Using dried blood spots to facilitate therapeutic drug monitoring of antiretroviral drugs in resource-poor regions.

Objectives: We evaluated whether dried blood spots (DBS) are suitable to monitor combined ART when samples are collected in rural Tanzania and transported over a long distance to a specialized bioanalytical laboratory. Methods: Plasma and DBS samples were collected in Tanzania from study patients treated with nevirapine, efavirenz or lopinavir. In addition, plasma, whole blood and DBS samples were obtained from a cohort of HIV patients at the site of the bioanalytical laboratory in Switzerland. DBS samples were analysed using a fully automated LC-MS/MS method. Results: Comparison of DBS versus plasma concentrations of samples obtained from the bridging study in Switzerland indicated an acceptable bias only for nevirapine (18.4%), whereas for efavirenz and lopinavir a pronounced difference of -47.4% and -48.1% was found, respectively. Adjusting the DBS concentrations by the haematocrit and the fraction of drug bound to plasma proteins removed this bias [efavirenz +9.4% (-6.9% to +25.7%), lopinavir +2.2% (-20.0% to +24.2%)]. Storage and transportation of samples from Tanzania to Switzerland did not affect the good agreement between plasma and DBS for nevirapine [-2.9% (-34.7% to +29.0%)] and efavirenz [-9.6% (-42.9% to +23.8%)]. For lopinavir, however, adjusted DBS concentrations remained considerably below [-32.8% (-70.4% to +4.8%)] corresponding plasma concentrations due to decay of lopinavir in DBS obtained under field conditions. Conclusions: Our field study shows that the DBS technique is a suitable tool for therapeutic drug monitoring in resource-poor regions; however, sample stability remains an issue for certain analytes and therefore needs special consideration.

[Rhabdomyolysis and severe hepatotoxicity due to a drug-drug interaction between ritonavir and simvastatin. Could we use the most cost-effective statin in all human immunodeficiency virus-infected patients?]. / Rabdomiólisis y hepatotoxicidad grave por interacción entre ritonavir y simvastatina. ¿Puede emplearse la estatina más coste-efectiva en todos los pacientes infectados por el virus de la inmunodeficiencia humana?

INTRODUCTION: Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism. PATIENTS AND METHODS: A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented. RESULTS: The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death. CONCLUSIONS: Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations.

Osteoarticular Cryptococcosis Successfully Treated with High-Dose Liposomal Amphotericin B Followed by Oral Fluconazole.

BACKGROUND: Skeletal involvement of Cryptococcus neoformans is infrequent and usually associated with disseminated cryptococcosis or underlying predisposing conditions. We present an atypical case of osteoarticular cryptococcosis in an immunocompetent patient. CASE PRESENTATION: We herein report a case of bone and soft tissue cryptococcal infection in a 42-year-old male from Pakistan with well-controlled diabetes without other associated immunodeficiencies treated with antifungal therapy without surgical debridement. Furthermore, the patient developed toxidermia due to fluconazole use, so a fluconazole desensitization was performed. Therapeutic management also included the performance of therapeutic drug monitoring of fluconazole plasma concentrations. CONCLUSION: To our knowledge, this is the first case of osteoarticular cryptococcosis treated with this treatment regimen. This strategy may be of interest to try to reduce hospital stay and associated complications.

Sociodemographic, clinical, and immunological factors associated with SARS-CoV-2 diagnosis and severe COVID-19 outcomes in people living with HIV: a retrospective cohort study.

BACKGROUND: Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV. METHODS: We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis. FINDINGS: We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0-52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31-1·83), men who have sex with men (1·42, 1·09-1·86), and those with four or more chronic comorbidities (1·46, 1·09-1·97). Age at least 75 years (5·2, 1·8-15·3), non-Spanish origin (2·1, 1·3-3·4), and neuropsychiatric (1·69, 1·07-2·69), autoimmune disease (1·92, 1·14-3·23), respiratory disease (1·84, 1·09-3·09), and metabolic disease (2·59, 1·59-4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15). INTERPRETATION: People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes. FUNDING: Fundació "la Caixa". TRANSLATIONS: For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.

Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing coronavirus disease 2019 (COVID-19). Hydroxychloroquine and chloroquine have garnered unprecedented attention as potential therapeutic agents against COVID-19 following several small clinical trials, uncontrolled case series, and public figure endorsements. While there is a growing body of scientific data, there is also concern for harm, particularly QTc prolongation and cardiac arrhythmias. Here, we perform a rapid narrative review and discuss the strengths and limitations of existing in vitro and clinical studies. We call for additional randomized controlled trial evidence prior to the widespread incorporation of hydroxychloroquine and chloroquine into national and international treatment guidelines.

A 10 year study of the cause of death in children under 15 years in Manhiça, Mozambique.

BACKGROUND: Approximately 46 million of the estimated 60 million deaths that occur in the world each year take place in developing countries. Further, this mortality is highest in Sub-Saharan Africa, although causes of mortality in this region are not well documented. The objective of this study is to describe the most frequent causes of mortality in children under 15 years of age in the demographic surveillance area of the Manhiça Health Research Centre, between 1997 and 2006, using the verbal autopsy tool. METHODS: Verbal autopsy interviews for causes of death in children began in 1997. Each questionnaire was reviewed independently by three physicians with experience in tropical paediatrics, who assigned the cause of death according to the International Classification of Diseases (ICD-10). Each medical doctor attributed a minimum of one and a maximum of 2 causes. A final diagnosis is reached when at least two physicians agreed on the cause of death. RESULTS: From January 1997 to December 2006, 568,499 person-year at risk (pyrs) and 10,037 deaths were recorded in the Manhiça DSS. 3,730 deaths with 246,658 pyrs were recorded for children under 15 years of age. Verbal autopsy interviews were conducted on 3,002 (80.4%) of these deaths. 73.6% of deaths were attributed to communicable diseases, non-communicable diseases accounted for 9.5% of the defined causes of death, and injuries for 3.9% of causes of deaths. Malaria was the single largest cause, accounting for 21.8% of cases. Pneumonia with 9.8% was the second leading cause of death, followed by HIV/AIDS (8.3%) and diarrhoeal diseases with 8%. CONCLUSION: The results of this study stand out the big challenges that lie ahead in the fight against infectious diseases in the study area. The pattern of childhood mortality in Manhiça area is typical of developing countries where malaria, pneumonia and HIV/AIDS are important causes of death.

Age-related comorbidities and mortality in people living with HIV in rural Tanzania.

OBJECTIVE: Causes of morbidity and mortality of people living with HIV are changing with access to antiretroviral therapy and increased life expectancy. Age-related data on comorbidities and their impact on mortality in sub-Saharan Africa are scarce. DESIGN: This prospective analysis evaluated comorbidities, assessed by means of International Classification of Diseases and Related Health problems 10th revision codes and clinical variables, derived from data collected from the Kilombero & Ulanga antiretroviral cohort of people living with HIV in rural Tanzania. METHODS: We calculated prevalences and incidences of comorbidities in patients enrolled from 2013 to 2017 and evaluated their association with a combined endpoint of death and loss to follow-up (LTFU) in various age groups (15-29, 30-49 and ≥50 years) using Cox regression analysis. RESULTS: Of 1622 patients [65% females, median age 38 years (interquartile range 31-46)], 11% were at least 50 years. During a median follow-up of 22.1 months (interquartile range 10.6-37.3), 48 (2.9%) patients died and 306 (18.9%) were LTFU. Anaemia was the most prevalent comorbidity (66.3%) irrespective of age and was associated with increased mortality/LTFU [hazard ratios 2.02 (95% confidence interval (CI) 1.57-2.60); P < 0.001]. In patients aged at least 50 years, arterial hypertension was highly prevalent (43.8%), but not associated with mortality/LTFU [hazard ratios 1.04 (95% CI 0.56-1.93), P = 0.9]. Undernutrition ranged from 25.5% in the youngest to 29.1% in the oldest age group and contributed to mortality/LTFU [hazard ratios 2.24 (95% CI 1.65-3.04); P < 0.001]. Prevalence of tuberculosis was 21.4% with hazard ratios of 2.54 (95% CI 1.72-3.75, P < 0.001) for mortality/LTFU. CONCLUSION: We show that anaemia, arterial hypertension and undernutrition are the most relevant comorbidities with different age-associated frequencies and impact on death/LTFU in this population.

Clinico-pathological discrepancies in the diagnosis of causes of death in adults in Mozambique: A retrospective observational study.

BACKGROUND: Clinico-pathological discrepancies are more frequent in settings in which limited diagnostic techniques are available, but there is little information on their actual impact. AIM: We assessed the accuracy of the clinical diagnoses in a tertiary referral hospital in sub-Saharan Africa by comparison with post-mortem findings. We also identified potential risk factors for misdiagnoses. METHODS: One hundred and twelve complete autopsy procedures were performed at the Maputo Central Hospital (Mozambique), from November 2013 to March 2015. We reviewed the clinical records. Major clinico-pathological discrepancies were assessed using a modified version of the Goldman and Battle classification. RESULTS: Major diagnostic discrepancies were detected in 65/112 cases (58%) and were particularly frequent in infection-related deaths (56/80 [70%] major discrepancies). The sensitivity of the clinical diagnosis for toxoplasmosis was 0% (95% CI: 0-37), 18% (95% CI: 2-52) for invasive fungal infections, 25% (95% CI: 5-57) for bacterial sepsis, 34% (95% CI: 16-57), for tuberculosis, and 46% (95% CI: 19-75) for bacterial pneumonia. Major discrepancies were more frequent in HIV-positive than in HIV-negative patients (48/73 [66%] vs. 17/39 [44%]; p = 0.0236). CONCLUSIONS: Major clinico-pathological discrepancies are still frequent in resource constrained settings. Increasing the level of suspicion for infectious diseases and expanding the availability of diagnostic tests could significantly improve the recognition of common life-threatening infections, and thereby reduce the mortality associated with these diseases. The high frequency of clinico-pathological discrepancies questions the validity of mortality reports based on clinical data or verbal autopsy.

AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial.

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM. METHODOLOGY/DESIGN: This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥ 18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat. TRIAL REGISTRATION: ISRCTN10248064. Date of Registration: 22 January 2014.

Uptake of guidelines on prevention of mother-to-child transmission of HIV in rural Tanzania: time for change.

Guidelines on prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) are inconsistently implemented in low-income countries. Strategies are needed to improve the uptake of these guidelines to prevent avoidable new HIV infections of infants. In 2010 the World Health Organisation presented its new PMTCT guidelines, offering two options for short courses of antiretroviral prophylaxis: Option A and Option B. Option A consists of antenatal prophylaxis with zidovudine followed by intrapartum and postpartum prophylaxis with single-dose nevirapine and zidovudine plus lamivudine. Option B recommends triple antiretroviral prophylaxis until after finishing breastfeeding. Tanzania has adopted Option A, and it is currently implementing it. A new option termed Option B+ has emerged recently, which recommends providing lifelong antiretroviral treatment to all HIV-positive pregnant women. In this article, we discuss the likely impact of this last PMTCT strategy in rural Africa with an example of an observational cross-sectional analysis in a rural referral hospital in Tanzania aiming to assess the uptake of PMTCT recommendations. Gaps were identified at all steps of the PMTCT pathway. Effective uptake of PMTCT guidelines has been shown to be extremely challenging in this setting. The continuously changing recommendations on PMTCT stress the need for a much simpler and effective approach. We argue in favour of implementing Option B+ in Tanzania. Financial challenges need to be faced, but Option B+ would help to overcome many barriers that prevent guidelines to be implemented in order to increase coverage and ultimately achieve the goal of 'virtual elimination' of mother-to-child transmission in sub-Saharan Africa.

Rabdomiólisis y hepatotoxicidad grave por interacción entre ritonavir y simvastatina. ¿Puede emplearse la estatina más coste-efectiva en todos los pacientes infectados por el virus de la inmunodeficiencia humana? / Rhabdomyolysis and severe hepatotoxicity due to a drug-drug interaction between ritonavir and simvastatin. Could we use the most cost-effective statin in all human immunodeficiency virus-infected patients?

INTRODUCCIÓN: Una de las posibles etiologías de la rabdomiólisis son los fármacos, y entre ellos, las estatinas. Especialmente simvastatina y lovastatina tienen un elevado metabolismo hepático, por lo que están más sujetas a interacciones con otros fármacos que puedan reducir su metabolismo y aumentar su toxicidad. PACIENTES Y MÉTODOS: Se describe un caso clínico de una paciente infectada por el VIH en tratamiento antirretroviral que desarrolló rabdomiólisis, insuficiencia renal y hepatotoxicidad grave tras la sustitución de atorvastatina por simvastatina. Se revisan los casos descritos en la literatura. RESULTADOS: La paciente requirió ingreso hospitalario y evolucionó favorablemente tras hidratación y alcalinización de la orina, recuperando su estado basal. Existen 4 casos publicados, de los cuales uno falleció. CONCLUSIONES: Las interacciones farmacológicas pueden aumentar el riesgo de rabdomiólisis por estatinas. Para evaluarlas es necesario que los facultativos de todos los niveles asistenciales conozcan todos los fármacos que reciben los pacientes y las asociaciones contraindicadas

INTRODUCTION: Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism. PATIENTS AND METHODS: A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented. RESULTS: The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death. CONCLUSIONS: Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations