Response Types and Factors Associated with Response Types to Biologic Therapies in Patients with Moderate-to-Severe Plaque Psoriasis from Two Randomized Clinical Trials.

INTRODUCTION: This study aimed to understand treatment response dynamics, including factors associated with favorable response, among patients with moderate-to-severe psoriasis who received guselkumab, adalimumab, or secukinumab. METHODS: These post hoc analyses used data from the phase III clinical trials ECLIPSE and VOYAGE 1, which were conducted between September 2021 and November 2022. On the basis of absolute Psoriasis Area and Severity Index (aPASI) scores, patients were divided into short-term response types (SRT1-6, based on week 20-48 response) and long-term response types (LRT1-4, based on week 52-252 response). Response types (RTs) were based on aPASI cutoffs deemed clinically relevant by the investigators; SRT1/LRT1 were the most favorable response types. Baseline characteristics were compared across RTs, and logistic regression analyses established factors associated with SRT1/LRT1. RESULTS: Overall, 1045, 662, and 272 patients were included in the ECLIPSE short-term, VOYAGE 1 short-term, and VOYAGE 1 long-term analyses, respectively. Mean age, body mass index (BMI), baseline aPASI score, and body surface area were lower in SRT1 than SRT6. In VOYAGE 1, adalimumab treatment, high BMI, and current/former smoking status resulted in less favorable responses. In the VOYAGE 1 long-term analysis, patients in LRT4 had the highest baseline aPASI score, were older, and were more often obese compared with other LRT groups. Regression analyses showed that SRT1 (both treatments) in VOYAGE 1 and ECLIPSE, and LRT1 (guselkumab group) in the VOYAGE 1 long-term analysis, were associated with week 16 aPASI response. In VOYAGE 1, SRT1 was associated with psoriasis duration and smoking status. CONCLUSIONS: Early treatment response and baseline characteristics, including smoking, psoriasis duration, and obesity, may be associated with longer-term response to biologics. TRIAL REGISTRATION NUMBERS: ECLIPSE: NCT03090100, VOYAGE 1: NCT02207231.

Guselkumab in Patients with Scalp Psoriasis: A post hoc Analysis of the VOYAGE 2 Phase III Randomized Clinical Trial.

Scalp psoriasis affects approximately 80% of patients with psoriasis and can negatively impact their quality of life. This post hoc analysis of the VOYAGE 2 Phase III randomized clinical trial evaluated scalp response to guselkumab treatment and its association with skin response and patient-reported outcomes. The study included patients with moderate-to-severe plaque psoriasis and baseline scalp psoriasis who were initially randomized to receive guselkumab. Patients were divided into 3 groups based on their achievement of a Psoriasis Area and Severity Index 90 response at week 28: responder continuation, non-responder continuation and responder withdrawal. In all 3 groups, mean Psoriasis Area and Severity Index head and scalp-specific Investigator's Global Assessment scores improved through week 28. In the responder withdrawal group, these scores worsened after treatment withdrawal at week 28, but remained stable through week 48 in both continuation groups. Trends in Dermatology Life Quality Index and Psoriasis Symptoms and Signs Diary itch scores mirrored those of mean scalp-specific Investigator's Global Assessment scores through week 48. Within-subject correlations were 0.83 between scalp-specific Investigator's Global Assessment and Psoriasis Area and Severity Index head scores and 0.78 between scalp-specific Investigator's Global Assessment and Psoriasis Symptoms and Signs Diary itch scores. Through week 252, Psoriasis Area and Severity Index head scores remained stable in the responder continuation group, improved in the non-responder continuation group and rapidly improved by week 84 in the responder withdrawal group after retreatment.

Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥ 156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

BACKGROUND: Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. MATERIALS AND METHODS: This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. RESULTS: Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. CONCLUSION: A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. TRIAL REGISTRATION: NCT02207231.

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

BACKGROUND: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown. METHODS: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures. RESULTS: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments. CONCLUSIONS: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Nail psoriasis dynamics during biologic treatment and withdrawal in patients with psoriasis who may be at high risk of developing psoriatic arthritis: a post hoc analysis of the VOYAGE 2 randomized trial.

BACKGROUND: Nail psoriasis is a common, physiologically, and psychologically disruptive, and yet often under-treated manifestation of psoriasis. The objectives of this analysis were to investigate the trajectory of nail psoriasis, a risk factor for psoriatic arthritis (PsA), with guselkumab vs adalimumab treatment followed by withdrawal, and determine characteristics associated with nail response in patients treated with guselkumab. METHODS: This post hoc analysis of the phase III trial VOYAGE 2 included patients with moderate-to-severe plaque psoriasis and baseline nail involvement. Nail Psoriasis Severity Index (NAPSI) and Psoriasis Area and Severity Index (PASI) were analyzed through week 48 in patients randomized to guselkumab or adalimumab. Multiple logistic regression analyzed factors associated with NAPSI 0/1 at week 24/week 48 following guselkumab treatment. In a separate analysis, patients were stratified by prior biologic experience. RESULTS: Overall, 272 vs 132 patients receiving guselkumab vs adalimumab had nail psoriasis at baseline. Lower baseline NAPSI and week 16 PASI were associated with achieving NAPSI 0/1 at week 24 (NAPSI, odds ratio 0.685 [95% confidence interval: 0.586, 0.802]; week 16 PASI, 0.469 [0.281, 0.782]) and week 48 (NAPSI, 0.784 [0.674, 0.914]; week 16 PASI, 0.557 [0.331, 0.937]) with guselkumab. Previous biologic experience did not impact NAPSI response. Following treatment withdrawal at week 28, mean NAPSI was maintained in the guselkumab arm (week 24 1.7, week 48 1.9) and increased slightly in the adalimumab arm (week 24 1.4, week 48 2.3). Mean PASI increased across both treatment arms. CONCLUSIONS: Higher skin efficacy at week 16 was associated with better nail responses during guselkumab treatment. Nail psoriasis improvements reflected skin improvements. Following guselkumab withdrawal, nail response was maintained longer than skin response. Future studies should investigate whether such improvements in nail response reduce patients' risk of later PsA development. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02207244. Registered July 31, 2014.

Prednisone for the prevention of tuberculosis-associated IRIS (randomized controlled trial): Impact on the health-related quality of life.

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in patients with HIV-associated tuberculosis (TB) starting antiretroviral treatment (ART) in sub-Saharan Africa. The PredART-trial recently showed that prophylactic prednisone reduces the incidence of paradoxical TB-IRIS by 30% in a population at high risk. This paper reports the impact of the intervention on health-related quality of life (HRQoL), a secondary endpoint of the trial, measured by an amended version of the PROQOL-HIV instrument-the instrument's validity and reliability is also assessed. Methods: A total of 240 adult participants (antiretroviral treatment (ART)-naïve, TB-HIV co-infected with CD4 count ≤100 cells/µL) were recruited and randomized (1:1) to (1) a prednisone arm or (2) a placebo arm. In this sub-study of the PredART-trial we evaluated (1) the performance of an HIV-specific HR-QoL instrument amended for TB-IRIS, i.e., the PROQOL-HIV/TB in patients with HIV-associated TB starting ART (reliability, internal and external construct validity and invariance across time) and (2) the impact of prednisone on self-reported HR-QoL in this population through mixed models. Results: The PROQOL-HIV/TB scale displayed acceptable internal reliability and good internal and external validity. This instrument, including the factor structure with the eight sub-dimensions, can thus be applied for measuring HR-QoL among HIV-TB patients at high risk for TB-IRIS. Prophylactic prednisone was statistically significantly associated only with the 'Physical Health and Symptoms'-subscale: a four-week course of prednisone resulted in an earlier improvement in the physical dimension of HR-QoL compared to placebo. Conclusion: We demonstrated that the PROQOL-HIV/TB scale adequately measures different aspects of self-reported HR-QoL in HIV-TB patients. Although more research is needed to understand how other domains related to HR-QoL can be improved, targeting patients at high risk for developing TB-IRIS with a four-week course of prednisone has a beneficial effect on the physical aspects of patient-reported quality of life.

Accuracy of C-reactive Protein and Procalcitonin for Diagnosing Bacterial Infections Among Subjects With Persistent Fever in the Tropics.

Background: In low-resource settings, inflammatory biomarkers can help identify patients with acute febrile illness who do not require antibiotics. Their use has not been studied in persistent fever (defined as fever lasting for ≥7 days at presentation). Methods: C-reactive protein (CRP) and procalcitonin (PCT) levels were measured in stored serum samples of patients with persistent fever prospectively enrolled in Cambodia, the Democratic Republic of Congo, Nepal, and Sudan. Diagnostic accuracy was assessed for identifying all bacterial infections and the subcategory of severe infections judged to require immediate antibiotics. Results: Among 1838 participants, CRP and PCT levels were determined in 1777 (96.7%) and 1711 (93.1%) samples, respectively, while white blood cell (WBC) count was available for 1762 (95.9%). Areas under the receiver operating characteristic curve for bacterial infections were higher for CRP (0.669) and WBC count (0.651) as compared with PCT (0.600; P <.001). Sensitivity for overall and severe bacterial infections was 76.3% (469/615) and 88.2% (194/220) for CRP >10 mg/L, 62.4% (380/609) and 76.8% (169/220) for PCT >0.1 µg/L, and 30.5% (184/604) and 43.7% (94/215) for WBC >11 000/µL, respectively. Initial CRP level was <10 mg/L in 45% of the participants who received antibiotics at first presentation. Conclusions: In patients with persistent fever, CRP and PCT showed higher sensitivity for bacterial infections than WBC count, applying commonly used cutoffs for normal values. A normal CRP value excluded the vast majority of severe infections and could therefore assist in deciding whether to withhold empiric antibiotics after cautious clinical assessment.

Gonococcal bacterial load in PrEP users with Mycoplasma genitalium coinfection.

OBJECTIVES: Gonococcal infections with a higher bacterial load may pose a higher risk of transmission. We assessed the association between gonococcal bacterial load and coinfection with Mycoplasma genitalium. METHODS: From September 2015 until May 2018, 200 men and transgender women who have sex with men participated in an HIV pre-exposure prophylaxis (PrEP) demonstration trial in Antwerp, Belgium. They underwent 3-monthly 3-site (anus, urine, and pharynx) molecular testing for N. gonorrhoeae and C. trachomatis and M. genitalium, irrespective of symptoms. Gonococcal bacterial load was determined on remnant DNA extracts using an in-house quantitative PCR. Results were expressed as log10 transformed copies/mL and analyzed with a linear regression model. RESULTS: Gonococcal bacterial load could be determined for 82 (80.4%) of 102 anal, 17 (73.9%) of 23 urine, and 64 (90.1%) of 71 pharyngeal samples. M. genitalium was detected in five of these anal, two urine, and two pharyngeal samples and C. trachomatis was detected in 16 anal, one urine, and two pharyngeal samples. Gonococcal bacterial load was significantly higher in the presence of M. genitalium (difference 0.92 log copies/mL, 95% CI 0.16-1.67). CONCLUSIONS: Gonococcal bacterial load was higher with M. genitalium coinfection. M. genitalium may thus be a cofactor in gonococcal transmission.

Development of a risk score to guide targeted hepatitis C testing among human immunodeficiency virus patients in Cambodia.

BACKGROUND: The World Health Organization recommends testing all human immunodeficiency virus (HIV) patients for hepatitis C virus (HCV). In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients, as in Cambodia, targeted testing is, in the short-term, potentially more feasible and cost-effective. AIM: To develop a clinical prediction score (CPS) to risk-stratify HIV patients for HCV coinfection (HCV RNA detected), and derive a decision rule to guide prioritization of HCV testing in settings where 'testing all' is not feasible or unaffordable in the short term. METHODS: We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh. Key populations were very rare in this cohort. Score development relied on the Spiegelhalter and Knill-Jones method. Predictors with an adjusted likelihood ratio ≥ 1.5 or ≤ 0.67 were retained, transformed to natural logarithms, and rounded to integers as score items. CPS performance was evaluated by the area-under-the-ROC curve (AUROC) with 95% confidence intervals (CI), and diagnostic accuracy at the different cut-offs. For the decision rule, HCV coinfection probability ≥1% was agreed as test-threshold. RESULTS: Among the 3045 enrolled HIV patients, 106 had an HCV coinfection. Of the 11 candidate predictors (from history-taking, laboratory testing), seven had an adjusted likelihood ratio ≥ 1.5 or ≤ 0.67: ≥ 50 years (+1 point), diabetes mellitus (+1), partner/household member with liver disease (+1), generalized pruritus (+1), platelets < 200 × 109/L (+1), aspartate transaminase (AST) < 30 IU/L (-1), AST-to-platelet ratio index (APRI) ≥ 0.45 (+1), and APRI < 0.45 (-1). The AUROC was 0.84 (95%CI: 0.80-0.89), indicating good discrimination of HCV/HIV coinfection and HIV mono-infection. The CPS result ≥0 best fits the test-threshold (negative predictive value: 99.2%, 95%CI: 98.8-99.6). Applying this threshold, 30% (n = 926) would be tested. Sixteen coinfections (15%) would have been missed, none with advanced fibrosis. CONCLUSION: The CPS performed well in the derivation cohort, and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e. cohorts without major risk factors as injecting drug use, men having sex with men), and where available resources do not allow to test all HIV patients as recommended by WHO. However, the score requires external validation in other patient cohorts before any wider use can be considered.

Hepatitis C Prevalence and Validation of a Clinical Prediction Score for Targeted Screening among People Living with HIV in Ghana.

WHO recommends hepatitis C (HCV) screening for all people living with HIV (PLHIV). Yet, HCV coinfection was shown to be rare in some Sub-Saharan HIV cohorts, and targeted testing was suggested more efficient for such settings. We studied HCV prevalence among Ghanaian PLHIV, and assessed the external validity of a score to guide targeted testing. This score was initially derived from a Cambodian HIV cohort, and uses as predictors: age, household member/partner with liver disease, diabetes, generalized pruritus, AST, platelets, and AST-to-platelet ratio index. We enrolled 4,023 PLHIV, most from Greater Accra and Central regions, 28.4% were male, median age was 47 years, and high-risk behavior was reported to be rare. HCV seroprevalence was 0.57%, and HCV-RNA was detectable in 0.5%. Sequencing revealed genotype 1(b) and 2(q/r) infections. The discriminatory performance of the score was suboptimal in the Ghanaian setting. The area under the curve was 0.69 (95% CI 0.59-0.79). HCV coinfection prevalence was very low in this Ghanaian PLHIV cohort with reported low-risk of onward transmission. To avoid the cost of screening all PLHIV in similar cohorts in resource-constrained settings, further research to develop better tools/scores to guide targeted HCV testing is needed.

The impact of physical restriction measures imposed during the two waves of COVID-19 on chlamydia and gonorrhea diagnoses in Belgium. Results of an sexually transmitted infection clinic.

Background: During the first two waves of COVID-19, several physical restriction measurements were imposed in Belgium. Our aim was to explore the impact of these restriction measures on the number of tests and positivity rate of Chlamydia trachomatis (CT)/Neisseria gonorrhoeae (NG) before, during, and after the two lockdowns in Belgium. Methods:Chlamydia trachomatis/Neisseria gonorrhoeae molecular data of a Belgian STI clinic were extracted for 2019 and 2020, and both years were divided into four periods (pre-lockdown 1, lockdown 1, after lockdown 1, and lockdown 2). Weekly testing rates and positivity rate for both STIs were estimated, and mixed-effects logistic regression was used to explore statistical significant changes between both years, and the different periods were compared with the corresponding time period in 2019. The same analysis was done for pre-exposure prophylaxis(PrEP) users only. Results: No overall significant changes in positivity rate were found for either CT (8.0% in 2019 and 7.8% in 2020) or NG (4.5% in 2019 and 5.5% in 2020). Besides a significant drop in the number of CT/NG tests during lockdown 1 (decrease of 87%) and a subsequent increase in NG positivity rate (p > 0.05), no changes in CT/NG positivity rate were found in the other periods. The highest positivity rate for either CT or NG was found in lockdown 2 (15.1% vs 12.4% in 2019). The number of CT/NG tests in lockdown 2 was still 25% lower than 2019 levels. Subanalysis of only PrEP users revealed the same trend; however, the number of CT/NG tests in lockdown 2 was exactly the same as in 2019. Conclusion: Despite a significant decline in absolute CT or NG cases in lockdown 1, which was most likely a consequence of both physical distancing and reduced testing, CT/NG testing and positivity rates returned to pre-corona levels in lockdown 2, which may depict physical distancing fatigue.

The Population-Level Effect of Screening for Mycoplasma genitalium on Antimicrobial Resistance: A Quasi-Experimental Study.

BACKGROUND: No studies have evaluated the utility and risks of screening for Mycoplasma genitalium in men who have sex with men taking preexposure prophylaxis (PrEP). We made use of a quasi-experimental design to evaluate the effect of screening for M. genitalium in a demonstration PrEP cohort with 3-monthly follow-up. METHODS: We compared the proportion of PrEP participants with M. genitalium clearance, the duration of persistence, proportion with incident symptoms, the incidence of fluoroquinolone and macrolide resistance, and the proportion of noncleared infections with resistance-associated mutations between 2 groups: those in whom the first episode of M. genitalium was treated and those in whom it was not treated. RESULTS: M. genitalium was detected in 70 of 179 individuals. The first episode of infection was treated in 46 individuals. Treatment was not significantly associated with the incidence of symptomatic infections or the acquisition of genotypic resistance. Treatment was associated with a higher probability of clearance of infection but at the expense of increasing the proportion of remaining infections that were resistant. In the nontreated group, the infections that did not clear were less likely to be fluoroquinolone resistant (1/6 [16.7%]) than those that did clear (4/4 [100%]; P = 0.048). In contrast, in the treated group, there was no significant difference in the proportion of fluoroquinolone resistance between the infections that persisted and cleared. CONCLUSIONS: If screening and treatment increase the ratio of resistant to susceptible M. genitalium in a population, then this could play a role in the spread of antimicrobial resistance.

Recurrent Sexually Transmitted Infections Among a Cohort of Men Who Have Sex With Men Using Preexposure Prophylaxis in Belgium Are Highly Associated With Sexualized Drug Use.

BACKGROUND: Men who have sex with men (MSM) experiencing recurrent sexually transmitted infections (STIs) may play a crucial role in the STI epidemic. However, there is limited understanding of what kind of behavior leads to recurrent STIs. METHODS: A total of 179 MSM using preexposure prophylaxis were followed up for 18 months and were screened quarterly for chlamydia, gonorrhea, and syphilis from 2015 to 2018 in Belgium. Participants were stratified into 3 different groups (no STI, one STI episode, recurrent STI episodes during the study). Sociodemographic and sexual behavioral characteristics were compared between the 3 groups, and significant associations with recurrent STI were explored using multivariate logistic regression models. RESULTS: A total of 62.0% (n = 111/179) of participants experienced at least one STI during the study, and more than 1 in 3 became reinfected with an STI at another visit (n = 66/179 [36.9%]). Participants experiencing recurrent STIs reported the highest frequency of sexualized drug use (86.4%) compared with participants experiencing one (60.0%) or no STI (47.1%). Therefore, sexualized drug use was highly associated with recurrent STIs (adjusted odds ratio [aOR]. 4.35). Other factors associated with recurrent STIs were being younger than 40 years (aOR, 3.29), had a high number (>4) of nonsteady partners with whom receptive (aOR, 1.17) or insertive (aOR, 1.12) condomless anal intercourse occurred in the last 3 months. CONCLUSIONS: Sexualized drug use was the greatest risk factor for having recurrent STIs. Tailoring prevention and care, including specialized services tackling problematic drug use in a sexual context, may help to curb the STI epidemic among MSM.

Miltefosine for the treatment of cutaneous leishmaniasis-A pilot study from Ethiopia.

BACKGROUND: Cutaneous leishmaniasis (CL) in Ethiopia, caused by Leishmania aethiopica, is often severe and hard to treat compared to CL caused by other species elsewhere. Miltefosine is the only oral anti-leishmanial drug, with a favorable side-effect profile compared to routinely available sodium stibogluconate (SSG), but evidence about its use for L. aethiopica is lacking. METHODOLOGY AND PRINCIPAL FINDINGS: In an observational cohort study, treatment outcomes, safety and adherence among CL patients who required systemic treatment and received miltefosine for 28 days in Boru Meda Hospital and University of Gondar Hospital were studied. Patient cure was defined as 100% flattening for non-ulcerated lesions and 100% flattening and 100% re-epithelization for ulcerated lesions. Outcomes were documented for day 28, 90 and 180, both per site, and pooled, adjusting for site as a fixed effect with effect coding. Among 94 included patients (32 in Gondar, 62 in Boru Meda), median lesion duration was 12 months, median size six cm, and mucosal involvement (46.8%) and diffuse (30.9%) lesions were common. Adherence to miltefosine was good, and side-effects were tolerable. Initial outcomes at day 28 were promising, with 68.8% and 94.0% of patients having good improvement or cure in Gondar and Boru Meda respectively. In Boru Meda, outcomes were good with 72.7% and 72.9% cure at day 90 and day 180 respectively. In Gondar, results were less promising, with only 12.5% and 26.7% cure at day 90 and day 180, although confidence intervals were wide. In pooled estimates, 48.7% of patients reached cure at day 180, and 32.3% relapsed. Outcomes were better in Boru Meda Hospital, for smaller lesions and for mucosal lesions. CONCLUSIONS/SIGNIFICANCE: Based on miltefosine's good initial response, tolerable side-effects, tablet-form, we propose to include miltefosine for future clinical trials using extended treatment schedules, combination therapy, or targeting specific subgroups. TRIAL REGISTRATION: ClinicalTrials.gov NCT04004754.

Antibacterial mouthwash to prevent sexually transmitted infections in men who have sex with men taking HIV pre-exposure prophylaxis (PReGo): a randomised, placebo-controlled, crossover trial.

BACKGROUND: Bacterial sexually transmitted infections (STIs) are highly prevalent among men who have sex with men who use HIV pre-exposure prophylaxis (PrEP), which leads to antimicrobial consumption linked to the emergence of antimicrobial resistance. We aimed to assess use of an antiseptic mouthwash as an antibiotic sparing approach to prevent STIs. METHODS: We invited people using PrEP who had an STI in the past 24 months to participate in this single-centre, randomised, double-blind, placebo-controlled, AB/BA crossover superiority trial at the Institute of Tropical Medicine in Antwerp, Belgium. Using block randomisation (block size eight), participants were assigned (1:1) to first receive Listerine Cool Mint or a placebo mouthwash. They were required to use the study mouthwashes daily and before and after sex for 3 months each and to ask their sexual partners to use the mouthwash before and after sex. Participants were screened every 3 months for syphilis, chlamydia, and gonorrhoea at the oropharynx, anorectum, and urethra. The primary outcome was combined incidence of these STIs during each 3-month period, assessed in the intention-to-treat population, which included all participants who completed at least the first 3-month period. Safety was assessed as a secondary outcome. This trial is registered with Clinicaltrials.gov, NCT03881007. FINDINGS: Between April 2, 2019, and March 13, 2020, 343 participants were enrolled: 172 in the Listerine followed by placebo (Listerine-placebo) group and 171 in the placebo followed by Listerine (placebo-Listerine) group. The trial was terminated prematurely because of the COVID-19 pandemic. 151 participants completed the entire study, and 89 completed only the first 3-month period. 31 participants withdrew consent, ten were lost to follow-up, and one acquired HIV. In the Listerine-placebo group, the STI incidence rate was 140·4 per 100 person-years during the Listerine period, and 102·6 per 100 person-years during the placebo period. In the placebo-Listerine arm, the STI incidence rate was 133·9 per 100 person-years during the placebo period, and 147·5 per 100 person-years during the Listerine period. We did not find that Listerine significantly reduced STI incidence (IRR 1·17, 95% CI 0·84-1·64). Numbers of adverse events were not significantly higher than at baseline and were similar while using Listerine and placebo. Four serious adverse events (one HIV-infection, one severe depression, one Ludwig's angina, and one testicular carcinoma) were not considered to be related to use of mouthwash. INTERPRETATION: Our findings do not support the use of Listerine Cool Mint as a way to prevent STI acquisition among high-risk populations. FUNDING: Belgian Research Foundation - Flanders (FWO 121·00).

Diagnostic Accuracy of the INSHI Consensus Case Definition for the Diagnosis of Paradoxical Tuberculosis-IRIS.

BACKGROUND: The diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) relies on characteristic clinical features synthesized as the International Network for the Study of HIV-associated IRIS (INSHI) case definition. There is no confirmatory laboratory test. SETTING: Site B HIV-TB clinic in Khayelitsha, Cape Town, South Africa. METHODS: Using data of participants with HIV-associated tuberculosis starting antiretroviral treatment from a prospective trial evaluating prednisone for TB-IRIS prevention, we applied latent class analysis to model a gold standard for TB-IRIS. The model-predicted probability of TB-IRIS for each participant was used to assess the performance of the INSHI case definition and compare its diagnostic accuracy with several adapted case definitions. RESULTS: Data for this analysis were complete for 217 participants; 41% developed TB-IRIS. Our latent class model included the following parameters: respiratory symptoms; night sweats; INSHI major criteria 1, 2, and 4; maximum C-reactive protein >90 mg/L; maximum heart rate >120/min; maximum temperature >37.7°C; and preantiretroviral therapy CD4 count <50 cells/µL. The model estimated a TB-IRIS incidence of 43% and had optimal goodness of fit (χ2 = 337, P = 1.0). The INSHI case definition displayed a sensitivity of 0.77 and a specificity of 0.86. Replacing all the minor INSHI criteria with objectives measures (C-reactive protein elevation, fever, and/or tachycardia) resulted in a definition with better diagnostic accuracy, with a sensitivity of 0.89 and a specificity of 0.88. CONCLUSION: The INSHI case definition identifies TB-IRIS with reasonable accuracy. Amending the case definition by replacing INSHI minor criteria with objective variables improved sensitivity without loss of specificity.

Patient-mix, programmatic characteristics, retention and predictors of attrition among patients starting antiretroviral therapy (ART) before and after the implementation of HIV "Treat All" in Zimbabwe.

BACKGROUND: Since the scale-up of the HIV "Treat All" recommendation, evidence on its real-world effect on predictors of attrition (either death or lost to follow-up) is lacking. We conducted a retrospective study using Zimbabwe ART program data to assess the association between "Treat All" and, patient-mix, programmatic characteristics, retention and predictors of attrition. METHODS: We used patient-level data from the electronic patient monitoring system (ePMS) from the nine districts, which piloted the "Treat All" recommendation. We compared patient-mix, programme characteristics, retention and predictors of attrition (lost to follow-up, death or stopping ART) in two cohorts; before (April/May 2016) and after (January/February 2017) "Treat All". Retention was estimated using survival analysis. Predictors of attrition were determined using a multivariable Cox regression model. Interactions were used to assess the change in predictors of attrition before and after "Treat All". RESULTS: We analysed 3787 patients, 1738 (45.9%) and 2049 (54.1%) started ART before and after "Treat All", respectively. The proportion of men was higher after "Treat All" (39.4.% vs 36.2%, p = 0.044). Same-day ART initiation was more frequent after "Treat All" (43.2% vs 16.4%; p<0.001) than before. Retention on ART was higher before "Treat All" (p<0.001). Among non-pregnant women and men, the adjusted hazard ratio (aHR) of attrition after compared to before "Treat All" was 1.73 (95%CI: 1.30-2.31). The observed hazard of attrition for women being pregnant at ART initiation decreased by 17% (aHR: 1.73*0.48 = 0.83) after "Treat All". Being male (vs female; aHR: 1.45; 95%CI: 1.12-1.87) and WHO Stage IV (vs WHO Stage I-III; aHR: 2.89; 95%CI: 1.16-7.11) predicted attrition both before and after "Treat All" implementation. CONCLUSION: Attrition was higher after "Treat All"; being male, WHO Stage 4, and pregnancy predicted attrition in both before and after Treat All. However, pregnancy became a less strong risk factor for attrition after "Treat All" implementation.

Strong association between adolescent obesity and consumption of macrolides in Europe and the USA: An ecological study.

BACKGROUND: The reasons underpinning the large variations in the prevalence of childhood obesity are inadequately understood. Individual level studies have found that macrolide consumption at a young age increases the risk of subsequent obesity. We hypothesized that differences in population level consumption of macrolides may explain part of the variation in the prevalence of childhood obesity. METHODS: Mixed effects beta regression was used to assess the association between the prevalence of childhood obesity in countries in Europe/ states in the United States and population level consumption of macrolides and total antibiotics. Different time lags between consumption and obesity measurement were used. RESULTS: We found that in both the USA and Europe, population level consumption of macrolides was positively associated with subsequent childhood obesity prevalence. According to our model, the observed differences in population-level macrolide consumption in Europe/USA would translate into a 13%/72% higher odds of childhood obesity 5 years later. The association held regardless of the lag period used between exposure and outcome. The association with total antibiotic consumption was more equivocal. CONCLUSIONS: Reducing macrolide consumption to that of low consumption countries may result in considerable reductions in childhood obesity.

Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis.

BACKGROUND: Visceral leishmaniasis (VL) is a vector-borne disease that is deadly if left untreated. Understanding which factors have prognostic value may help to focus clinical management and reduce case fatality. However, information about prognostic factors is scattered and conflicting. We conducted a systematic review and meta-analysis to identify prognostic factors for mortality among VL patients in East Africa. METHODOLOGY/PRINCIPAL FINDINGS: The review protocol was registered in PROSPERO (CRD42016043112). We included studies published in English after 1970 describing VL patients treated in East African health facilities. To be included, studies had to report on associations between clinical or laboratory factors and mortality during admission or during VL treatment, with a minimal study size of ten patients. Conference abstracts and evaluations of genetic or immunological prognostic factors were excluded. We searched for studies in MEDLINE and four other databases in December 2018. To assess the risk of bias in observational studies and clinical trials, we used the Quality in Prognostic Studies (QUIPS) tool. We included 48 studies in the systematic review, describing 150,072 VL patients of whom 7,847 (5.2%) died. Twelve prognostic factors were evaluated in five or more studies and these results were submitted to meta-analysis producing one pooled crude odds ratio (OR) per prognostic factor. The following factors were strongly (OR>3) and significantly (P-value<0.05) associated with mortality: jaundice (OR = 8.27), HIV (OR = 4.60), tuberculosis (OR = 4.06), age >45 years (OR = 3.69), oedema (OR = 3.52), bleeding (OR = 3.37), and haemoglobin ≤6.5 g/dl (OR = 3.26). Factors significantly and moderately (OR between one and three) associated with death were severe malnutrition, long duration of illness, young age (<5 years), and large spleen size. CONCLUSIONS/SIGNIFICANCE: These prognostic factors can be identified by health professionals in resource-constrained settings. They should be considered as "core" prognostic factors in future studies that aim at improving the prognosis of VL patients.

Comparison of predictive models for hepatitis C co-infection among HIV patients in Cambodia.

BACKGROUND: Hepatitis C virus (HCV) infection is a major global health problem. WHO guidelines recommend screening all people living with HIV for hepatitis C. Considering the limited resources for health in low and middle income countries, targeted HCV screening is potentially a more feasible screening strategy for many HIV cohorts. Hence there is an interest in developing clinician-friendly tools for selecting subgroups of HIV patients for whom HCV testing should be prioritized. Several statistical methods have been developed to predict a binary outcome. Multiple studies have compared the performance of different predictive models, but results were inconsistent. METHODS: A cross-sectional HCV diagnostic study was conducted in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh, Cambodia. We compared the performance of logistic regression, Spiegelhalter-Knill-Jones and CART to predict Hepatitis C co-infection in this cohort. We estimated the number of HCV co-infections that would be missed. To correct for over-optimism, the leave-one-out bootstrap estimator was used for estimating this quantity. RESULTS: Logistic regression misses the fewest HCV co-infections (8%), but would still refer 98% of HIV patients for HCV testing. Spiegelhalter-Knill-Jones (SKJ) and CART respectively miss 12% and 29% of HCV co-infections but would only refer about 30% for HCV testing. CONCLUSIONS: In our dataset, logistic regression has the highest log-likelihood and smallest proportions of HCV co-infections missed but Spiegelhalter-Knill-Jones has the highest area under the ROC curve. The likelihood ratios estimated by Spiegelhalter-Knill-Jones might be easier to interpret for clinicians than odds ratios estimated by logistic regression or the decision tree from CART. CART is the most flexible method, and no model has to be specified regarding presence of interactions and form of the relationship between outcome and predictor variables.