Costs and acceptability of simplified monitoring in HIV-suppressed patients switching to dual therapy: the SIMPL'HIV open-label, factorial randomised controlled trial.

BACKGROUND: Clinical and laboratory monitoring of patients on antiretroviral therapy is an integral part of HIV care and determines whether treatment needs enhanced adherence or modification of the drug regimen. However, different monitoring and treatment strategies carry different costs and health consequences. MATERIALS AND METHODS: The SIMPL'HIV study was a randomised trial that assessed the non-inferiority of dual maintenance therapy. The co-primary outcome was a comparison of costs over 48 weeks of dual therapy with standard antiretroviral therapy and the costs associated with a simplified HIV care approach (patient-centred monitoring [PCM]) versus standard, tri-monthly routine monitoring. Costs included outpatient medical consultations (HIV/non-HIV consultations), non-medical consultations, antiretroviral therapy, laboratory tests and hospitalisation costs. PCM participants had restricted immunological and blood safety monitoring at weeks 0 and 48, and they were offered the choice to complete their remaining study visits via a telephone call, have medications delivered to a specified address, and to have blood tests performed at a location of their choice. We analysed the costs of both strategies using invoices for medical consultations issued by the hospital where the patient was followed, as well as those obtained from health insurance companies. Secondary outcomes included differences between monitoring arms for renal function, lipids and glucose values, and weight over 48 weeks. Patient satisfaction with treatment and monitoring was also assessed using visual analogue scales. RESULTS: Of 93 participants randomised to dolutegravir plus emtricitabine and 94 individuals to combination antiretroviral therapy (median nadir CD4 count, 246 cells/mm3; median age, 48 years; female, 17%),patient-centred monitoring generated no substantial reductions or increases in total costs (US$ -421 per year [95% CI -2292 to 1451]; p = 0.658). However, dual therapy was significantly less expensive (US$ -2620.4 [95% CI -2864.3 to -2331.4]) compared to standard triple-drug antiretroviral therapy costs. Approximately 50% of participants selected one monitoring option, one-third chose two, and a few opted for three. The preferred option was telephone calls, followed by drug delivery. The number of additional visits outside the study schedule did not differ by type of monitoring. Patient satisfaction related to treatment and monitoring was high at baseline, with no significant increase at week 48. CONCLUSIONS: Patient-centred monitoring did not reduce costs compared to standard monitoring in individuals switching to dual therapy or those continuing combined antiretroviral therapy. In this representative sample of patients with suppressed HIV, antiretroviral therapy was the primary factor driving costs, which may be reduced by using generic drugs to mitigate the high cost of lifelong HIV treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03160105.

Routine Infectious Disease Consultation Prior to an Allogeneic Hematopoietic Cell Transplant.

Background: A transplant infectious disease (TID) assessment is essential to select recipients for an allogeneic hematopoietic cell transplant (HCT) and tailor prophylactic and empirical treatment recommendations. Methods: We performed a retrospective single-center study to describe our model of care based on a routine TID consultation prior to an allogeneic HCT between 2018 and 2022 in 292 adult (≥18-year-old) consecutive patients. We describe the performance of a TID consultation, arbitrarily defined as major (HCT postponement, procedure, cytomegalovirus [CMV] recipient serology reinterpretation) and minor interventions. Results: Overall, 765 interventions were observed in 257 of 292 (88%) patients: 88 of 765 (11.5%) major and 677 of 765 (88.5%) minor interventions. Among major interventions, HCT was postponed in 8 of 292 (2.7%) patients and a procedure was requested in 18 of 292 (6.2%) patients. The CMV recipient serostatus was changed from indeterminate/low-titer positive to negative in 60 of 292 (20.5%) patients. Among 677 minor interventions, there were 68 (8.8%) additional consultations with other services requested, 260 (33.7%) additional diagnostic tests requested, 102 (13.2%) additional treatments recommended, 60 (7.8%) non-CMV serology reinterpretations performed, 115 (14.9%) deviations from routine anti-infective prophylaxis, and 72 (9.3%) deviations from routine empirical antibiotic treatment recommendations in case of neutropenic fever. Conclusions: We are proposing a structured, clearly defined, and comprehensive pretransplant checklist for an effective assessment of infectious disease risks and complications prior to an allogeneic HCT. Further studies or experiences like ours could help to define a global strategy or new models of care to be implemented in HCT centers in the future.

Post-exposure Lopinavir-Ritonavir Prophylaxis versus Surveillance for Individuals Exposed to SARS-CoV-2: The COPEP Pragmatic Open-Label, Cluster Randomized Trial.

BACKGROUND: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19. METHODS: We conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732. FINDINGS: Of 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18). INTERPRETATION: The role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials. FUNDING: Swiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).

Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir-based regimens in SIMPL'HIV clinical trial.

This study aims to evaluate the association between dolutegravir (DTG) pharmacokinetic parameters and weight changes in treatment-experienced people with HIV (PWHIV) from the Simpl'HIV study newly switched to a dual DTG-based regimen. We used multivariable linear regressions to evaluate the association between DTG pharmacokinetic parameters at week 48 (derived using an established model) and weight change between week 0 and week 48. We adjusted our model for potential confounders including CD4 nadir, female sex, African origin, age, weight at week 0 and presence of a non-nucleoside reverse transcriptase inhibitor-based regimen before switch to DTG. The analysis included data from 39 PWHIV. An average significant weight gain of 2.4 kg was observed between baseline and week 48. DTG plasma exposure was not significantly associated with weight gain, even after adjusting for potential confounders (P = .9). We found no significant association between DTG pharmacokinetic parameters and weight gain amongst PWHIV newly switched to a DTG-based dual regimen.

Prophylaxis for COVID-19: a systematic review.

BACKGROUND: While the landscape of vaccine and treatment candidates against the novel coronavirus disease 2019 (COVID-19) has been reviewed systematically, prophylactic candidates remain unexplored. OBJECTIVES: To map pre- and postexposure prophylactic (PrEP and PEP) candidate for COVID-19. DATA SOURCES: PubMed/Medline, Embase, International Committee of Medical Journal Editors and International Clinical Trials Registry Platform clinical trial registries and medRxiv. STUDY ELIGIBILITY CRITERIA AND PARTICIPANTS: All studies in humans or animals and randomized controlled trials (RCTs) in humans reporting primary data on prophylactic candidates against COVID-19, excluding studies focused on key populations. INTERVENTIONS: PrEP and PEP candidate for COVID-19. METHODS: Systematic review and qualitative synthesis of COVID-19 PrEP and PEP studies and RCTs complemented by search of medRxiv and PubMed and Embase for studies reporting RCT outcomes since systematic review search completion. RESULTS: We identified 13 studies (from 2119 database records) and 117 RCTs (from 5565 RCTs listed in the registries) that met the inclusion criteria. Non-RCT studies reported on cross-sectional studies using hydroxychloroquine (HCQ) in humans (n = 2) or reported on animal studies (n = 7), most of which used antibodies. All five completed RCTs focused on the use of HCQ as either PrEP or PEP, and these and the cross-sectional studies reported no prophylactic effect. The majority of ongoing RCTs evaluated HCQ or other existing candidates including non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, anti(retro)virals or use of vitamins and supplements. CONCLUSIONS: The key message from completed studies and RCTs seems to be that HCQ does not work. There is little evidence regarding other compounds, with all RCTs using candidates other than HCQ still ongoing. It remains to be seen if the portfolio of existing molecules being evaluated in RCTs will identify successful prophylaxis against COVID-19 or if there is a need for the development of new candidates.

Efficacy of pragmatic same-day ring prophylaxis for adult individuals exposed to SARS-CoV-2 in Switzerland (COPEP): protocol of an open-label cluster randomised trial.

INTRODUCTION: Lopinavir/ritonavir (LPV/r) has been proposed as repurposed drugs for pre-exposure and postexposure prophylaxis as well as therapy of COVID-19. Coronavirus postexposure prophylaxis (COPEP) trial aims at assessing their efficacy as postexposure ring-prophylaxis among adults exposed to SARS-CoV-2. METHODS AND ANALYSIS: COPEP is a two-arm open-label cluster-randomised trial conducted in three cantons of Switzerland. Asymptomatic contacts (≥16 years) of individuals diagnosed with COVID-19 will be randomised (2:1) to either LPV/r (400 mg/100 mg two times per day) for 5 days, or a standard of care arm (no treatment). Asymptomatic individuals may be either SARS-CoV-2 positive or negative. Contacts living in the single household will form a cluster and will be randomised into the same arm. All participants will be followed-up for 21 days and undergo daily monitoring for COVID-19 symptoms. The primary endpoint is 21-day incidence of laboratory-confirmed COVID-19 with ≥1 compatible symptom, analysed in an intention-to-treat (ITT) analysis. The secondary endpoints include the 21-day incidence of COVID-19 as well as SARS-CoV-2 infection in a modified ITT analysis, excluding participants who had a positive SARS-CoV-2 RT-PCR from oropharyngeal swab and/or a positive SARS-CoV-2 IgG serology at baseline. Assuming a 21-day incidence for COVID-19 of 20% among contacts without postexposure chemoprophylaxis, to detect a relative risk reduction of 60% (ie, translating in an absolute reduction from 20% to 8%), with a power of 80%, an alpha of 5%. Accounting for design effect of cluster design of circa 1.1, we plan to enrol 200 participants to the LPV/r arm and 100 to the standard of care arm, 300 participants in total. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Commission Cantonale d'Ethique de la Recherche, Ethikkommission Nordwest- und Zentralschweiz and Comitato Etico Cantonale (ref 2020-00864) and Swissmedic (2020DR3056). Results from this trial will be disseminated via journal articles and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registry (NCT04364022); Swiss National Clinical Trial Portal Registry (SNCTP 000003732). REGISTERED REPORT IDENTIFIER: CCER 2020-0864.

Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL'HIV trial.

BACKGROUND: Dolutegravir (DTG)-based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL'HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC). We present the 48-week efficacy and safety data on DTG + FTC versus cART. METHODS AND FINDINGS: SIMPL'HIV was a multicenter, open-label, non-inferiority randomized trial with a factorial design among treatment-experienced people with HIV in Switzerland. Participants were enrolled between 12 May 2017 and 30 May 2018. Patients virologically suppressed for at least 24 weeks on standard cART were randomized 1:1 to switching to DTG + FTC or to continuing cART, and 1:1 to simplified patient-centered monitoring versus standard monitoring. The primary endpoint was the proportion of patients virologically suppressed with <100 copies/ml through 48 weeks. The secondary endpoints included virological suppression at 48 weeks according to the US Food and Drug Administration (FDA) snapshot analysis. Non-inferiority of DTG + FTC versus cART for viral suppression was assessed using a stratified Mantel-Haenszel risk difference, with non-inferiority declared if the lower bound of the 95% confidence interval was greater than -12%. Adverse events were monitored to assess safety. Quality of life was evaluated using the PROQOL-HIV questionnaire. Ninety-three participants were randomized to DTG + FTC, and 94 individuals to cART. Median nadir CD4 count was 246 cells/mm3; median age was 48 years; 17% of participants were female. DTG + FTC was non-inferior to cART. The proportion of patients with viral suppression (<100 copies/ml) through 48 weeks was 93.5% in the DTG + FTC arm and 94.7% in the cART arm in the intention-to-treat population (risk difference -1.2%; 95% CI -7.8% to 5.6%). Per-protocol analysis showed similar results, with viral suppression in 96.5% of patients in both arms (risk difference 0.0%; 95% CI -5.6% to 5.5%). There was no relevant interaction between the type of treatment and monitoring (interaction ratio 0.98; 95% CI 0.85 to 1.13; p = 0.81). Using the FDA snapshot algorithm, 84/93 (90.3%) participants in the DTG + FTC arm had an HIV-1 RNA viral load of <50 copies/ml compared to 86/94 (91.5%) participants on standard cART (risk difference -1.1%; 95% CI -9.3% to 7.1%; p = 0.791). The overall proportion of patients with adverse events and discontinuations did not differ by randomization arm. The proportion of patients with serious adverse events was higher in the cART arm (16%) compared to the DTG + FTC arm (6.5%) (p = 0.041), but none was considered to be related to the study medication. Quality of life improved more between baseline and week 48 in the DTG + FTC compared to the cART arm (adjusted difference +2.6; 95% CI +0.4 to +4.7). The study's main limitations included a rather small proportion of women included, the open label design, and its short duration. CONCLUSIONS: In this study, DTG + FTC as maintenance therapy was non-inferior to cART in terms of efficacy, with a similar safety profile and a greater improvement in quality of life, thus expanding the offer of 2-drug simplification options among virologically suppressed individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03160105.

Viral Infections and Cutaneous Drug-Related Eruptions.

In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus- and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.

Prevention and management of hearing loss in syndromic craniosynostosis: A case series.

OBJECTIVE: To assess the audiological profile in a cohort of children affected by syndromic craniosynostosis. METHODS: Eleven children with Apert syndrome (n=4), Saethre-Chotzen syndrome (n=3), Muenke syndrome (n=2), Crouzon syndrome (n=1) and Pfeiffer syndrome type 1 (n=1) were submitted to a complete audiologic evaluation including otoscopy, pure-tone audiometry, tympanometry and acoustic reflex testing, ABR, otoacustic emissions, temporal bone High Resolution CT (HRCT) scan. The main outcome measures were prevalence, type and severity of hearing loss, prevalence of chronic otitis media, correlation with the time of first surgical correction. RESULTS: Seven of 11 patients (64%) presented hearing loss (HL), conductive in 3/7 patients (43%) and mixed in 4/7 (57%). No patients showed a purely sensorineural HL. All hearing impaired patients displayed middle ear disorders: the patients with conductive HL had otitis media with effusion (OME) and 3/4 patients with mixed HL showed tympanic alterations or cholesteatoma. A bilateral vestibular aqueduct enlargement was detected by HRCT scan in one normal hearing patient. The ABRs resulted normal in all cases. CONCLUSION: Our study confirms the high prevalence of otologic diseases in such patients. In contrast with previous studies, middle ear disorders were responsible for the hearing impairment also in patients with mixed HL due to secondary inner ear damage. These findings restate the necessity of a close audiologic follow-up. We did not detect the specific ABR abnormalities previously reported, possibly because of an early correction of the cranial vault malformations.