Annemie Stewart

Adverse Drug Reactions Causing Admission to Medical Wards: A Cross-Sectional Survey at 4 Hospitals in South Africa.

AbstractLimited data exist on the burden of serious adverse drug reactions (ADRs) in sub-Saharan Africa, which has high HIV and tuberculosis prevalence. We determined the proportion of adult admissions attributable to ADRs at 4 hospitals in South Africa. We characterized drugs implicated in, risk factors for, and the preventability of ADR-related admissions.We prospectively followed patients admitted to 4 hospitals’ medical wards over sequential 30-day periods in 2013 and identified suspected ADRs with the aid of a trigger tool. A multidisciplinary team performed causality, preventability, and severity assessment using published criteria. We categorized an admission as ADR-related if the ADR was the primary reason for admission.There were 1951 admissions involving 1904 patients: median age was 50 years (interquartile range 34–65), 1057 of 1904 (56%) were female, 559 of 1904 (29%) were HIV-infected, and 183 of 1904 (10%) were on antituberculosis therapy (ATT). There were 164 of 1951 (8.4%) ADR-related admissions. After adjustment for age and ATT, ADR-related admission was independently associated (P ⩽ 0.02) with female sex (adjusted odds ratio [aOR] 1.51, 95% confidence interval [95% CI] 1.06–2.14), increasing drug count (aOR 1.14 per additional drug, 95% CI 1.09–1.20), increasing comorbidity score (aOR 1.23 per additional point, 95% CI 1.07–1.41), and use of antiretroviral therapy (ART) if HIV-infected (aOR 1.92 compared with HIV-negative/unknown, 95% CI 1.17–3.14). The most common ADRs were renal impairment, hypoglycemia, liver injury, and hemorrhage. Tenofovir disoproxil fumarate, insulin, rifampicin, and warfarin were most commonly implicated, respectively, in these 4 ADRs. ART, ATT, and/or co-trimoxazole were implicated in 56 of 164 (34%) ADR-related admissions. Seventy-three of 164 (45%) ADRs were assessed as preventable.In our survey, approximately 1 in 12 admissions was because of an ADR. The range of ADRs and implicated drugs reflect South Africas high HIV and tuberculosis burden. Identification and management of these ADRs should be considered in HIV and tuberculosis care and treatment programs and should be emphasized in health care worker training programmes.

Severe antiretroviral-associated skin reactions in South African patients: a case series and case-control analysis.

Severe skin reactions may complicate combination antiretroviral therapy (cART). Nevirapine is known to be associated with severe skin reactions, but there are conflicting data on risk factors in African patients. We reviewed cases of severe skin reactions admitted to a tertiary hospital in Cape Town, South Africa. We identified associations with severe skin reactions in patients on cART.

Optimizing Tuberculosis Diagnosis in Human Immunodeficiency Virus–Infected Inpatients Meeting the Criteria of Seriously Ill in the World Health Organization Algorithm

Background The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill human immunodeficiency virus (HIV)-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. Methods We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard. A priori selected variables were assessed for univariate associations with tuberculosis. The most predictive variables were assessed in a multivariate logistic regression model and used to establish a clinical prediction rule for diagnosing tuberculosis. Results We enrolled 484 participants. The median age was 36 years, 65.5% were female, the median CD4 count was 89 cells/µL, and 35.3% were on antiretroviral therapy. Tuberculosis was diagnosed in 52.7% of participants. The c-statistic of our clinical prediction rule (variables: cough ≥14 days, unable to walk unaided, temperature >39°C, chest radiograph assessment, hemoglobin, and white cell count) was 0.811 (95% confidence interval, .802-.819). The classic tuberculosis symptoms (fever, night sweats, weight loss) added no discriminatory value in diagnosing tuberculosis. Xpert MTB/RIF assay sensitivity was 86.3% and specificity was 96.1%. Conclusions Our clinical prediction rule had good diagnostic utility for tuberculosis among seriously ill HIV-infected inpatients. Xpert MTB/RIF assay, incorporated into the updated 2016 WHO algorithm, had high sensitivity and specificity in this population. Our findings could facilitate improved diagnosis of tuberculosis among seriously ill HIV-infected inpatients in resource-constrained settings.

The Cape Town Clinical Decision Rule for Streptococcal Pharyngitis in Children

Background: Existing clinical decision rules (CDRs) to diagnose group A streptococcal (GAS) pharyngitis have not been validated in sub-Saharan Africa. We developed a locally applicable CDR while evaluating existing CDRs for diagnosing GAS pharyngitis in South African children. Methods: We conducted a prospective cohort study and enrolled 997 children 3–15 years of age presenting to primary care clinics with a complaint of sore throat, and whose parents provided consent. Main outcome measures were signs and symptoms of pharyngitis and a positive GAS culture from a throat swab. Bivariate and multivariate analyses were used to develop the CDR. In addition, the diagnostic effectiveness of 6 existing rules for predicting a positive culture in our cohort was assessed. Results: A total of 206 of 982 children (21%) had a positive GAS culture. Tonsillar swelling, tonsillar exudates, tender or enlarged anterior cervical lymph nodes, absence of cough and absence of rhinorrhea were associated with positive cultures in bivariate and multivariate analyses. Four variables (tonsillar swelling and one of tonsillar exudate, no rhinorrhea, no cough), when used in a cumulative score, showed 83.7% sensitivity and 32.2% specificity for GAS pharyngitis. Of existing rules tested, the rule by McIsaac et al had the highest positive predictive value (28%), but missed 49% of the culture-positive children who should have been treated. Conclusion: The new 4-variable CDR for GAS pharyngitis (ie, tonsillar swelling and one of tonsillar exudate, no rhinorrhea, no cough) outperformed existing rules for GAS pharyngitis diagnosis in children with symptomatic sore throat in Cape Town.

Random lopinavir concentrations predict resistance on lopinavir-based antiretroviral therapy

Considering that most patients who experience virological failure (VF) on lopinavir-based antiretroviral therapy (ART) fail due to poor adherence rather than resistance, an objective adherence measure could limit costs by rationalising the use of genotype antiretroviral resistance testing (GART) in countries with access to third-line ART. A cross-sectional study was conducted in a resource-limited setting at two large clinics in Kwazulu-Natal, South Africa, in patients experiencing VF (HIV-RNA > 1000 copies/mL) on lopinavir-based ART who had undergone GART. Associations between major protease inhibitor (PI) resistance mutations and random plasma lopinavir concentrations were explored. A total of 134 patients, including 31 children, were included in the analysis. The prevalence of patients with major PI resistance mutations was 20.9% (n = 28). A random lopinavir concentration above the recommended minimum trough of 1 µg/mL [adjusted odds ratio (aOR) = 5.81, 95% confidence interval (CI) 2.04-16.50; P = 0.001] and male sex (aOR = 3.19, 95% CI 1.22-8.33; P = 0.018) were predictive of the presence of at least one major PI resistance mutation. Random lopinavir concentrations of <1 µg/mL had a negative predictive value of 91% for major PI resistance mutations. Random lopinavir concentrations are strongly associated with the presence of major PI resistance mutations. Access to costly GART in patients experiencing VF on second-line ART could be restricted to patients with lopinavir concentrations above the recommended minimum trough of 1 µg/mL or, in areas where GART is unavailable, could be used as a criterion to empirically switch to third-line ART.

Development of a clinical prediction rule to diagnose Pneumocystis jirovecii pneumonia in the World Health Organization’s algorithm for seriously ill HIV-infected patients

Background The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill HIV-infected patients recommends that treatment for Pneumocystis jirovecii pneumonia (PJP) should be considered without giving clear guidance on selecting patients for empiric PJP therapy. PJP is a common cause of hospitalisation in HIV-infected patients in resource-poor settings where diagnostic facilities are limited. Methods We developed clinical prediction rules for PJP in a prospective cohort of HIV-infected inpatients with WHO danger signs and cough of any duration. The reference standard for PJP was > 1000 copies/mL of P. jirovecii DNA on real-time sputum polymerase chain reaction (PCR). Four potentially predictive variables were selected for regression models: dyspnoea, chest X-ray, haemoglobin and oxygen saturation. Respiratory rate was explored as a replacement for oxygen saturation as pulse oximetry is not always available in resource-poor settings. Results We enrolled 500 participants. After imputation for missing values, there were 56 PJP outcome events. Dyspnoea was not independently associated with PJP. Oxygen saturation and respiratory rate were inversely correlated. Two clinical prediction rules were developed: chest X-ray possible/likely PJP, haemoglobin ≥ 9 g/dL and either oxygen saturation < 94% or respiratory rate. The area under the receiver operating characteristic curve of the clinical prediction rule models was 0.761 (95% CI 0.683–0.840) for the respiratory rate model and 0.797 (95% CI 0.725–0.868) for the oxygen saturation model. Both models had zero probability for PJP for scores of zero, and positive likelihood ratios exceeded 10 for high scores. Conclusion We developed simple clinical prediction rules for PJP, which, if externally validated, could assist decision-making in the WHO seriously ill algorithm.

Incremental yield and cost of urine Determine TB-LAM and sputum induction in seriously ill adults with HIV

Background: Tuberculosis is a major cause of mortality among HIV-infected inpatients, and the World Health Organization (WHO) recommends an algorithm to improve diagnosis. The urine lateral flow lipoarabinomannan (LAM) and sputum Xpert MTB/RIF tests are promising tools, but the optimal diagnostic algorithm is unclear. Methods: This prospective cohort study enrolled HIV-positive inpatients with cough and WHO danger signs. The Xpert MTB/RIF test and mycobacterial culture were performed on sputum using sputum induction when necessary, and the LAM test was performed on stored urine. Tuberculosis was diagnosed by culture from any site. The diagnostic accuracy and costs of testing were determined for single and combined tests. Results: Tuberculosis was confirmed in 169 of 332 patients (50.9%). The yield of LAM, Xpert MTB/RIF on spontaneous sputum (Xpert Spot), and Xpert MTB/RIF on spontaneous or induced sputum (Xpert SI) was 35.5%, 23.1%, and 90.5%, respectively. When LAM was placed before Xpert Spot and Xpert SI in an algorithm, the yield was 50.9% and 92.3%, respectively. Adding culture to Xpert MTB/RIF only increased the yield by 1.2% and 2.7%, respectively. Use of the LAM test reduced costs. Conclusions: Sputum induction is important to increase the yield of Xpert MTB/RIF for seriously ill patients with HIV and cough. LAM testing has little effect on yield when sputum induction is available, but reduces costs and may have other benefits.

Improved Treatment Outcomes With Bedaquiline When Substituted for Second-line Injectable Agents in Multidrug-resistant Tuberculosis: A Retrospective Cohort Study

BACKGROUND Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown. METHODS In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment. RESULTS Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 -.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1-1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97). CONCLUSIONS Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings.