Therapeutic Drug Monitoring of Long-Acting Rilpivirine and Cabotegravir for Treatment of HIV-1 Infection-A Case Series of Five Patients With One Virologic Failure After Development of Two-Class Resistance.

Virologic failure of long-acting rilpivirine/cabotegravir is rare but may result in severely limited treatment options. Known risk factors cannot predict all cases. Therapeutic drug monitoring (TDM) may help identify patients at risk, but reliable thresholds are missing. We report retrospective TDM in a cohort of 5 patients, including 1 virological failure.

Mpox-specific immune responses elicited by vaccination or infection in people living with HIV.

In the recent mpox outbreak, people living with HIV (PLWH) were at high risk both for contracting infection and for suffering a more severe disease course. We studied cellular and humoral immune responses elicited by mpox infection (n = 5; n = 3 PLWH) or smallpox vaccination (n = 17; all PLWH) in a cohort of men who have sex with men. All PLWH were successfully treated, with stable CD4 counts and undetectable HIV viral loads. 11/17 vaccinated individuals had received childhood smallpox vaccination. In this group of individuals, both two-dose MVA-vaccination and natural infection evoked mpox-specific immune responses mediated by B cells as well as CD4 and CD8 T cells. This study improves our understanding of smallpox vaccination mediated cross-reactivity to other orthopox viruses, and the long-lasting durability of childhood smallpox vaccination mediated immune responses including in PLWH.

Persistent immune abnormalities discriminate post-COVID syndrome from convalescence.

BACKGROUND: Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. METHODS AND RESULTS: Here, we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection or healthy controls. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL-1RA, PDGF-AA). CONCLUSION: These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.

The DoDo experience: an alternative antiretroviral 2-drug regimen of doravirine and dolutegravir.

BACKGROUND: Currently available antiretroviral 2-drug regimen (2DR) fixed dose combinations may not be suitable for specific situations including the presence of resistance associated mutations (RAM) or drug - drug interactions (DDI). The data on the use of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR) and the integrase inhibitor dolutegravir (DTG) as an alternative 2DR remain scarce. METHODS: People living with HIV with DOR + DTG as a 2DR are being followed in a prospective observational study. RESULTS: This analysis describes 85 participants with a median age of 57 years. Median CD4-nadir was 173/µl and a majority (66%) had a history of HIV-associated or AIDS-defining conditions. Antiretroviral history was mostly extensive, and documentation of RAM was frequent. The main reasons for choosing DOR + DTG were DDI (29%), tolerability (25%), and cardiovascular risk reduction (21%). Plasma viral load at switch was < 50 copies/ml in all but 3 instances, median CD4 count was 600/µl. DOR + DTG was later changed to another regimen in 10 participants after a median of 265 days, the other 75 participants have remained on DOR + DTG for a median of 947 days. CONCLUSION: DOR + DTG as a 2DR proved to be a durable treatment option even in extensively pretreated individuals.

Rapid point of care testing for four bacterial sexually transmitted infections using the portable isothermal loop-mediated nucleic acid amplification eazyplex platform.

PURPOSE: To analyze sensitivity and specificity of the rapid point-of-care (POC) eazyplex testing platform for bacterial sexually transmitted infections (STI) among men who have sex with men (MSM). METHODS: 272 anal, urethral, and pharyngeal swabs collected from 153 MSM were tested by both the eazyplex platform and an in-house PCR or culture in the university microbiology reference laboratory. RESULTS: Compared to the reference diagnostic method, the overall sensitivity/specificity of eazyplex was 88%/98% for N. gonorrhoeae, 82%/100% for C. trachomatis, 70%/ > 99% for U. urealyticum, and 85%/98% for M. hominis, respectively. Sensitivity for N. gonorrhoeae and U. urealyticum in urethral samples was 100%. CONCLUSION: With good to very good sensitivity depending on the sampling site and pathogen as well as very good specificity overall the eazyplex platform is a useful rapid diagnostic method for POC bacterial STI-testing especially for N. gonorrhoeae and C. trachomatis, allowing for almost immediate treatment initiation.

Development and validation of a liquid chromatography coupled to tandem mass spectrometry method for the monitoring of temsavir plasma concentrations in people living with HIV.

A majority of people living with HIV (PLWH) now have access to HIV treatment with high antiviral potency and favorable tolerability profile. However, in some treatment experienced PLWH viral strains resistant to major current classes of antiretrovirals have emerged, usually due to periods with continued virus replication in the presence of failing drug regimens and thus selection pressure. In such context, new treatment options are therefore needed. Fostemsavir (RUKOBIA®) is the prodrug of temsavir, a first-in-class oral attachment inhibitor approved for the treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. In this case RUKOBIA® is part of a complex regimen of antiretroviral drugs, often in addition to other drugs for chronic co-morbidities (e.g., heart disease, diabetes mellitus, hepatic and renal impairment, etc). In such a multi-drug regimen context, therapeutic drug monitoring (TDM) of temsavir can be necessary to exclude or adjust for relevant drug-drug interactions. A highly selective assay by liquid chromatography method coupled to tandem mass spectrometry (LC-MS/MS) was therefore developed for the quantification of temsavir in human plasma. A convenient sample preparation using protein precipitation with acetonitrile followed by supernatant dilution was carried out. Temsavir and fostemsavir were separated in less than 2 min using a multi-step UPLC gradient, thus ensuring adequate quantification of temsavir. The assay for the quantification of temsavir was extensively validated over the large range of clinically relevant concentrations from 1 to 10,000 ng/mL, in accordance with international bioanalytical method guidelines. The method achieves excellent performance in terms of trueness (99.7 - 105.3%), repeatability and intermediate precision (both from 1.6% to 5.8%). This LC-MS/MS method is now part of the routine analyses of the Laboratory of the Service of Clinical Pharmacology of Lausanne (CHUV), Switzerland, as an integrated part of our general TDM Service for antiretrovirals.

Clinical characteristics of monkeypox virus infections among men with and without HIV: A large outbreak cohort in Germany.

BACKGROUND: Since May 2022, increasing numbers of monkeypox virus (MPXV) infections have been reported from across Europe and North America. Studies, mainly from Africa, have suggested a higher risk for severe MPXV cases in people living with HIV. METHODS: This was a retrospective study of all confirmed MPXV infections observed in the participating centres since 19 May 2022. We conducted a chart review to evaluate clinical characteristics, comorbidities, and coinfections, including HIV, viral hepatitis, and sexually transmitted infections (STIs). RESULTS: By 30 June 2022, a total of 546 MPXV infections were reported from 42 German centres. All patients were men who have sex with men (MSM), of whom 256 (46.9%) were living with HIV, mostly with a preserved immune system and with viral suppression. In total, 232 (42.5%) MSM were also taking HIV pre-exposure prophylaxis (PrEP) and 58 (10.6%) MSM had no known HIV infection or PrEP use. The median age was 39 years (range 20-67), and comorbidities were rare. However, 52.4% and 29.4% of all patients had been diagnosed with at least one STI within the last 6 months or within the last 4 weeks, respectively. The most frequent localizations of MPXV infection were genital (49.9%) and anal (47.9%), whereas fever (53.2%) and lymphadenopathy (42.6%) were the most frequent general symptoms. The hospitalization rate was low (4.0%), and no fatal course was observed. The clinical picture showed no apparent differences between MSM with or without HIV. CONCLUSIONS: In this preliminary cohort analysis from a current large outbreak among MSM in Germany, the clinical picture of MPXV infection did not differ between MSM with and without HIV infection. Severe courses were rare and hospitalization rates were low. However, most patients were relatively healthy, and only a few people living with HIV were viremic or severely immunosuppressed.

[HIV First Diagnoses in Germany in 2014 - A Regional Analysis]. / HIV-Erstdiagnosen in Deutschland im Jahr 2014 ­ eine regionale Analyse.

BACKGROUND: Information on testing units in health care is scarce, particularly the group of late-presenters among the HIV-first diagnoses is still a challenge in Germany. AIM: Analysis of the impact of testing units on and reasons for the prevalence of HIV-first diagnoses and late presentation, taking 2014 for illustrative purposes. MATERIAL AND METHODS: Cross-sectional analysis of all individuals, treated in the Network HIV-Regional who were first diagnosed with HIV in 2014; patient characteristics, demographic and clinical data, including information on HIV testing were collected retrospectively and in a decentralised manner, pseudonymized and statistically evaluated. RESULTS: A total of 971 individuals with HIV-first diagnosis from 31 specialised care centres throughout Germany (15 hospitals, 16 private practices) represented 27.5% of all National HIV-first diagnoses -registrations from Robert Koch Institute for 2014, with similar results for CD4-cell count and HIV-transmission risk. The most common test site was a hospital (34.8%), followed by the office of a family doctor (19.6%) and medical specialist (16.1%). If the first diagnosis was established in hospital, then the patients were on average older than those tested on an ambulant care basis (42 vs. 37 years, p=0.001); moreover, the HI-viral load was higher (585 vs. 270 thousand copies/mL, p<0.001) and the CD4-cell count lower (265 vs. 414/µL, p<0.001). In 208/971 individuals with first diagnosis, at least one AIDS-defining disease was found, most frequently pneumocystis-pneumonia (43.8%), candidiasis (36.5%) and Kaposi sarcoma (10.6%). A regional comparison revealed that in eastern Germany, for first diagnosed HIV-patients were younger, had a higher HIV-RNA viral load and also more often clinical AIDS. CONCLUSION: This analysis of HIV-Regional for 2014 enables a deeper insight into HIV first diagnoses, on the eve of the introduction of important prevention tools in Germany, e. g., HIV home testing and pre-exposure prophylaxis. This cross-sectional analysis was representative for Germany and underscores the importance of specialised hospitals, in particular for eastern Germany, and furthermore the involvement of late-presenters into HIV health care.

Comparison of ß-D-Glucan and Galactomannan in Serum for Detection of Invasive Aspergillosis: Retrospective Analysis with Focus on Early Diagnosis.

The early diagnosis of invasive aspergillosis (IA) relies mainly on computed tomography imaging and testing for fungal biomarkers such as galactomannan (GM). We compared an established ELISA for the detection of GM with a turbidimetric assay for detection of the panfungal biomarker ß-D-glucan (BDG) for early diagnosis of IA. A total of 226 serum specimens from 47 proven and seven probable IA cases were analysed. Sensitivity was calculated for samples obtained closest to the day of IA-diagnosis (d0). Additional analyses were performed by including samples obtained during the presumed course of disease. Most IA cases involved the respiratory system (63%), and Aspergillus fumigatus was the most frequently isolated species (59%). For proven cases, sensitivity of BDG/GM analysis was 57%/40%. Including all samples dating from -6 to +1 weeks from d0 increased sensitivities to 74%/51%. Sensitivity of BDG testing was as high as or higher than GM testing for all subgroups and time intervals analysed. BDG testing was less specific (90-93%) than GM testing (99-100%). Combining BDG and GM testing resulted in sensitivity/specificity of 70%/91%. Often, BDG testing was positive before GM testing. Our study backs the use of BDG for diagnosis of suspected IA. We suggest combining BDG and GM to improve the overall sensitivity.