is needed to support dolutegravir plus lamivudine combination in the test and treat approach, and long-acting cabotegravir and rilpivirine in the public health system in sub-Saharan Africa., Competing Interests: Declarationsof interests FVC has received research funding from Janssen, ViiV, and Gilead. Additionally, FVC is a DSMB member of same-day treatment for a TB trial in South Africa. LAO has received research funding from ViiV, Gilead, and Janssen, and consulting fees from ViiV and GSK. ER has received research funding from Janssen. SS has received research funding from Janssen and ViiV. IM, CN, EALO, DSL, NO, and FVC have received salary support through research funding awarded by Janssen. 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.)

Introduction: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48 weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters., Methods: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48 weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48 weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms., Results: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR., Conclusions: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h -1 , respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h -1 . The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573., Competing Interests: H.C. is an employee of GSK and owns stock in GSK. T.P.D. and R.S. were employees of GSK at the time the study was conducted and may own stock in the company. M.A.-K. and K.A. are employees of ViiV Healthcare and own stock in GSK.

This study intended to investigate the impact of long-term tenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine β2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood β2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood β2 microglobulin was statistically significant at month 6 and months 12-30 (P < .05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine β2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P < .05). The abnormal concentration proportion of urine β2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood β2 microglobulin, urine β2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P > .05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine β2 microglobulin levels may be helpful in screening for renal dysfunction., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Lamivudine (3TC)/dolutegravir (DTG) single tablet regimen (STR) has shown long-term efficacy and tolerability in people living with HIV (PLWH). Dolutegravir has been approved for use in children, while data on the efficacy of 3TC plus DTG in maintaining virological suppression in this population are still under evaluation. In this case series, we describe three children with perinatally acquired HIV who maintained virological suppression after switching antiretroviral therapy to DTG/3TC. We present three case reports of three children enrolled in the Italian Register for HIV Infection in Children: a 9-year-old boy, a 10-year-old girl, and a 2-year-old girl with perinatally acquired HIV who immediately started antiretroviral therapy with a three-drug regimen upon diagnosis, which occurred at delivery, after 6 months of life, and after 2 years of life, respectively. They achieved and maintain virological suppression after 1, 6, and 7 months of therapy, respectively; then a switch strategy was performed with a two-drug regimen with DTG/3TC STR at the age of 7 years for the first child and at the age of 9 years for the second, while the third was switched to a DTG plus 3TC not STR, owing to weight requirements, at the age of 2 years and 10 months. All children maintained virological suppression at last follow-up visit (January 2024), showing an excellent growth curve and maintaining good adherence and tolerability to DTG plus 3TC. A two-drug regimen with DTG/3TC demonstrated efficacy in maintaining virological suppression in a switch strategy in these children, with important advantages such as better tolerability and comfort of taking a single tablet once daily.

The efficacy of 400mg efavirenz (EFV) once daily is reported to be similar to that of 600mg EFV. However, EFV-related toxic and side effects of 400mg EFV are significantly reduced. Here, the feasibility of reducing EFV to 400mg once a day in HIV-infected/AIDS patients was evaluated. Fifty patients were included. Patients were given 3TC+TDF+400mg EFV (n=25) or 3TC+TDF+600mg EFV (n=25). The proportion of patients with HIV RNA < 40 copies/mL and the adverse events served as the primary and secondary outcomes, respectively. HIV inhibition rates of the 3TC+TDF+400mg EFV group and 3TC+TDF+600mg EFV group were both 56.52% at week 24 and respectively 100%, 91.3% at week 48. During 48 weeks, 27 cases of adverse events were reported in the 3TC+TDF+400mg EFV group, lower than those in the 3TC+TDF+600mg EFV group, which had 39 cases. Compared with the 3TC+TDF+400mg EFV group, the incidence of transaminase, dizziness, hyperlipidemia and rashes all increased in the 3TC+TDF+600mg EFV group (P>0.05). No serious adverse events of the central nervous system occurred. The incidence of depression, sleep disturbance, and vertigo were similar (P>0.05). The efficacy of 400mg EFV is comparable to 600mg EFV. However, patients receiving 400mg EFV have fewer adverse events.

Background/aim: People living with human immunodeficiency virus (PLWH) are getting older. Age-related comorbidities in PLWH result in polypharmacy and increase the risk for potential drug-drug interactions (pDDIs). This study aimed to evaluate how the rate of pDDIs would change if the treatment of patients receiving different combined antiretroviral therapies (ARTs) were theoretically changed with dolutegravir/lamivudine (DTG+3TC) or cabotegravir/rilpivirine (CAB+RPV)., Materials and Methods: This study was conducted at the infectious disease outpatient clinic of a university hospital as a follow-up of a previous study. The data of PLWH receiving at least 1 comedication other than antiretrovirals (ARVs) were retrospectively reviewed and analyzed. The Drugs.com/Drug Interactions Checker and University of Liverpool HIV Drug Interactions Checker databases were used to identify pDDIs and their severities., Results: A total of 75 PLWH, of whom 83% were male, with a mean age (± standard deviation) of 46.5 (±12.98) years were included. Polypharmacy was observed in 59 (79%) of the participants; however, with dual ARV options, the probability of polypharmacy was 35 (47%) (p < 0.001). In the Drugs.com database, no significant difference was found in terms of pDDIs between the treatment of current ARTs (64%) and DTG/3TC (%44) (p = 0.06) or CAB/RPV (%64) (p = 0.521). However, in the University of Liverpool database, the current rate of pDDIs (55%) was significantly higher compared to the theoretical treatment of DTG/3TC (40%) (p = 0.029), oral CAB/RPV (48%) (p = 0.003), and injectable CAB/RPV (31%) use (p = 0.006)., Conclusion: The results suggest that dual treatment regimens can reduce pDDIs, resulting in better tolerance and probably higher quality of life among PLWH., Competing Interests: Conflict of interest: The authors declare they have no conflicts of interest., (© TÜBİTAK.)

Background: Although many drug regimens have been used in the treatment of human immunodeficiency virus (HIV) infection, the National AIDS Control Organization (NACO) of India recommends the use of a fixed-dose combination of tenofovir/lamivudine/dolutegravir (TLD) as a first-line regimen since 2020. In spite of much global data on the use of this combination, experience in the Indian population is still limited. We aim to find out the efficacy and tolerability of this novel regimen, in a tertiary care center of Eastern India., Materials and Methods: A descriptive observational study, longitudinal in design performed in the antiretroviral therapy (ART) center of a tertiary care hospital in Kolkata, West Bengal, India. All patients who attended the ART center from April 2021 to October 2022 were enrolled in the study following inclusion and exclusion criteria. A detailed history, clinical examination, necessary biochemical tests, and CD4 count of all patients were done at baseline. Subsequently, they were followed up for 6 months with monthly visits when they were enquired about any adverse effects requiring therapy interruptions. At the end of 6 months, CD4 count and viral load were measured., Results: Out of a total sample of 249 patients, the TLD regimen was efficacious in 99.2% ( n = 247) in whom viral load was suppressed to <1,000 copies/mL after 6 months of treatment. The regimen had to be temporarily discontinued in 6% of patients ( n = 15). The most common cause of treatment interruption was hepatic dysfunction (3.2%) followed by cutaneous manifestation (2.4%). In 14 out of 15 patients, the regimen could be reintroduced and was safely tolerated afterward. Only one patient had to be shifted to an alternative regimen due to tenofovir-induced nephrotoxicity. Thus TLD was tolerated in 99.6% ( n = 248) patients., Conclusion: The fixed-dose combination of TLD is a highly efficacious and well-tolerated first-line regimen for ART naïve patients with HIV infection having >95% adherence. How to cite this article: Sengupta D, Ghosh S, Pain S, et al. Efficacy and Tolerability of Tenofovir/Lamivudine/Dolutegravir among Antiretroviral Therapy Naive Human Immunodeficiency Virus Infected Patients of a Tertiary Care Center in Eastern India. J Assoc Physicians India 2023;71(9):72-74., (© Journal of the Association of Physicians of India 2023.)

The cell membrane properties create a significant obstacle in intracellular delivery of cell-impermeable and negatively charged molecules. Herein, we report the synthesis and biological evaluation of a novel series of hybrid cyclic-linear peptides containing alternative positive and hydrophobic amino acids on the ring and side chain [(RW) 5 ]K(RW) X ( X = 1-5) to compare their molecular transporter efficiency. The peptides were synthesized through Fmoc solid-phase peptide synthesis. In vitro cytotoxicity of the peptides showed that the peptides did not exhibit any significant cytotoxicity at the concentration of 10 μM in human leukemia carcinoma cell line (CCRF-CEM), human ovarian adenocarcinoma cells (SK-OV-3), human epithelial embryonic kidney healthy (HEK-293), and human epithelial mammary gland adenocarcinoma cells (MDA-MB-231) after 3 h incubation. The cellular uptake of a fluorescence-labeled phosphopeptide (F'-GpYEEI) and anti-human immunodeficiency virus (HIV) drugs (lamivudine (F'-3TC), emtricitabine (F'-FTC), Stavudine (F'-d4T)), where F' is carboxyfluorescein, was measured in the presence of the peptides in CCRF-CEM and SK-OV-3 cells. Among all peptides, [(RW) 5 K](RW) 5 (10 μM) was the most efficient transporter that improved the cellular uptake of F'-GpYEEI (2 μM) by 18- and 11-fold in CCRF-CEM and SK-OV-3, respectively, compared with F'-GpYEEI alone. Fluorescence-activated cell sorting (FACS) analysis results indicated that the cellular uptake of fluorescence-labeled peptide (F'-[(RW) 5 K](RW) 5 ) was only partially inhibited by chlorpromazine as an endocytosis inhibitor after 3 h incubation in MDA-MB-231 cells. These data suggest the potential of this series of hybrid cyclic-linear peptides as cell-penetrating peptides and molecular transporters.

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single-arm, open-label, single-dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8-hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 μg/mL (time to maximum concentration [t max ], 1.01 hours) for abacavir, 4.13 μg/mL (t max , 3.50 hours) for dolutegravir, and 3.35 μg/mL (t max , 2.98 hours) for lamivudine. Geometric mean area under the concentration-time curve values were 18.20, 71.60, and 16.60 μg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12-lead electrocardiographic parameters. Single-tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV-1 or increase the risk for adverse events., (© 2021 ViiV Healthcare. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy., Methods: DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per μL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435., Findings: Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0·8 percentage points (95% CI -3·3 to 5·2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0·68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group., Interpretation: Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART., Funding: Instituto de Salud Carlos III, Red de Investigación en Sida, and ViiV Healthcare., Competing Interests: Declaration of interests PD reports grants and personal fees from Gilead Sciences, ViiV Healthcare, and Janssen & Cilag, and personal fees from Merck, Sharp & Dohme and Theratechnologies, outside the submitted work. JT reports personal fees from Gilead Sciences, ViiV Healthcare, Merck, Sharp & Dohme, and Janssen, outside the submitted work. ER reports personal fees from Merck, Sharp & Dohme, Gilead Sciences, Janssen, and ViiV Healthcare, outside the submitted work. DP reports research grants and honoraria for advisory boards and conferences from Viiv Healthcare, Pfizer, Bristol Myers Squibb, Gilead Sciences, Janssen, and Merck, Sharp & Dohme, outside the submitted work. RP reports grants from ViiV Healthcare during the conduct of the study, and grants and personal fees from Merck, Sharp & Dohme and Gilead Sciences, outside the submitted work. JMG is currently a full employee at ViiV Healthcare, reports grants from ViiV Healthcare during the conduct of the study, and personal fees from ViiV Healthcare, outside the submitted work. JLB reports grants, personal fees, and non-financial support from ViiV Healthcare and Janssen, and personal fees and non-financial support from Merck, Sharp & Dohme, Gilead Sciences, and Theratechnologies, outside the submitted work. EM reports grants from Instituto de Salud Carlos III and ViiV Healthcare during the conduct of the study, grants and personal fees from Merck, Sharp & Dohme and ViiV Healthcare, and personal fees from Gilead Sciences and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

What Is Known and Objective: Therapeutic alternatives to simplify antiretroviral therapy (ART) in HIV-infected children are needed. We report our experience with abacavir(ABC)/lamivudine(3TC) individualized dose compounded capsules (IDCC)., Comment: We present a prospective case series of HIV-infected children who did not weigh enough to receive the adult fixed-dose combination including ABC/3TC 600mg/300mg, and were treated with weight-adapted ABC/3TC IDCC in Barcelona, Spain. Thirteen patients (12 girls) received ABC/3TC IDCC for a median(IQR) time of 30(17-54) months. No significant changes were observed in CD4 cell counts, weight or height z-scores over time. Suppression of viral replication was maintained in 7 patients with undetectable viremia at baseline. Another 5 patients achieved viral suppression with ABC/3TC IDCC-based ART, while one non-adherent girl did not. No adverse events related to ABC/3TC IDCC were observed., What Is New and Conclusion: Despite small numbers, the long-term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV-infected children., (© 2021 John Wiley & Sons Ltd.)

Introduction: We aimed to assess the effectiveness and tolerability of dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) administered as branded STR (DTG/ABC/3TC) or as two separate pills (DTG and either branded ABC/3TC [DTG+(ABC/3TC)b] or generic ABC/3TC [DTG+(ABC/3TC)g])., Methods: We included individuals from the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) who received DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g during 2015 to 2018. We used multivariable logistic regression to compare the proportion of antiretroviral-naïve individuals who achieved viral suppression (VS) (viral load ≤50 copies/mL) at 24 weeks of initiating with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g versus DTG/ABC/3TC. We also calculated the proportion of virologically suppressed individuals who maintained VS at 24 weeks after switching from DTG/ABC/3TC to DTG+(ABC/3TC)g., Results: During the study period, 829, 68 and 47 treatment-naïve individuals started treatment with DTG/ABC/3TC, DTG+(ABC/3TC)b or DTG+(ABC/3TC)g respectively. The proportions of individuals who changed their regimens due to side effects during the first 24 weeks were 3.7%, 4.4% and 6.4% respectively (p = 0.646). We did not find significant differences in VS at 24 weeks among individuals starting with DTG+(ABC/3TC)b or DTG+(ABC/3TC)g compared to those initiating with DTG/ABC/3TC. Among 177 virologically suppressed individuals who switched from DTG/ABC/3TC to DTG+(ABC/3TC)g, 170 (96.0%) maintained VS at 24 weeks., Conclusions: In naïve individuals, the effectiveness and tolerability at 24 weeks of DTG plus ABC/3TC administered as two separate pills, either as branded or generic ABC/3TC, was similar to the STR DTG/ABC/3TC. Switching the STR DTG/ABC/3TC to its separate components DTG+(ABC/3TC)g in virologically suppressed individuals did not seem to impair its effectiveness., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Post-natal HIV infection through breastfeeding remains a challenge in many low and middle-income countries, particularly due to non-availability of alternative infant feeding options and the suboptimal Prevention of Mother to Child Transmission of HIV-1 (PMTCT) cascade implementation and monitoring. The PROMISE-EPI study aims to address the latter by identifying HIV infected mothers during an almost never-missed visit for their infant, the second extended program on immunization visit at 6-8 weeks of age (EPI-2). The study is divided into 3 components inclusive of an open-label randomized controlled trial aiming to assess the efficacy of a responsive preventive intervention compared to routine intervention based on the national PMTCT guidelines for HIV-1 uninfected exposed breastfeeding infants. The preventive intervention includes: a) Point of care testing for early infant HIV diagnosis and maternal viral load; b) infant, single-drug Pre-Exposure Prophylaxis (PrEP) (lamivudine) if mothers are virally unsuppressed. The primary outcome is HIV-transmission rate from EPI-2 to 12 months. The study targets to screen 37,000 mother/infant pairs in Zambia and Burkina Faso to identify 2000 mother/infant pairs for the clinical trial. The study design and challenges faced during study implementation are described, including the COVID-19 pandemic and the amended HIV guidelines in Zambia in 2020 (triple-drug PrEP in HIV exposed infants guided by quarterly maternal viral load). The changes in the Zambian guidelines raised several questions including the equipoise of PrEP options, the standard of care-triple-drug (control arm in Zambia) versus the study-single-drug (intervention arm). Trial registration number (www.clinicaltrials.gov): NCT03869944. Submission category: Study Design, Statistical Design, Study Protocols., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Drug potency is a pharmacological parameter defining dose or concentration of drug required to obtain 50% of the drug's maximal effect. Pharmacokinetic-pharmacodynamic modelling and simulation allows estimation of potency and evaluate strategies improving treatment outcome. The objective of our study is to determine potency of atazanavir in hair, defined as atazanavir level in hair associated with 50% probability of failing to achieve viral load below 1000 copies/ml among adolescents, and explore the effect of participant specific variables on potency., Methods: A secondary analysis was performed on data from a previous study conducted in HIV-infected adolescents failing 2nd line ART from Harare central hospital, Zimbabwe, between 2015 and 2016. We simulated atazanavir concentrations in hair using NONMEM (version 7.3) ADVAN 13, based on a previously established pharmacokinetic model. Logistic regression methods were used for PKPD analysis. Simulations utilising PKPD model focused on estimation of potency and exploring the effect of covariates., Results: The potency of atazanavir in hair was found to be 4.5 ng/mg hair before adjusting for covariate effects. Participants at three months follow-up, reporting adequate adherence, having normal BMI-for-age, and cared for by mature guardians had increased potency of atazanavir in hair of 2.6 ng/mg, however the follow-up event was the only statistically significant factor at 5% level., Conclusion: Atazanavir in hair in the range 2.6 to 4.5 ng/mg is associated with above 50% probability of early viral load suppression. Adherence monitoring to adolescents with lower potency of atazanavir is recommended. The effect self-reported adherence level, BMI-for-age, and caregiver status require further evaluation.

In the ANRS 12174 trial, HIV-exposed uninfected African neonates who received lopinavir-ritonavir (LPV/r) prophylaxis for 1 year exhibited slower growth from birth to week 50 compared with those receiving lamivudine (3TC). We assessed whether this difference in growth persisted over time, and was accompanied by differences in neuropsychological and clinical outcomes. Between February 2017 and February 2018, we conducted a cross-sectional clinical evaluation among former trial participants who completed the 50-week follow-up and who were not HIV-infected. In addition to clinical examination, neuropsychological outcomes were assessed using the tests Kaufman-ABCII, Test of Variables of Attention, Movement Assessment Battery for Children and the Strengths and Difficulties questionnaire, parent version. Of 1101 eligible children, aged 5-7 years, 553 could be traced and analysed (274 in the LPV/r and 279 in the 3TC groups). Growth, clinical and neuropsychological outcomes did not differ between treatment groups. At school age, children exposed to LPV/r and 3TC at birth for 1 year had comparable growth and neuropsychological outcomes without evidence of long-term side-effects of LPV/r. It provides reassuring data on clinical outcomes for all HIV-infected children treated with this antiretroviral drug in early life.

Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.

The objective of this study was to investigate the efficacy and potential side-effects of nucleotide/nucleoside analogues and hepatitis B immunoglobulin injection of newborns in blocking mother-to-child transmission of hepatitis B virus in the middle and late pregnancy period. 238 cases of enrolled pregnant women were divided into the Telbivudine group, the Tenofovir group, the Lamivudine group, and the hepatitis B immunoglobulin (HBIG) group. Enrolled patients received corresponding therapies. Clinical and laboratory data were collected. Results showed that the levels of HBV DNA of the enrolled pregnant women in the Telbivudine, Tenofovir, and Lamivudine groups decreased rapidly after 12 weeks of drug intervention compared with those in the control. HBsAg positive rate in newborns and in children 24 weeks after birth was 0/60, 0/60, 0/60, 3/30, and 11/28 in the Telbivudine, Tenofovir, Lamivudine, HBIG, and control groups, respectively. No significant side-effects were identified after following up to 12 months after birth. Our results show that routine HBV vaccine plus HBIG injections is insufficient in blocking mother-to-child HBV transmission. Administration of nucleotide/nucleoside analogues or HBIG at pregnancy is suggested to maximize the blocking of vertical HBV transmission., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Xiaojun Sun et al.)

Objective: To review data on efficacy and safety of dolutegravir (DTG) and lamivudine (3TC) in treatment-naïve adults with HIV-1 infection., Data Sources: Phase III clinical trials and review articles were identified through PubMed (1996 to March 2020) and ClinicalTrials.gov (2000 to May 2020) using the keywords dolutegravir, lamivudine , and HIV ., Study Selection and Data Extraction: Relevant clinical trials and review articles available in English evaluating efficacy and safety of DTG and 3TC were included., Data Synthesis: The once-daily, single-tablet regimen of DTG/3TC is the first dual antiretroviral therapy (ART) recommended for initial therapy in treatment-naïve adults with HIV-1 infection. DTG and 3TC were compared with a regimen of DTG and tenofovir disoproxil fumarate/emtricitabine in the GEMINI studies and demonstrated noninferiority for the primary end point of virological suppression at up to 96 weeks. No treatment-emergent resistance mutations were identified in a small group of participants who did not reach virological suppression. The regimen is well tolerated, and the most common adverse events reported in trials include headache, diarrhea, nausea, insomnia, and fatigue., Relevance to Patient Care and Clinical Practice: This dual-ART regimen is a favorable treatment option for ART-naïve patients with HIV-1 RNA <500 000 copies/mL, absence of hepatitis B virus, and no resistance to DTG or 3TC. Benefits of dual ART include reduction in treatment-related adverse events and toxicities, drug interactions, and cost. In addition, the once-daily, single-tablet formulation promotes adherence., Conclusions: DTG/3TC has demonstrated efficacy in maintaining virological suppression in ART-naïve patients at up to 96 weeks while minimizing treatment-related adverse events and toxicities.

Objective: Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study., Designs: This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC)., Results: During follow-up (median=26.9 months, IQR=12.2-49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38)., Conclusion: The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA., Competing Interests: Competing interests: SUK reports receiving grants from Yuhan Pharmaceuticals, and lecture fees from Bristol-Myers Squibb, Gilead Science and Yuhan Pharmaceuticals; JWJ reports receiving research grants from Yuhan Pharmaceuticals and lecture fees from Abbie, Bristol-Myers Squibb, Gilead Science and MSD Korea, and serving as an advisory board member of Abbie, Gilead Science and MSD Korea; Y-SL reports receiving research grants from Bayer HealthCare Pharmaceuticals and Gilead Science, and serving as an advisory board member of Bayer HealthCare Pharmaceuticals and Gilead Science; HWL reports receiving lecture fee from Abbie, Chongkundang Pharmaceuticals, Dong-A ST Pharmaceuticals, Ildong Pharmaceuticals and Yuhan Pharmaceuticals; JHK, lecture fee from Abbie, Bristol-Myers Squibb, Gilead Science, and MSD Korea; SWL reports receiving research grants from Yuhan Pharmaceuticals, lecture fees from Abbie, Bristol-Myers Squibb, Bukwang Pharmaceuticals, Daewoong Pharmaceuticals, MSD Korea and Yuhan Pharmaceuticals, and serving as an advisory board member of Eisai and Gilead Science; JYJ reports receiving research grants from Bukwang and Yuhan Pharmaceuticals, lecture fees from Bristol-Myers Squibb, Bukwang Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Celltrion, Daewoong Pharmaceuticals, Gilead Science and Yuhan Pharmaceuticals; YJK reports receiving research grants from Bristol-Myers Squibb, Roche, JW Creagene, Bukwang Pharmaceuticals, Handok Pharmaceuticals, Hanmi Pharmaceuticals, Yuhan Pharmaceuticals and Pharmaking, and lecture fees from Bayer HealthCare Pharmaceuticals, Gilead Science, MSD Korea, Yuhan Pharmaceuticals, Samil Pharmaceuticals, CJ Pharmaceuticals, Bukwang Pharmaceuticals and Handok Pharmaceuticals; J-HY reports receiving research grant from Bayer HealthCare Pharmaceuticals, Bukwang Pharmaceuticals and Daewoong Pharmaceuticals, and J-HL reports receiving lecture fees from GreenCross Cell, Daewoong Pharmaceuticals and Gilead Korea., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Antiretroviral therapy (ART) in pregnancy has dramatically reduced HIV vertical transmission rates. Consequently, there is a growing number of children that are HIV exposed uninfected (CHEUs). Studies suggest that CHEUs exposed in utero to ART may experience developmental delays compared to their peers. We investigated the effects of in utero ART exposure on perinatal neurodevelopment in mice, through assessment of developmental milestones. Developmental milestone tests (parallel to reflex testing in human infants) are reflective of brain maturity and useful in predicting later behavioral outcomes. We hypothesized that ART in pregnancy alters the in utero environment and thereby alters developmental milestone outcomes in pups. Throughout pregnancy, dams were treated with boosted-atazanavir combined with either abacavir/lamivudine (ATV/r/ABC/3TC), or tenofovir/emtricitabine (ATV/r/TDF/FTC), or water as control. Pups were assessed daily for general somatic growth and on a battery of tests for primitive reflexes including surface-righting, negative-geotaxis, cliff-aversion, rooting, ear-twitch, auditory-reflex, forelimb-grasp, air-righting, behaviors in the neonatal open field, and olfactory test. In utero exposure to either ART regimen delayed somatic growth in offspring and evoked significant delays in the development of negative geotaxis, cliff-aversion, and ear-twitch reflexes. Exposure to ATV/r/ABC/3TC was also associated with olfactory deficits in male and forelimb grasp deficits in female pups. To explore whether delays persisted into adulthood we assessed performance in the open field test. We observed no significant differences between treatment arm for males. In females, ATV/r/TDF/FTC exposure was associated with lower total distance travelled and less ambulatory time in the centre, while ATV/r/ABC/3TC exposure was associated with higher resting times compared to controls. In utero PI-based ART exposure delays the appearance of primitive reflexes that involve vestibular and sensory-motor pathways in a mouse model. Our findings suggest that ART could be disrupting the normal progress/maturation of the underlying neurocircuits and encourage further investigation for underlying mechanisms., Competing Interests: The authors have no conflicts of interest to disclose in relation to this work. LS reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank. This does not alter our adherence to PLOS ONE policies on sharing data and materials.