How can we optimize the diagnostic and therapeutic approach to pneumonia? Expert opinion-based recommendations.

Pneumonia continues to be one of the most frequent infectious syndromes and a relevant cause of death and health resources utilization. The OPENIN ("Optimización de procesos clínicos para el diagnóstico y tratamiento de infecciones") Group is composed of Infectious Diseases specialists and Microbiologists and aims at generating recommendations that can contribute to improve the approach to processes with high impact on the health system. Such task relies on a critical review of the available scientific evidence. The first Group meeting (held in October 2023) aimed at answering the following questions: Can we optimize the syndromic and microbiological diagnosis of pneumonia? Is it feasible to safely shorten the length of antibiotic therapy? And, is there any role for the immunomodulatory strategies based on the adjuvant use of steroids, macrolides or immunoglobulins? The present review summarizes the literature reviewed for that meeting and offers a series of expert recommendations.

Early Detection of Cancer and Precancerous Lesions in Persons with HIV through a Comprehensive Cancer Screening Protocol.

BACKGROUND: Non-AIDS defining malignancies present a growing challenge for persons with HIV (PWH), yet tailored interventions for timely cancer diagnosis are lacking. The Spanish IMPAC-Neo protocol was designed to compare two comprehensive cancer screening strategies integrated into routine HIV care. This study reports baseline data on the prevalence and types of precancerous lesions and early-stage cancer among participants at enrolment. Acceptability of the procedure was additionally assessed. METHODS: Cross-sectional analysis of a comprehensive screening protocol to detect precancer and cancer. The readiness of healthcare providers to implement the protocol was evaluated using a validated 4-item survey. RESULTS: Among the 1430 enrolled PWH, 1172 underwent 3181 screening tests, with positive findings in 29.4% of cases, leading to further investigation in 20.7%. Adherence to the protocol was 84%, with HIV providers expressing high acceptability (97.1%), appropriateness (91.4%), and feasibility (77.1%). A total of 145 lesions were identified in 109 participants, including 60 precancerous lesions in 35 patients (3.0%), 9 early-stage cancers in 9 patients (0.8%), and 76 low-risk lesions in 65 subjects (5.5%). Adverse events related to screening occurred in 0.8% of participants, all mild. The overall prevalence of cancer precursors or early-stage cancer was 3.8% (95% CI, 2.74%-5.01%), with highest rates observed in individuals screened for anal and colorectal cancers. CONCLUSIONS: The baseline comprehensive cancer screening protocol of the IMPAC-Neo study successfully identified a significant proportion of PWH with precancerous lesions and early-stage cancer. High adherence rates and positive feedback from providers suggest effective implementation potential in real-world healthcare settings.

Stigma and fear of getting sick in the care of people living with HIV: an exploratory systematic review.

The aim of the present study was to explore the stigma and fear of getting sick in health professionals who treat people living with HIV. An exploratory systematic review was conducted. The search was limited to the presence of stigma and fear of getting sick on the part of healthcare workers who treat people living with HIV, documented by the health workers or patients themselves. No language restriction was made and systematic reviews, comments or communications were excluded. The sources of information were Scopus, PubMed/MEDLINE, Science Direct, and the CENTRAL Registry, from the last 5 years. The quality of the evidence was assessed with an adapted tool and the synthesis of the results was carried out using a narrative synthesis approach. Twenty-three articles were included, which related structural stigma, stigma by health professionals and fear of getting sick. Among the findings, data stood out such as that more than 50% of patients reported having experienced discrimination due to HIV and even accumulated stigma for other additional causes. Stigma enacted in healthcare settings was related to suboptimal adherence to treatment (OR 1.38; 95% CI: 1.03-1.84; p=0.028). Stigma is a structural barrier in the care of people living with HIV and generates a psychological, physical, and social health impact for these people. Some limitations of the present study are that, despite searching the major databases, important manuscripts may have been left out. Additionally, there are regions that are not represented in this review because no manuscripts from those areas were found.

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.

Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV.

BACKGROUND: Fixed-dose combinations of antiretroviral drugs are commonly used to treat HIV infection and therapeutic monitoring is not part of routine clinical practice. However, drug concentrations monitoring might have role in different clinical scenarios as well as for research purposes. This study aimed to develop and validate UHPLC-MS/MS procedures for measuring total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. MATERIAL AND METHODS: Equilibrium dialysis preceded sample preparation (based on protein precipitation) for measuring unbound antiretroviral concentrations. Chromatographic separations were achieved on an Acquity®-UPLC® HSS™-T3 column (50 mm × 2.1 mm; 1.8 µm) using a non-linear water/acetonitrile gradient containing 0.1 % formic acid at a 0.5 mL/min flow rate. Antiretrovirals were detected by tandem mass spectrometry in positive electrospray ionisation and multiple reaction monitoring modes. RESULTS: No significant interferences or carry-over were observed. Imprecisions, absolute relative biases, normalised matrix effects and recoveries were ≤15.0 %, ≤11.1 %, (94.7-104.1)% and (96.7-105.5)%, respectively. Non-linear measuring intervals were observed between (25-10,000) µg/L for total/plasma dialysate concentrations and linearity schemes (1.00-100) µg/L for buffer dialysate concentrations. CONCLUSIONS: The UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.

Decay of HIV RNA in Seminal Plasma and Rectal Fluid in Treatment-Naive Adults Starting Antiretroviral Therapy With Dolutegravir Plus Lamivudine or Bictegravir/Emtricitabine/Tenofovir Alafenamide.

BACKGROUND: Decay of HIV in seminal plasma (SP) and rectal fluid (RF) has not yet been described for the antiretroviral combination of dolutegravir (DTG) + lamivudine (3TC). METHODS: In this randomized multicenter pilot trial, males who were antiretroviral naive were randomized (2:1) to DTG + 3TC or bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). HIV-1 RNA was measured in blood plasma (BP), SP, and RF at baseline; days 3, 7, 14, and 28; and weeks 12 and 24. RESULTS: Of 25 individuals enrolled, 24 completed the study (DTG + 3TC, n = 16; BIC/FTC/TAF, n = 8). No significant differences were observed between groups for median decline in HIV-1 RNA from baseline at each time point or median time to achieve HIV-1 RNA <20 copies/mL in BP and SP and <20 copies/swab in RF. HIV-1 RNA decay patterns were compared in individuals receiving DTG + 3TC. Despite significantly higher percentages for changes from baseline in BP, median (IQR) times to HIV-1 RNA suppression were shorter in SP (7 days; 0-8.75) and RF (10.5 days; 3-17.5) than in BP (28 days; 14-84; P < .001). CONCLUSIONS: Comparable HIV-1 RNA decay in BP, SP, and RF was observed between DTG + 3TC and BIC/FTC/TAF. As shown with triple-drug integrase inhibitor-based regimens, rapid HIV-1 RNA suppression in SP and RF is achieved with DTG + 3TC, despite decay patterns differing from those of BP. CLINICAL TRIALS REGISTRATION: EudraCT 2019-004109-28.

Behaviour changes following HIV diagnosis among men who have sex with men in the era of treatment as prevention: data from a prospective study.

We described the longitudinal changes in sexual behaviour and associated factors among newly diagnosed with HIV men who have sex with men participating in a prospective observational study from a London HIV clinic (2015-2018). Participants self-completed questionnaires at baseline, months 3 and 12. Information collected included socio-demographic, sexual behaviour, health, lifestyle and social support. Trends in sexual behaviours over one year following diagnosis and associated factors were assessed using generalized estimating equations with logit link. Condomless sex (CLS) dropped from 62.2% at baseline to 47.6% at month-three but increased again to 61.8% at month-12 (p-trend = 0.790). Serodiscordant-CLS increased between month-three and month-12 (from 13.1% to 35.6%, p-trend < 0.001). The prevalence of serodiscordant-CLS with high risk of transmitting to their partners at month-three was 10.7%. CLS was higher among men who reported recreational drug use (adjusted Odds Ratio (aOR) 3.03, 95%CI 1.47-6.24, p = 0.003), those with undetectable viral load (aOR 2.17, 95%CI 1.22-3.84, p = 0.008) and those who agreed with a statement "condoms are not necessary when HIV viral load is undetectable" (aOR 3.41, 95%CI 1.58-7.38, p = 0.002). MSM continued to engage in CLS after HIV diagnosis, which coincided with U = U publications and increased throughout the study.

Effectiveness and tolerability of dolutegravir/lamivudine for the treatment of HIV-1 infection in clinical practice.

OBJECTIVES: To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018-2021. METHODS: We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens. RESULTS: We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30-0.74) compared with dolutegravir/lamivudine.For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event. CONCLUSIONS: In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects.

Determinants of long-term survival in late HIV presenters: The prospective PISCIS cohort study.

Background: Late HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined. Methods: From PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005-2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4<500 cells/µL). We used logistic regression and propensity score matching. Findings: We included 2,719 participants (16593·1 person-years): 1441 (53%) late presenters (LP) and 1278 non-LP (1145 non-LP with two-year CD4 count >500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200-500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or <200 cells/µL (aMRR 4·59[2·25-9·37]).Conversely, no differences were observed in participants with two-year CD4 counts >500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]). Interpretation: Two-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens. Funding: Southern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Short-term Neuropsychiatric and Body Weight Changes in Patients Switching From EVG/Cobi/FTC/TAF to BIC/FTC/TAF (PreEC/RIS69).

BACKGROUND: We report NP, clinical and laboratory changes in patients switching from EVG/Cobi/FTC/TAF to BIC/FTC/TAF in clinical practice. METHODS: A group of subjects switching from EVG/Cobi/FTC/TAF to BIC/F/TAF was prospectively followed. A validated sleep quality questionnaire (Pittsburgh Sleep Quality Index), as well as the Hospital Anxiety and Depression Scale (HADS), were administered after 4 weeks from the treatment switch. Adverse events, side effects and discontinuation were recorded at weeks 4 and 24. Pretreatment switch and week 24 body weight and laboratory data were compared. RESULTS: A total of 96 virologically suppressed patients (86% male) were included. All patients received EVG/Cobi/FTC/TAF at least 1 year before the treatment switch. Median (IQR) nadir CD4 was 367 (263). The most common comorbidities were dyslipidemia, HTA and diabetes, 26%, 14% and 7%, respectively. Depression was reported by 8%. Five patients discontinued BIC/FTC/TAF before week 4 due to intolerance (2 insomnia, 1 headache and 2 GI symptoms). No changes in sleep quality, anxiety and depression outcomes were observed at week 4 (p = 0.1, p = 0.1 and p = 0.3, respectively). After 6 months, the median body weight change was statistically significant (0.6 kg, p = 0.003). All patients maintained HIV suppression. CONCLUSION: Except in a few cases, sleep quality, anxiety and depression symptoms remain stable in HIV virologically suppressed patients on EVG/Cobi/FTC/TAF who switch to BIC/F/TAF. NPAEs are mild and tend to occur in those with previous neuropsychiatric symptoms. Weight gain tends to be small but statistically significant. Long-term follow-up in "real-life" cohorts would be needed to confirm these findings.

Long-lasting adaptive immune memory specific to SARS-CoV-2 in convalescent coronavirus disease 2019 stable people with HIV.

OBJECTIVE: While the course of natural immunization specific to SARS-CoV-2 has been described among convalescent coronavirus disease 2019 (COVID-19) people without HIV (PWOH), a thorough evaluation of long-term serological and functional T- and B-cell immune memory among people with HIV (PWH) has not been reported. METHODS: Eleven stable PWH developing mild ( n  = 5) and severe ( n  = 6) COVID-19 and 39 matched PWOH individuals with mild (MILD) ( n  = 20) and severe (SEV) ( n  = 19) COVID-19 infection were assessed and compared at 3 and 6 months after infection for SARS-CoV-2-specific serology, polyfunctional cytokine (interferon-γ [IFN-γ], interleukin 2 [IL-2], IFN-γ/IL-2, IL-21) producing T-cell frequencies against four main immunogenic antigens and for circulating SARS-CoV-2-specific immunoglobulin G (IgG)-producing memory B-cell (mBc). RESULTS: In all time points, all SARS-COV-2-specific adaptive immune responses were highly driven by the clinical severity of COVID-19 infection, irrespective of HIV disease. Notably, while a higher proportion of mild PWH showed a higher decay on serological detection between the two time points as compared to PWOH, persistently detectable IgG-producing mBc were still detectable in most patients (4/4 (100%) for SEV PWH, 4/5 (80%) for MILD PWH, 10/13 (76.92%) for SEV PWOH and 15/18 (83.33%) for MILD PWOH). Likewise, SARS-CoV-2-specific IFN-γ-producing T-cell frequencies were detected in both PWH and PWOH, although significantly more pronounced among severe COVID-19 (6/6 (100%) for SEV PWH, 3/5 (60%) for MILD PWH, 18/19 (94.74%) for SEV PWOH and 14/19 (73.68%) for MILD PWOH). CONCLUSIONS: PWH develop a comparable short and long-term natural functional cellular and humoral immune response than PWOH convalescent patients, which are highly influenced by the clinical severity of the COVID-19 infection.

Doravirine Concentrations and Human Immunodeficiency Virus Type 1 RNA in the Genital Fluids of Virologically Suppressed Adults Switching to Doravirine Plus Emtricitabine/Tenofovir Alafenamide.

Doravirine (DOR) concentrations and HIV-1 RNA were evaluated in genital fluids from adults with HIV on stable therapy who switched to DOR + FTC/TAF. High protein-unbound DOR concentrations were observed in both seminal plasma and cervicovaginal fluid. DOR + FTC/TAF maintained viral suppression in genital fluids in all but 1 participant.

Total and Unbound Doravirine Concentrations and Viral Suppression in CSF.

We determined total and unbound concentrations of doravirine (DOR) in cerebrospinal fluid and blood plasma. Total and unbound DOR concentrations in cerebrospinal fluid exceeded the half-maximal effective concentration against wild-type virus (5.1 ng/mL) in all patients, suggesting that DOR may contribute to inhibit viral replication in this compartment.

Efficacy and safety of switching to dolutegravir plus lamivudine versus continuing triple antiretroviral therapy in virologically suppressed adults with HIV at 48 weeks (DOLAM): a randomised non-inferiority trial.

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.

Dynamics of the Decay of Human Immunodeficiency Virus (HIV) RNA and Distribution of Bictegravir in the Genital Tract and Rectum in Antiretroviral-naive Adults Living With HIV-1 Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (Spanish HIV/AIDS Research Network, PreEC/RIS 58).

BACKGROUND: The pharmacokinetics of bictegravir (BIC) and its association with the decay of human immunodeficiency virus (HIV)-1 RNA in genital fluids and the rectum have not yet been addressed. METHODS: We conducted a prospective, multicenter study of antiretroviral-naive people living with HIV-1 and initiating BIC/emtricitabine (FTC)/tenofovir alafenamide (TAF). HIV-1 RNA was measured (limit of quantification, 40 copies/mL) in blood plasma (BP), seminal plasma (SP), rectal fluid (RF), and cervicovaginal fluid (CVF) at baseline; Days 3, 7, 14, and 28; and Weeks 12 and 24. Total and protein-unbound BIC concentrations at 24 hours postdose (C24h) were quantified in BP, SP, CVF and rectal tissue (RT) on Day 28 and Week 12 using a validated liquid chromatography-tandem mass spectrometry assay. RESULTS: The study population comprised 15 males and 8 females. In SP, RF, and CVF, the baseline HIV-1 RNA was >40 copies/mL in 12/15, 13/15, and 4/8 individuals, respectively, with medians of 3.54 (2.41-3.79), 4.19 (2.98-4.70), and 2.56 (1.61-3.56) log10 copies/mL, respectively. The initial decay slope was significantly lower in SP than in RF and BP. The time to undetectable HIV-1 RNA was significantly shorter in SP and RF than in BP. All women achieved undetectable HIV-1 RNA in CVF at Day 14. The median total BIC concentrations in SP, RT, and CVF were 65.5 (20.1-923) ng/mL, 74.1 (6.0-478.5) ng/g, and 61.6 (14.4-1760.2) ng/mL, respectively, representing 2.7%, 2.6%, and 2.8% of the BP concentration, respectively, while the protein-unbound fractions were 51.1%, 44.6%, and 42.6%, respectively. CONCLUSIONS: BIC/FTC/TAF led to rapid decay of HIV-1 RNA in genital and rectal fluids. Protein-unbound BIC concentrations in SP, RT, and CVF highly exceeded the half-maximal effective concentration (EC50) value (1.1 ng/mL). CLINICAL TRIALS REGISTRATION: EudraCT 2018-002310-12.

No Changes in Human Immunodeficiency Virus (HIV) Suppression and Inflammatory Markers in Cerebrospinal Fluid in Patients Randomly Switched to Dolutegravir Plus Lamivudine (Spanish HIV/AIDS Research Network, PreEC/RIS 62).

A major concern of human immunodeficiency virus (HIV) dual therapy is a potentially lower efficacy in viral reservoirs, especially in the central nervous system (CNS). We evaluated HIV RNA, neuronal injury, and inflammatory biomarkers and dolutegravir (DTG) exposure in cerebrospinal fluid (CSF) in patients switching to DTG plus lamivudine (3TC). All participants maintained viral suppression in plasma and CSF at week 48. We observed no increase in CSF markers of inflammation or neuronal injury. Median (interquartile range) total and unbound DTG in CSF were 7.3 (5.9-8.4) and 1.7 (1.2-1.9) ng/mL, respectively. DTG+3TC may maintain viral control without changes in inflammatory/injury markers within the CNS reservoir.

Nothing is perfect: the safety issues of integrase inhibitor regimens.

INTRODUCTION: Since the administration of the first integrase strand transfer inhibitor (INSTI) in 2007, most international treatment guidelines consider INSTI-based regimens to be the preferred antiretroviral combinations for HIV-1-infected patients as a result of their safety and efficacy profile. INSTIs are generally well tolerated, and reported rates of discontinuation due to drug-related adverse events (AEs) have been very low to date. However, recent reports indicate that physicians should be aware of potential INSTI-related AEs to ensure good clinical practice. AREAS COVERED: The authors performed a critical review of the safety issues affecting INSTIs based on published evidence from original studies and new data from researchers. EXPERT OPINION: Almost all antiretroviral drugs, including INSTIs, are associated with undesirable AEs. Dolutegravir in particular has been associated with more frequent AEs such as neuropsychiatric disorders, neural tube defect in newborns, and weight gain. Data with bictegravir in routine practice are still scarce. While this association and its clinical relevance are not clear, physicians should be alert to the appearance of the aforementioned AEs and others in the future. In the meantime, INSTIs continue to be the preferred option in guidelines on antiretroviral therapy.

Measurement of total and unbound bictegravir concentrations in plasma and cerebrospinal fluid by UHPLC-MS/MS.

Bictegravir is a novel integrase strand transfer inhibitor, administrated in co-formulation with tenofovir alafenamide and emtricitabine (Biktarvy®), indicated in the management of HIV-1 infection in patients not previously treated with antiretroviral therapy. Bictegravir is highly bound to plasma proteins, and this significantly determines its clearance, solubility, and activity. These characteristics are crucial determinants of bictegravir penetration into human body compartments, as the central nervous system. We developed and validated UHPLC-MS/MS procedures to measure total and unbound bictegravir concentrations in plasma and cerebrospinal fluid. Simple protein precipitation with acetonitrile was implemented to prepare plasma and cerebrospinal fluid samples. Sample preparation was preceded by ultrafiltration for measuring unbound bictegravir concentrations. Chromatographic separations were achieved on an Acquity® UHPLC® BEHTM (2.1 × 100 mm id, 1.7 µm) reverse-phase C18 column using an isocratic mobile phase 20:80 (v/v) water/acetonitrile with 0.1% formic. Bictegravir and its internal standard (bictegravir-15N d2) were detected by electrospray ionization mass spectrometry in positive and multiple reaction monitoring modes, using transitions of 450.2→289.2/145.4 and 453.2→289.2, respectively. Ultrafiltration procedures presented non-specific bindings of (8.6 ±â€¯1.2) % for bictegravir in plasma and (26.6 ±â€¯3.1) % for bictegravir in cerebrospinal fluid. Linearity was observed between (10.70-8560) µg/L, (1.07-856.0) µg/L for total and unbound bictegravir in plasma, and 0.107-26.75 µg/L for total and unbound bictegravir in cerebrospinal fluid. Imprecisions, absolute relative biases, normalized-matrix factors, and normalized-recoveries were ≤14.4%, ≤13.8%, (97.4-102.5) %, and (99.8-105.1) %, respectively. No significant interferences and carry-over were observed. The validated UHPLC-MS/MS procedures could be useful for pharmacokinetic and pharmacodynamic studies.

Total and Unbound Bictegravir Concentrations and Viral Suppression in Cerebrospinal Fluid of Human Immunodeficiency Virus-Infected Patients (Spanish HIV/AIDS Research Network, PreEC/RIS 56).

We determined total and unbound concentrations of bictegravir (BIC) in cerebrospinal fluid (CSF) in 15 asymptomatic, virologically suppressed patients. The median plasma and CSF total BIC concentrations were 1837.1 ng/mL (interquartile range [IQR], 1237.2-2586.7) and 6.9 (IQR, 4.8-10.9), respectively. Median unbound BIC concentration was 2.48 ng/mL (IQR, 1.6-3.7). Total and unbound BIC CSF concentrations were above the half-maximal effective concentration value in all patients, and all subjects had human immunodeficiency virus viral suppression in plasma and CSF. Bictegravir may contribute to inhibit viral replication in this compartment.