Combined HIV Adolescent Prevention Study (CHAPS): comparison of HIV pre-exposure prophylaxis regimens for adolescents in sub-Saharan Africa-study protocol for a mixed-methods study including a randomised controlled trial.

BACKGROUND: HIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation. METHODS: We propose a mixed-methods study amongst young people aged 13-24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13-24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue. DISCUSSION: This study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019.

Impella use in acute myocardial infarction complicated by cardiogenic shock and cardiac arrest: Analysis of 10 years registry data.

AIMS: To assess characteristics and outcome of patients treated with Impella for acute myocardial infarction (AMI) complicated by severe cardiogenic shock (CS) or cardiac arrest (CA). METHODS AND RESULTS: From 2008 through 2017, 92 patients with AMI complicated by CS were treated with Impella. Survival varied according to clinical presentation. Patients in cardiogenic shock without CA had a 75% 30-day survival. Patients with CA and return of spontaneous circulation (ROSC) had a 43% survival and those with CA and ongoing cardio-pulmonary resuscitation (CPR) had a 6% 30-day survival. Age, pre-existing hypertension, coronary disease, ventilatory support and use of adrenergic agents were associated with worse prognosis. Complications were predominantly access site related. CONCLUSIONS: In this registry of patients with AMICS treated with Impella, hypertension and older age were found to be negatively predictive for survival. Patients without CA had the highest 30-day survival. In patients with ROSC, survival was strongly related to age and comorbidity. Patients with ongoing CPR had very high mortality.

Widespread use of herbal medicines by people living with human immunodeficiency virus and contamination of herbal medicines with antiretrovirals in Nigeria.

Herbal medication use amongst people living with human immunodeficiency virus (PLWH) is widespread and understudied. This study aimed to evaluate the prevalence of herbal medicine use amongst PLWH and possible contamination with antiretrovirals (ARVs). Countrywide collection of herbal samples sold by street vendors in Nigeria for the following indications: human immunodeficiency virus (HIV), acquired immune deficiency syndrome, fever and general weakness. Samples were screened using a validated liquid chromatography-mass spectrometry/mass spectrometry method for the presence of the following ARVs: efavirenz, nevirapine, lopinavir, darunavir, ritonavir, atazanavir, emtricitabine, tenofovir and lamivudine. A survey was conducted among 742 PLWH attending four HIV clinics in Nigeria. Data were collected using a structured questionnaire and analysed using IBM SPSS statistics version 22.0 (IBM Corp., 2013, Armond, NY). Of the 138 herbal medicines sampled, three (2%) contained detectable levels of tenofovir, emtricitabine and/or lamivudine. Additionally, of the 742 PLWH surveyed, 310 (41.8%) reported herbal medicine use. Among the users, 191 (61.6%) started taking herbals after commencing HIV therapy while herbal medicine use preceded ARVs treatment in 119 (38.4%) PLWH. We found herbal use to be widespread among PLWH in Nigeria, with increasing use after commencing ARV. Three herbal preparations were also found to contain detectable levels of ARVs. This is a concern and should be studied widely across the region and countries where herbal medicine use is prevalent and poorly regulated.

Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

Pharmacogenetics of pregnancy-induced changes in efavirenz pharmacokinetics.

Pregnancy-induced physiological changes alter many drugs' pharmacokinetics. We investigated pregnancy-induced changes in efavirenz pharmacokinetics in 25 pregnant and 19 different postpartum women stratified from 211 HIV-positive women in whom a preliminary pharmacogenetic study had been undertaken. Despite significant changes in CL/F during pregnancy (42.6% increase; P = 0.023), median (range) Cmin was 1,000 ng/mL (429-5,190) with no significant change in Cmax (P = 0.072). However, when stratified for CYP2B6 516G>T (rs3745274) genotype, efavirenz AUC0-24 , Cmax and Cmin were 50.6% (P = 0.0013), 17.2% (P = 0.14), and 61.6% (P = 0.0027) lower during pregnancy (n = 8) compared with postpartum (n = 6) in 516G homozygotes, with values of 25,900 ng.h/mL (21,700-32,600), 2,640 ng/mL (1,260-3,490), and 592 ng/mL (429-917), respectively, and CL/F was 100% higher (P = 0.0013). No changes were apparent in CYP2B6 516 heterozygotes (14 pregnant vs. 7 postpartum). The clinical implications of these findings warrant further investigation.

Evidence-based Danish guidelines for the treatment of Malassezia-related skin diseases.

Internationally approved guidelines for the diagnosis and management of Malassezia-related skin diseases are lacking. Therefore, a panel of experts consisting of dermatologists and a microbiologist under the auspices of the Danish Society of Dermatology undertook a data review and compiled guidelines for the diagnostic procedures and management of pityriasis versicolor, seborrhoeic dermatitis and Malassezia folliculitis. Main recommendations in most cases of pityriasis versicolor and seborrhoeic dermatitis include topical treatment which has been shown to be sufficient. As first choice, treatment should be based on topical antifungal medication. A short course of topical corticosteroid or topical calcineurin inhibitors has an anti-inflammatory effect in seborrhoeic dermatitis. Systemic antifungal therapy may be indicated for widespread lesions or lesions refractory to topical treatment. Maintenance therapy is often necessary to prevent relapses. In the treatment of Malassezia folliculitis systemic antifungal treatment is probably more effective than topical treatment but a combination may be favourable.

A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis.

Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6-8 and were present in plasma and genital-tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital-tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.

Therapeutic drug monitoring of atazanavir/ritonavir in pregnancy.

OBJECTIVES: Pregnant women experience physiological changes during pregnancy that can have a significant impact on antiretroviral pharmacokinetics. Ensuring optimal plasma concentrations of antiretrovirals is essential for maternal health and to minimize the risk of vertical transmission. Here we describe atazanavir/ritonavir (ATV/r) plasma concentrations in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM). METHODS: Pregnant HIV-positive women received ATV/r as part of their routine pre-natal care. Demographic and clinical data were collected. ATV plasma concentrations ([ATV]) were determined in the first (T1), second (T2) and third (T3) trimesters and at postpartum (PP) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: From January 2007, 44 women (37 black African) were enrolled in the study. All received ATV/r at a dose of 300/100 mg once a day. Twenty-four had received antiretroviral therapy (ART) prior to pregnancy, and 20 initiated ATV/r in pregnancy. At the time nearest to delivery, 36 patients had undetectable plasma viral loads. [ATV] values were determined in 11 (T1), 25 (T2), 34 (T3) and 28 (PP) patients. [ATV] at 24 hours post-dose (C24) values significantly lower at T2/T3 relative to PP. CONCLUSIONS: This study was carried out in one of the larger cohorts of women undergoing TDM for ATV in pregnancy. Lower [ATV] values were seen in T2/T3 compared with T1/PP. However, [ATV] were not associated with a lack of virologic suppression at delivery. Nonetheless, careful monitoring of women in pregnancy is required, and dose adjustment of ATV to 400 mg may be an option.

Improved oral bioavailability of lopinavir in melt-extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations.

Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC(0-12)) and maximum concentration were ∼15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.

Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy.

OBJECTIVES: The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum. METHODS: Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C(trough) ) were compared independently [using analysis of variance (anova)] and on a longitudinal basis (using a paired t-test). RESULTS: Forty-six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15-36) weeks and median (range) baseline CD4 count and viral load were 346 (14-836) cells/µL and 8724 (<50-267408) HIV-1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild-type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823-4227) ng/mL; n=16] and third [3346 (2813-3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693-6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851-4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM-guided dose adjustment in certain cases.

Prevalence of toe nail onychomycosis in diabetic patients.

Onychomycosis among diabetic patients has been reported in some studies to be of high prevalence. This study aimed to investigate the prevalence of onychomycosis among diabetic patients at a Danish University Hospital. Clinical and mycological examinations were performed on type 1 and 2 diabetic patients from in- and out-patient clinics. A total of 271 patients were enrolled, 72% males, mean age 61.3 years, 26% of the patients had diabetes type 1. The prevalence of toe nail onychomycosis (positive culture and/or microscopy) was 22% (n = 59) of which 55 cases were caused by dermatophytes (93%) and 4 cases by yeasts (7%). A correlation was found between onychomycosis and age (p =0.02) and severity of nail changes (p <0.001), respectively. However, no significant correlation was found to gender, type of diabetes, lower extremity arterial disease, neuropathy, toe amputation or oedema. Onychomycosis occurred with a high prevalence in diabetic patients, especially among older patients and those with severe nail changes.

Comparison of the centrifugal and roller pump in elective coronary artery bypass surgery--a prospective, randomized study with special emphasis upon platelet activation.

Objective--Evaluation of the centrifugal pump vs roller pump concerning effects upon platelet function, hemolysis and clinical outcome in elective coronary artery bypass surgery. Design--Thirty-four patients were randomized to centrifugal or roller pump. Platelet activation was studied by flow cytometry before, during and up to 3 days after bypass. Results--Duration of bypass, ischemic period, peripheral anastomoses, hospital stay and mortality did not differ. In roller pump patients, platelet aggregates increased by 250% between end of bypass and 3 h postoperatively (p < 0.001). A secondary, fivefold increase in number of platelet aggregates was found on the 3rd postoperative day (p < 0.001). In the centrifugal pump group, these changes were not significant. Hemolysis increased (20%) at end of bypass and 3 h postoperatively (p < 0.005), and decreased to preoperative levels the next day without group difference. Conclusion--Platelet aggregation was significantly increased in roller compared with centrifugal pump patients, indicating higher susceptibility to postoperative thrombotic complications with the roller pump. Otherwise, there was no clinical evidence for superiority of the centrifugal pump.

The prevalence of onychomycosis in patients with psoriasis and other skin diseases.

Onychomycosis among psoriasis patients is reported with varying prevalence. This prospective, controlled study investigates the occurrence of onychomycosis among inpatients with psoriasis versus inpatients with other skin diseases. The inclusion period was 15 months. Scrapings from clinically abnormal nails (both fingernails and toenails) were examined using microscopy and culture. The prevalence of onychomycosis in patients with psoriasis was 17/79 = 21.5% compared to 18/142 = 12.7% for patients with other skin diseases (p = 0.13). In 17 mycologically positive psoriasis patients, dermatophytes, yeasts and moulds were isolated in 8, 10 and 4 cases, respectively, and in 18 mycologically positive patients with other skin diseases in 12, 7 and 5, respectively. Onychomycosis occurred more frequently in men than in women (psoriasis patients (p = 0.02), patients with other skin diseases (p = 0.03)). Psoriasis patients had a higher frequency of abnormal nails (82.3%) compared to patients with other skin diseases (37.3%) (p < 0.01) and more severe affection of their toenails than patients with other skin diseases (p < 0.01). It is concluded that the frequency of onychomycosis among inpatients with psoriasis compared to inpatients with other skin diseases is not significantly different.

Personality characteristics of men who physically abuse women.

OBJECTIVE: Studies have suggested that personality disorders may be common among men who habitually commit domestic violence. The study reported here attempted to characterize personality traits and psychological and cognitive characteristics of men who batter women in order to distinguish them from nonbattering men. METHODS: A group of 21 batterers were compared with a group of nonbatterers using the Minnesota Multiphasic Personality Inventory and its personality disorder scales (MMPIPDS) and the Hostility and Direction of Hostility Questionnaire. Comparability of the two groups was assessed on several demographic variables and on scores on the Revised Michigan Alcoholism Screening Test, three cognitive measures, and three measures of affective disturbance. RESULTS: Batterers scored higher on only the borderline and antisocial MMPIPDS and on the acting-out hostility and self-criticism scales of the hostility questionnaire. Problem-solving skills for both of the groups were considerably poorer than published norms. No significant differences were found between the groups in age, race, education, socioeconomic status, alcohol abuse, performance on cognitive measures, depression scale scores, or overall scores on the MMPI. As children, batterers were more likely to have experienced physical or emotional abuse. CONCLUSIONS: Men who commit domestic violence may be found among a larger pool of men with poor problem-solving skills, but in addition they appear to have borderline-antisocial personality traits, certain types of hostility, and histories of abuse as children that may predispose them to become violent with their female companions.