Simplified clinical prediction scores to target viral load testing in adults with suspected first line treatment failure in Phnom Penh, Cambodia.

BACKGROUND: For settings with limited laboratory capacity, 2013 World Health Organization (WHO) guidelines recommend targeted HIV-1 viral load (VL) testing to identify virological failure. We previously developed and validated a clinical prediction score (CPS) for targeted VL testing, relying on clinical, adherence and laboratory data. While outperforming the WHO failure criteria, it required substantial calculation and review of all previous laboratory tests. In response, we developed four simplified, less error-prone and broadly applicable CPS versions that can be done 'on the spot'. METHODOLOGY/PRINCIPAL: Findings From May 2010 to June 2011, we validated the original CPS in a non-governmental hospital in Phnom Penh, Cambodia applying the CPS to adults on first-line treatment >1 year. Virological failure was defined as a single VL >1000 copies/ml. The four CPSs included CPS1 with 'current CD4 count' instead of %-decline-from-peak CD4; CPS2 with hemoglobin measurements removed; CPS3 having 'decrease in CD4 count below baseline value' removed; CPS4 was purely clinical. Score development relied on the Spiegelhalter/Knill-Jones method. Variables independently associated with virological failure with a likelihood ratio ≥ 1.5 or ≤ 0.67 were retained. CPS performance was evaluated based on the area-under-the-ROC-curve (AUROC) and 95% confidence intervals (CI). The CPSs were validated in an independent dataset. A total of 1490 individuals (56.6% female, median age: 38 years (interquartile range (IQR 33-44)); median baseline CD4 count: 94 cells/µL (IQR 28-205), median time on antiretroviral therapy 3.6 years (IQR 2.1-5.1)), were included. Forty-five 45 (3.0%) individuals had virological failure. CPS1 yielded an AUROC of 0.69 (95% CI: 0.62-0.75) in validation, CPS2 an AUROC of 0.68 (95% CI: 0.62-0.74), and CPS3, an AUROC of 0.67 (95% CI: 0.61-0.73). The purely clinical CPS4 performed poorly (AUROC-0.59; 95% CI: 0.53-0.65). CONCLUSIONS: Simplified CPSs retained acceptable accuracy as long as current CD4 count testing was included. Ease of field application and field accuracy remains to be defined

Incidence of Treatment-Limiting Toxicity with Stavudine-Based Antiretroviral Therapy in Cambodia: A Retrospective Cohort Study

Background: Although stavudine (D4T) remains frequently used in low-income countries in Asia, associated long-term toxicity data are scarce. The aim of this study was to determine the long-term incidence of severe D4T-toxicity (requiring drug substitution) and associated risk factors in HIV-infected Cambodians up to six years on antiretroviral treatment (ART). Methodology/Principal Findings: This is a retrospective analysis of an observational cohort, using data from an ART program with systematic monitoring for D4T-toxicity. Probabilities of time to D4T substitution due to suspected D4T toxicity (treatment-limiting D4T toxicity) were calculated, a risk factor analysis was performed using multivariate Cox regression modelling. Out of 2581 adults initiating a D4T-containing regimen, D4T was replaced in 276 (10.7%) patients for neuropathy, 14 (0.5%) for lactic acidosis and 957 (37.1%) for lipoatrophy. The main early side effect was peripheral neuropathy (7.0 % by 1 year). After the first year, lipoatrophy became predominant, with a cumulative incidence of 56.1 % and 72.4 % by 3 and 6 years respectively. Older age (aHR 1.8; 95%CI: 1.4–2.3) and lower baseline haemoglobin (aHR 1.7; 95%CI: 1.4–2.2) were associated with the occurrence of neuropathy. Being female (aHR 3.8; 95%CI: 1.1–12.5), a higher baseline BMI (aHR 12.6; 95%CI: 3.7–43.1), and TB treatment at ART initiation (aHR 8.6; 95%CI: 2.7–27.5) increased the likelihood of lactic acidosis. Lipoatrophy was positively associated with female gender (aHR 2.3; 95%CI: 2.0–2.6), an older age (aHR 1.3; 95%CI: 1.1–1.4), and a CD4 count,200 cells/mL (aHR 1.3; 95%CI: 1.1–1.5)

Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen

<p>Abstract</p> <p>Background</p> <p>Vitamin D is an important determinant of bone health and also plays a major role in the regulation of the immune system. Interestingly, vitamin D status before the start of highly active antiretroviral therapy (HAART) has been recently associated with HIV disease progression and overall mortality in HIV-positive pregnant women. We prospectively studied vitamin D status in HIV individuals on HAART in Belgium.</p> <p>We selected samples from HIV-positive adults starting HAART with a pre-HAART CD4 T-cell count >100 cells/mm³followed up for at least 12 months without a treatment change. We compared 25-hydroxyvitamin D plasma [25-(OH)D] concentration in paired samples before and after 12 months of HAART. 25-(OH)D levels are presented using two different cut-offs: <20 ng/ml and <30 ng/ml.</p> <p>Results</p> <p>Vitamin D deficiency was common before HAART, the frequency of plasma 25-(OH)D concentrations below 20 ng/ml and 30 below ng/ml was 43.7% and 70.1% respectively. After 12 months on HAART, the frequency increased to 47.1% and 81.6%.</p> <p>HAART for 12 months was associated with a significant decrease of plasma 25-(OH)D concentration (p = 0.001). Decreasing plasma 25-(OH)D concentration on HAART was associated in the multivariate model with NNRTI-based regimen (p = 0.001) and lower body weight (p = 0.008). Plasma 25-(OH)D concentrations decreased significantly in both nevirapine and efavirenz-containing regimens but not in PI-treated patients.</p> <p>Conclusions</p> <p>Vitamin D deficiency is frequent in HIV-positive individuals and NNRTI therapy further decreases 25-(OH)D concentrations. Consequently, vitamin D status need to be checked regularly in all HIV-infected patients and vitamin D supplementation should be given when needed.</p

Decision-making in the diagnosis of tuberculous meningitis

CITATION: Boyles, Tom H. et al. 2020. Decision-making in the diagnosis of tuberculous meningitis. Wellcome Open Research, 5:11, doi:10.12688/wellcomeopenres.15611.1.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) but diagnosis is difficult and delays in initiating therapy increase mortality. All currently available tests are imperfect; culture of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) is considered the most accurate test but is often negative, even when disease is present, and takes too long to be useful for immediate decision making. Rapid tests that are frequently used are conventional Ziehl-Neelsen staining and nucleic acid amplification tests such as Xpert MTB/RIF and Xpert MTB/RIF Ultra. While positive results will often confirm the diagnosis, negative tests frequently provide insufficient evidence to withhold therapy. The conventional diagnostic approach is to determine the probability of TBM using experience and intuition, based on prevalence of TB, history, examination, analysis of basic blood and CSF parameters, imaging, and rapid test results. Treatment decisions may therefore be both variable and inaccurate, depend on the experience of the clinician, and requests for tests may be inappropriate. In this article we discuss the use of Bayes' theorem and the threshold model of decision making as ways to improve testing and treatment decisions in TBM. Bayes' theorem describes the process of converting the pre-test probability of disease to the post-test probability based on test results and the threshold model guides clinicians to make rational test and treatment decisions. We discuss the advantages and limitations of using these methods and suggest that new diagnostic strategies should ultimately be tested in randomised trials.Publisher's versio

Exploring three approaches to offer distance learning courses through a social network of health researchers in three African countries

The Institute of Tropical Medicine in Antwerp hereby presents the results of two pilot distance learning training programmes, developed under the umbrella of the AFRICA BUILD project (FP7). The two courses focused on evidence-based medicine (EBM): with the aim of enhancing research and education, via novel approaches and to identify research needs emanating from the field. These pilot experiences, which were run both in English-speaking (Ghana), and French-speaking (Mali and Cameroon) partner institutions, produced targeted courses for the strengthening of research methodology and policy. The courses and related study materials are in the public domain and available through the AFRICA BUILD Portal (http://www.africabuild.eu/taxonomy/term/37); the training modules were delivered live via Dudal webcasts. This paper assesses the success and difficulties of transferring EBM skills with these two specific training programmes, offered through three different approaches: fully online facultative courses, fully online tutor supported courses or through a blended approach with both online and face-to-face sessions. Key factors affecting the selection of participants, the accessibility of the courses, how the learning resources are offered, and how interactive online communities are formed, are evaluated and discussed

Evaluation of the 2007 WHO guideline to improve the diagnosis of tuberculosis in ambulatory HIV-positive adults.

BACKGROUND: In 2007 WHO issued a guideline to improve the diagnosis of smear-negative and extrapulmonary tuberculosis (EPTB) in HIV-positive patients. This guideline relies heavily on the acceptance of HIV-testing and availability of chest X-rays. METHODS AND FINDINGS: Cohort study of TB suspects in four tuberculosis (TB) clinics in Phnom Penh, Cambodia. We assessed the operational performance of the guideline, the incremental yield of investigations, and the diagnostic accuracy for smear-negative tuberculosis in HIV-positive patients using culture positivity as reference standard. 1,147 (68.9%) of 1,665 TB suspects presented with unknown HIV status, 1,124 (98.0%) agreed to be tested, 79 (7.0%) were HIV-positive. Compliance with the guideline for chest X-rays and sputum culture requests was 97.1% and 98.3% respectively. Only 35 of 79 HIV-positive patients (44.3%) with a chest X-ray suggestive of TB started TB treatment within 10 days. 105 of 442 HIV-positive TB suspects started TB treatment (56.2% smear-negative pulmonary TB (PTB), 28.6% smear-positive PTB, 15.2% EPTB). The median time to TB treatment initiation was 5 days (IQR: 2-13 days), ranging from 2 days (IQR: 1-11.5 days) for EPTB, over 2.5 days (IQR: 1-4 days) for smear-positive PTB to 9 days (IQR: 3-17 days) for smear-negative PTB. Among the 34 smear-negative TB patients with a confirmed diagnosis, the incremental yield of chest X-ray, clinical suspicion or abdominal ultrasound, and culture was 41.2%, 17.6% and 41.2% respectively. The sensitivity and specificity of the algorithm to diagnose smear-negative TB in HIV-positive TB suspects was 58.8% (95%CI: 42.2%-73.6%) and 79.4% (95%CI: 74.8%-82.4%) respectively. CONCLUSIONS: Pending point-of-care rapid diagnostic tests for TB disease, diagnostic algorithms are needed. The diagnostic accuracy of the 2007 WHO guideline to diagnose smear-negative TB is acceptable. There is, however, reluctance to comply with the guideline in terms of immediate treatment initiation

The Use of Ebola Convalescent Plasma to Treat Ebola Virus Disease in Resource-Constrained Settings: A Perspective From the Field.

The clinical evaluation of convalescent plasma (CP) for the treatment of Ebola virus disease (EVD) in the current outbreak, predominantly affecting Guinea, Sierra Leone, and Liberia, was prioritized by the World Health Organization in September 2014. In each of these countries, nonrandomized comparative clinical trials were initiated. The Ebola-Tx trial in Conakry, Guinea, enrolled 102 patients by 7 July 2015; no severe adverse reactions were noted. The Ebola-CP trial in Sierra Leone and the EVD001 trial in Liberia have included few patients. Although no efficacy data are available yet, current field experience supports the safety, acceptability, and feasibility of CP as EVD treatment. Longer-term follow-up as well as data from nontrial settings and evidence on the scalability of the intervention are required. CP sourced from within the outbreak is the most readily available source of anti-EVD antibodies. Until the advent of effective antivirals or monoclonal antibodies, CP merits further evaluation

Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014-2015 outbreak.

The Ebola virus disease outbreak in 2014-2015 led to a huge caseload with a high case fatality rate. No specific treatments were available beyond supportive care for conditions such as dehydration and shock. Evaluation of treatment with convalescent plasma from Ebola survivors was identified as a priority. We evaluated this intervention in an emergency setting, where randomization was unacceptable. The original trial design was an open-label study comparing patients receiving convalescent plasma and supportive care to patients receiving supportive care alone. The comparison group comprised patients recruited at the start of the trial before convalescent plasma became available, as well as patients presenting during the trial for whom there was insufficient blood group-compatible plasma or no staffing capacity to provide additional transfusions. However, during the trial, convalescent plasma was available to treat all new patients. The design was changed to use a comparator group comprising patients previously treated at the same Ebola treatment center prior to the start of the trial. In the analysis, it was planned to adjust for any differences in prognostic variables between intervention and comparison groups, specifically baseline polymerase chain reaction cycle threshold and age. In addition, adjustment was planned for other potential confounders, identified in the analysis, such as patient presenting symptoms and time to treatment seeking. Because plasma treatment started up to 3 days after diagnosis and we could not define a similar time-point for the comparator group, patients who died before the third day after confirmation of diagnosis were excluded from both intervention and comparison groups in a per-protocol analysis. Some patients received additional experimental treatments soon after plasma treatment, and these were excluded. We also analyzed mortality including all patients from the time of confirmed diagnosis, irrespective of whether those in the trial series actually received plasma, as an intention-to-treat analysis. Per-protocol and intention-to-treat approaches gave similar conclusions. An important caveat in the interpretation of the findings is that it is unlikely that all potential sources of confounding, such as any variation in supportive care over time, were eliminated. Protocols and electronic data capture systems have now been extensively field-tested for emergency evaluation of treatment with convalescent plasma. Ongoing studies seek to quantify the level of neutralizing antibodies in different plasma donations to determine whether this influences the response and survival of treated patients

Appropriateness of Antibiotic Prescribing for Acute Conjunctivitis: A Cross-Sectional Study at a Specialist Eye Hospital in Ghana, 2021

Most presentations of conjunctivitis are acute. Studies show that uncomplicated cases resolve within 14 days without medication. However, antibiotic prescription remains standard practice. With antimicrobial resistance becoming a public health concern, we undertook this study to assess antibiotic prescription patterns in managing acute conjunctivitis in an eye hospital in Ghana. We recorded 3708 conjunctivitis cases; 201 were entered as acute conjunctivitis in the electronic medical records (January to December 2021). Of these, 44% were males, 56% were females, 39% were under 5 years, 21% were children and adolescents (5–17 years) and 40% were adults (≥18 years). A total of 111 (55.2%) patients received antibiotics, of which 71.2% were appropriately prescribed. The use of antibiotics was more frequent in children under 17 years compared to adults (p < 0.0001). Of the prescribed antibiotics, 44% belonged to the AWaRe “Access” category (Gentamycin, Tetracycline ointment), while 56% received antibiotics in the “Watch” category (Ciprofloxacin, Tobramycin). Although most of the antibiotic prescribing were appropriate, the preponderance of use of the Watch category warrants stewardship to encompass topical antibiotics. The rational use of topical antibiotics in managing acute conjunctivitis will help prevent antimicrobial resistance, ensure effective health care delivery, and contain costs for patients and the health system