Effect of Carbamazepine on Darunavir Trough Concentrations: When the Dose Can Make the Difference-A Case Study.

BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.

Comparative Effectiveness of Baloxavir Marboxil and Oseltamivir Treatment in Reducing Household Transmission of Influenza: A Post Hoc Analysis of the BLOCKSTONE Trial.

BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.

PRESTIGIO RING "a 59-year-old man with multidrug resistant HIV-1 infection failing a regimen including dolutegravir, rilpivirine, atazanavir/cobicistat: successful treatment tailoring based on genotypic and phenotypic resistance tests".

Management of virological failure in heavily treatment-experienced people with multidrug-resistant (MDR) HIV infection is a serious clinical challenge. New drugs with novel mechanisms of action have recently been approved, and their use has improved the outcome of subjects with limited treatment options (LTO). In this setting, the choice of antiretroviral therapy (ART) should be tailored based on the pattern of resistance, treatment history and patients' individual characteristics. While genotypic resistance testing is the reference method for analysing residual drug susceptibility, phenotypic resistance testing can provide additional support when facing LTO. Herein, we present the case of a patient with MDR HIV-1 infection on virological failure enrolled in the PRESTIGIO Registry. The salvage ART regimen, which included drugs with novel mechanisms of action (MoA), was tailored to the patient's clinical characteristics and on the resistance pattern explored with genotypic and phenotypic investigation, allowing the achievement of viro-immunological success. The use of recently approved drugs with novel MoA, combined with an optimized background regimen, may also achieve virological suppression in people with LTO.

Treatment with fostamatinib in patients with immune thrombocytopenia: Experience from the Andalusian region in Spain-The Fostasur Study.

Immune thrombocytopenia (ITP) is characterized by low platelet counts (PLTs) and an increased risk of bleeding. Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved as a second-line treatment for ITP. Real-world data on fostamatinib are lacking. This observational, retrospective, multicentre study, conducted in the Andalusia region of Spain, evaluated 44 adult primary ITP patients (47.7% female; median age 58 years; newly diagnosed ITP 6.8%; persistent 13.6%; chronic 79.5%; median four prior treatments) after ≥ 4 weeks of fostamatinib therapy. The median PLT at the initiation of fostamatinib was 15 × 109/L. Common reasons for starting fostamatinib were refractoriness or intolerance to prior therapy, oral medication preference, history of thrombosis and cardiovascular risk. Dosing was individualized based on efficacy and tolerance. After 2 weeks, global response rate was 56.8% (response and complete response). Response rates were 70.5%, 62.5% and 64% at 4 weeks, 12 weeks and at the end of the study respectively. Adverse events were mild, and no patients discontinued as a result. This real-world study demonstrated a response rate similar to fostamatinib as seen in the pivotal clinical trials while including newly diagnosed patients and allowing for individualized dosing.

The translocator protein 18kDa ligand etifoxine in the treatment of depressive disorders-a double-blind, randomized, placebo-controlled proof-of-concept study.

BACKGROUND: Recent developments suggest that neurosteroids may achieve rapid antidepressant effects. As such, neurosteroidogenesis mediated by the translocator protein 18 kDa (TSPO) might constitute a promising option for the treatment of depression. Therefore, the current clinical trial aims to get the first evidence of whether TPSO ligands promote rapid antidepressant effects. Furthermore, we study which mechanisms of action, e.g., modulation of distinct neuronal networks, neurosteroidogenesis, endocrinological mechanisms, TSPO expression or microbiome composition, contribute to their putative antidepressant effects. METHODS: This is a randomized, placebo-controlled, double-blind single-center trial of 2-week treatment with the TSPO ligand etifoxine versus placebo in depressive patients. Main eligibility criteria: male or female individuals aged 18 to 65 years with unipolar/bipolar depressive disorder with no other psychiatric main diagnosis or acute neurological/somatic disorder or drug/alcohol dependence during their lifetime. The primary endpoint is the time point at which 50% of the maximal effect has occurred (ET50) estimated by the scores of the Hamilton Depression Scale (HAMD-21). A total of 20 patients per group are needed to detect changes of therapeutic efficacy about 5% and changes of ET50 about 10% with a power of 70%. Assuming a drop-out rate of 10-20%, 50 patients will be randomized in total. The study will be conducted at the Department of Psychiatry and Psychotherapy of the University of Regensburg. DISCUSSION: This study will provide a first proof-of-concept on the potential of the TSPO ligand etifoxine in the treatment of depressive disorders. TRIAL REGISTRATION: Clinical Trials Register (EudraCT number: 2021-006773-38 , registration date: 14 September 2022) and German Register of Clinical Studies (DRKS number: DRKS00031099 , registration date: 23 January 2023).

Clinical Trials That Have Changed Clinical Practice and Care of Pregnant People With HIV.

Over the last 4 decades, significant advances in the care of HIV during pregnancy have successfully reduced, and nearly eliminated, the risk of perinatal HIV transmission. The baseline risk of transmission without intervention (25% to 30%) is now <1% to 2% in the United States with contemporary antepartum, intrapartum, and postnatal interventions. In this review, we discuss 3 landmark clinical trials that substantially altered obstetric practice for pregnant individuals with HIV and contributed to this extraordinary achievement: 1) the Pediatric AIDS Clinical Trials Group 076 Trial determined that antepartum and intrapartum administration of antiretroviral drug zidovudine to the pregnant individual, and postnatally to the newborn, could reduce the risk of perinatal transmission by approximately two-thirds; 2) the European Mode of Delivery Collaboration Trial demonstrated performance of a prelabor cesarean birth before rupture of membranes among pregnant people with viremia reduced the risk of perinatal transmission compared with vaginal birth; and 3) the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 Trial identified that dolutegravir-containing, compared with efavirenz-containing, antiretroviral regimens during pregnancy achieved a significantly higher rate of viral suppression at delivery with shorter time to viral suppression, with fewer adverse pregnancy outcomes. Collectively, these trials not only advanced obstetric practice but also advanced scientific understanding of the timing, mechanisms, and determinants of perinatal HIV transmission. For each trial, we will describe key aspects of the study protocol and outcomes, insights gleaned about the dynamics of perinatal transmission, how each study changed clinical practice, and relevant updates to current practice since the trial's publication.

Multiomics plasma effects of switching from triple antiretroviral regimens to dolutegravir plus lamivudine.

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.

Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Pharmacokinetics of Single-Dose Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen.

BACKGROUND: Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. METHODS: We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomized some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14, and 28 were evaluated. The primary outcome was the geometric mean ratio of dolutegravir trough concentrations on day 7 versus day 28. RESULTS: Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard dose for the first 14 days. Baseline characteristics were 77% female, median age 36 years, CD4 cell count 254 cells/mm3, and HIV-1 RNA 4.0 log10 copies/mL. The geometric mean ratio (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 was 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3. CONCLUSIONS: No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction postswitch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.

An orally active entry inhibitor of influenza A viruses protects mice and synergizes with oseltamivir and baloxavir marboxil.

Seasonal or pandemic illness caused by influenza A viruses (IAVs) is a major public health concern due to the high morbidity and notable mortality. Although there are several approved drugs targeting different mechanisms, the emergence of drug resistance calls for new drug candidates that can be used alone or in combinations. Small-molecule IAV entry inhibitor, ING-1466, binds to hemagglutinin (HA) and blocks HA-mediated viral infection. Here, we show that this inhibitor demonstrates preventive and therapeutic effects in a mouse model of IAV with substantial improvement in the survival rate. When administered orally it elicits a therapeutic effect in mice, even after the well-established infection. Moreover, the combination of ING-1466 with oseltamivir phosphate or baloxavir marboxil enhances the therapeutic effect in a synergistic manner. Overall, ING-1466 has excellent oral bioavailability and in vitro absorption, distribution, metabolism, excretion, and toxicity profile, suggesting that it can be developed for monotherapy or combination therapy for the treatment of IAV infections.

Exploring the Roles of Vitamins C and D and Etifoxine in Combination with Citalopram in Depression/Anxiety Model: A Focus on ICAM-1, SIRT1 and Nitric Oxide.

The study of intercellular adhesion molecule-1 (ICAM-1) and SIRT1, a member of the sirtuin family with nitric oxide (NO), is emerging in depression and anxiety. As with all antidepressants, the efficacy is delayed and inconsistent. Ascorbic acid (AA) and vitamin D (D) showed antidepressant properties, while etifoxine (Etx), a GABAA agonist, alleviates anxiety symptoms. The present study aimed to investigate the potential augmentation of citalopram using AA, D and Etx and related the antidepressant effect to brain and serum ICAM-1, SIRT1 and NO in an animal model. BALB/c mice were divided into naive, control, citalopram, citalopram + etx, citalopram + AA, citalopram + D and citalopram + etx + AA + D for 7 days. On the 8th day, the mice were restrained for 8 h, followed by a forced swim test and marble burying test before scarification. Whole-brain and serum expression of ICAM-1, Sirt1 and NO were determined. Citalopram's antidepressant and sedative effects were potentiated by ascorbic acid, vitamin D and etifoxine alone and in combination (p < 0.05), as shown by the decreased floating time and rearing frequency. Brain NO increased significantly (p < 0.05) in depression and anxiety and was associated with an ICAM-1 increase versus naive (p < 0.05) and a Sirt1 decrease (p < 0.05) versus naive. Both ICAM-1 and Sirt1 were modulated by antidepressants through a non-NO-dependent pathway. Serum NO expression was unrelated to serum ICAM-1 and Sirt1. Brain ICAM-1, Sirt1 and NO are implicated in depression and are modulated by antidepressants.

Clinical outcomes of baloxavir versus oseltamivir in immunocompromised patients.

BACKGROUND: Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear. METHODS: We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality. RESULTS: Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes. CONCLUSION: Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.

HIV viral suppression in children and adolescents 2 years after transition to dolutegravir: a multicentre cohort study.

BACKGROUND: Treatment failure is common among children and adolescents with HIV. Antiretroviral therapy (ART) containing dolutegravir has recently been rolled out across Africa, though long-term real-world data in paediatric populations are lacking. Here, we report treatment outcomes among children and adolescents in Lesotho who transitioned from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based to dolutegravir-based ART through 2 years' follow-up. METHODS: Data were derived from two open cohort studies in Lesotho. Children and adolescents aged less than 18 years who transitioned from NNRTI-based to dolutegravir-based ART at least 18 months before data closure were included. We report viral load results less than 12 months before, 12 (window: 6-17) months after, and 24 (window: 18-29) months after transition to dolutegravir. Associations of pretransition demographic and clinical factors with 24-month viraemia were assessed through multivariable logistic regression. RESULTS: Among 2126 included individuals, 1100 (51.7%) were female individuals, median age at transition to dolutegravir was 14.0 years [interquartile range (IQR) 11.5-15.8], and median time taking ART at transition was 7.6 years (IQR 4.4-10.6). Among those with a viral load result at the respective time points, viral suppression to less than 50 copies/ml was achieved by 1635 of 1973 (82.9%) less than 12 months before, 1846 of 2012 (91.8%) 12 months after, and 1725 of 1904 (90.6%) 24 months after transition to dolutegravir. Pretransition viraemia was associated with viraemia at 24 months, though more than 80% of individuals with pretransition viraemia achieved resuppression to less than 50 copies/ml at 24 months. CONCLUSION: The proportion of children and adolescents with viral suppression increased after transition to dolutegravir, though further progress is needed to reach global targets.

Different effects of the companion antiretroviral drugs on dolutegravir trough concentrations.

BACKGROUND: Dolutegravir is widely used in different dual and triple antiretroviral regimens. Here, we sought to investigate the effect of the companion antiretroviral drug(s) on dolutegravir plasma trough concentrations in persons with HIV, with a focus on dual regimens. METHODS: Dolutegravir concentrations collected from October 2015 to March 2023 ( n  = 900) were stratified according to the main antiretroviral classes (NRTIs, NNRTIs, protease inhibitors) and according to single drugs. Dolutegravir concentrations measured in persons with HIV concomitantly treated with lamivudine were considered as the reference group. RESULTS: Dolutegravir trough concentrations were significantly higher in persons with HIV given protease inhibitors compared with the reference [1886 (1036-2940) versus 1575 (1026-2226) ng/ml; P  = 0.004]. The highest dolutegravir concentrations were measured in persons with HIV concomitantly treated with unboosted atazanavir [2908 (2130-4135) ng/ml]. Conversely, co-administration of darunavir/ritonavir resulted in significantly lower dolutegravir exposure [909 (496-1397) ng/ml; P  = 0.002 versus reference]. Among NNRTIs, the higher dolutegravir concentrations were measured in presence of rilpivirine [2252 (1489-2686); P  < 0.001 versus reference]. CONCLUSION: Dolutegravir trough concentrations are differently affected by individual antiretroviral drugs, with some drug combinations (i.e. dolutegravir/darunavir/cobicistat, or dolutegravir/rilpivirine) providing significantly higher than expected dolutegravir exposure. Such combinations might be advantageous when there are concerns about dolutegravir plasma exposure or resistance.

Comparison of dolutegravir and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent, these symptoms occur in pregnant and postpartum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48 weeks postpartum. RESULTS: Among 268 women, median (IQR) Edinburgh Post Natal Depression Score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir and efavirenz arm, respectively, 23.7 and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow-up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen ( P  = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir and efavirenz were 6 (5-7) and 5 (5-6.5), respectively, P  = 0.70. CONCLUSION: No statistically significant differences were observed between efavirenz-containing or dolutegravir-containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Natural course of AIDS following HIV-2 infection.

In a 21-year-old female, AIDS following infection with HIV-2 was diagnosed alongside an HIV-associated high-grade B cell lymphoma. Treatment of HIV-2 with dolutegravir, emtricitabine, and tenofovir resulted in viral suppression and slow recovery of CD4 cell counts. Treatment of lymphoma caused significant adverse effects but led to complete remission. The patient denied sexual activity and intravenous drug abuse. The patient had been born to an HIV-2-positive mother but appropriate perinatal testing based on national guidelines had remained negative. This case recapitulates the natural course of HIV-2 infection.

Effectiveness, Weight Changes, and Metabolic Outcomes on Switch to Generic Dolutegravir/Lamivudine Among People with HIV in Western India: An Observational Study.

We assessed the effectiveness and safety of switching to generic dolutegravir/lamivudine (DTG/3TC) among People living with Human Immunodeficiency Virus (PWH) in Western India. In this single-center, retrospective observational study, PWH, who switched to DTG/3TC, were followed for virologic, immunologic, and clinical effectiveness, and safety, including weight changes, hyperglycemia, and dyslipidemia. Multivariate linear mixed-effects models were used to predict average change in weight adjusted for age, sex, duration of previous antiretroviral (ARV) regimens, and baseline weight. From May 2017 to July 2022, out of 434 PWH switched to DTG/3TC, 304 with at least 1 follow-up visit were included. Median [interquartile range (IQR)] age was 54 (IQR 49-61) years and 70.1% were male. Prevalence of baseline comorbidities was 57.9% (hypertension-41.5%, chronic kidney disease-40.9%, and diabetes mellitus-18.8%). Reasons for switch were affordability (47.4%), desire for simplification (41.8%), ARV toxicities (19.1%), and concern about potential toxicities (10.2%). Median (IQR) duration of follow-up on DTG/3TC was 40 (IQR 31-49) weeks. No virologic failure was observed. Rates of virologic suppression [viral load (VL) ≤20 copies/mL or target not detected (TND)] at 12, 24, 48, 72, 96 and 120 weeks were 95.2%, 95.9%, 90%, 100%, 81.3%, and 88.4%, respectively. Only 9 (3%) PWH permanently discontinued DTG/3TC. Predicted adjusted mean weight gain of +3.3 kg was observed at 96 weeks. Switching from tenofovir disoproxil fumarate (TDF)/emtricitabine or lamivudine (XTC)/non-nucleoside reverse transcriptase inhibitor (NNRTI) and duration on DTG/3TC were significantly associated with weight gain. Apart from trend in worsening hyperglycemia (nine PWH with new onset diabetes), no clinically significant change in lipids and estimated glomerular filtration rate (eGFR) was documented. Switching to DTG/3TC is an effective and safe option among virologically suppressed PWH with high comorbidity burden in India. In view of the several advantages of DTG/3TC, it may be considered for potential scale-up in the right population, both in private and public health care settings in India.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine in Virologically Suppressed People Living with HIV-1 Aged Over 65 Years.

Clinical trials of dual regimen dolutegravir/lamivudine (DOL/3TC) demonstrated potent efficacy and favorable safety in both antiretroviral therapy-naïve and -experienced patients, but data on older people are lacking. We aimed to evaluate virological efficacy and safety of DOL/3TC in suppressed older patients over a 12-month period. We performed a retrospective cohort study evaluating people living with HIV (PLWHIV) aged ≥65 years at our HIV Clinic who were switched to DOL/3TC. Eligible patients had baseline HIV-1 RNA <20 copies/mL, and no previous virological failures or known resistance mutations for lamivudine or dolutegravir. Inclusion criteria were met by 72 patients: 59 were men, median age was 69.2 years, and one or more comorbidities were present in 89% of patients. The most common reason for switch was simplification, followed by drug-drug interactions (DDIs) and toxicities. After 12 months, 64 (88.9%, by the intention-to-treat analysis) patients maintained HIV-1 RNA <20 copies/mL, and reasons for treatment failure were virological failure in three cases, adverse events in three, and missing data in two. Genotype resistance testing showed no resistance mutations for lamivudine or dolutegravir in subjects with virological failure. The number of potential DDIs decreased from 92 to 12 after switching to DOL/3TC, and a significant reduction in median total and low-density lipoprotein cholesterol was reported, while median change in body weight was not significant. In this real-life cohort, switching to DOL/3TC was associated with maintenance of virological control and good tolerability among persons aged >65 years, supporting use of this dual regimen in older PLWHIV.