A Randomized Controlled Trial of Intravenous N-Acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.

BACKGROUND: Liver injury is a common complication of anti-tuberculosis therapy. N-acetylcysteine (NAC) used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of intravenous NAC in hospitalized adult patients with anti-tuberculosis drug-induced liver injury (AT-DILI). The primary endpoint was time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality, and adverse events. RESULTS: Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female, 89 (87%) were HIV positive. Median (IQR) serum ALT and bilirubin at presentation were 462 (266-790) U/L and 56 (25-100) µmol/L, respectively. Median time to ALT <100 U/L was 7.5 (6-11) days in the NAC arm and 8 (5-13) days in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 [6-15] days) than in the placebo arm (18 [10-25] days) (HR, 1.73; 95% CI, 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC (nausea and vomiting [3], anaphylaxis [1], pain at drip site [1]). CONCLUSIONS: NAC did not shorten time to ALT <100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI. CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Registry (SANCTR: DOH-27-0414-4719).

Serious adverse drug reactions at two children's hospitals in South Africa.

BACKGROUND: The high HIV prevalence in South Africa may potentially be shaping the local adverse drug reaction (ADR) burden. We aimed to describe the prevalence and characteristics of serious ADRs at admission, and during admission, to two South African children's hospitals. METHODS: We reviewed the folders of children admitted over sequential 30-day periods in 2015 to the medical wards and intensive care units of each hospital. We identified potential ADRs using a trigger tool developed for this study. A multidisciplinary team assessed ADR causality, type, seriousness, and preventability through consensus discussion. We used multivariate logistic regression to explore associations with serious ADRs. RESULTS: Among 1050 patients (median age 11 months, 56% male, 2.8% HIV-infected) with 1106 admissions we found 40 serious ADRs (3.8 per 100 drug-exposed admissions), including 9/40 (23%) preventable serious ADRs, and 8/40 (20%) fatal or near-fatal serious ADRs. Antibacterials, corticosteroids, psycholeptics, immunosuppressants, and antivirals were the most commonly implicated drug classes. Preterm neonates and children in middle childhood (6 to 11 years) were at increased risk of serious ADRs compared to infants (under 1 year) and term neonates: adjusted odds ratio (aOR) 5.97 (95% confidence interval 1.30 to 27.3) and aOR 3.63 (1.24 to 10.6) respectively. Other risk factors for serious ADRs were HIV infection (aOR 3.87 (1.14 to 13.2) versus HIV-negative) and increasing drug count (aOR 1.08 (1.04 to 1.12) per additional drug). CONCLUSIONS: Serious ADR prevalence in our survey was similar to the prevalence found elsewhere. In our setting, serious ADRs were associated with HIV-infection and the antiviral drug class was one of the most commonly implicated. Similar to other sub-Saharan African studies, a large proportion of serious ADRs were fatal or near-fatal. Many serious ADRs were preventable.

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.

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.

Prognostic indicators in the World Health Organization's algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis.

BACKGROUND: Criteria for the 2007 WHO algorithm for diagnosing tuberculosis among HIV-infected seriously ill patients are the presence of one or more danger signs (respiratory rate > 30/min, heart rate > 120/min, temperature > 39 °C, and being unable to walk unaided) and cough ≥ 14 days. Determining predictors of poor outcomes among HIV-infected inpatients presenting with WHO danger signs could result in improved treatment and diagnostic algorithms. METHODS: We conducted a prospective cohort study of inpatients presenting with any duration of cough and WHO danger signs to two regional hospitals in Cape Town, South Africa. The primary outcome was all-cause mortality up to 56 days post-discharge, and the secondary outcome a composite of any one of: hospital admission for > 7 days, died in hospital, transfer to a tertiary level or tuberculosis hospital. We first assessed the WHO danger signs as predictors of poor outcomes, then assessed the added value of other variables selected a priori for their ability to predict mortality in common respiratory opportunistic infections (CD4 count, body mass index (BMI), being on antiretroviral therapy (ART), hypotension, and confusion) by comparing the receiver operating characteristic (ROC) area under the curve (AUC) of the two multivariate models. RESULTS: 484 participants were enrolled, median age 36, 66% women, 53% had tuberculosis confirmed on culture. The 56-day mortality was 13.2%. Inability to walk unaided, low BMI, low CD4 count, and being on ART were independently associated with poor outcomes. The multivariate model of the WHO danger signs showed a ROC AUC of 0.649 (95% CI 0.582-0.717) for predicting 56-day mortality, which improved to ROC AUC of 0.740 (95% CI 0.681-0.800; p = 0.004 for comparison between the two ROC AUCs) with the multivariate model including the a priori selected variables. Findings were similar in sub-analyses of participants with culture-positive tuberculosis and with cough duration ≥ 14 days. CONCLUSION: The study design prevented a rigorous evaluation of the prognostic value of the WHO danger signs. Our prognostic model could result in improved algorithms, but needs to be validated.

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

PURPOSE: 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. METHODS: We described severe skin reaction cases in patients taking cART admitted to Groote Schuur Hospital in Cape Town, South Africa, between 2006 and 2012. We included those patients who developed a severe skin reaction within 120 days of cART initiation in a case-control analysis. We identified control patients matched on date of cART initiation and primary care facility by linkage with the Western Cape electronic provincial HIV database. We conducted a conditional (fixed effects) logistic regression modelling. RESULTS: We identified 169 severe skin reactions in patients on cART. The most common presentations were Stevens Johnson syndrome/toxic epidermal necrolysis (49%) and drug hypersensitivity syndrome (36%). One hundred forty-one patients were female, of which 27 were pregnant. Median duration of hospitalization was 12 days (interquartile range 8 to 19) and six patients died. We included 91 cases and 361 matched controls in the analysis. Severe skin reaction was associated with nevirapine exposure, adjusted odds ratio of 7.6 (95%CI 3.7 to 15.7) and with pregnancy, adjusted odds ratio 3.7 (95%CI 1.3 to 10.8) compared with men. CONCLUSIONS: Severe skin reactions resulted in prolonged admission to hospital in this setting. We found that nevirapine use and pregnancy are independently associated with severe skin reaction. Copyright © 2016 John Wiley & Sons, Ltd.

Cases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa.

BACKGROUND: Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. METHODS: We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes. RESULTS: We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6-42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%). CONCLUSIONS: Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.

Mortality from adverse drug reactions in adult medical inpatients at four hospitals in South Africa: a cross-sectional survey.

AIMS: Fatal adverse drug reactions (ADRs) are important causes of death, but data from resource-limited settings are scarce. We determined the proportion of deaths in South African medical inpatients attributable to ADRs, and their preventability, stratified by human immunodeficiency virus (HIV) status. METHODS: We reviewed the folders of all patients who died over a 30 day period in the medical wards of four hospitals. We identified ADR-related deaths (deaths where an ADR was 'possible', 'probable' or 'certain' using WHO-UMC criteria and where the ADR contributed to death). We determined preventability according to previously published criteria. RESULTS: ADRs contributed to the death of 2.9% of medical admissions and 56 of 357 deaths (16%) were ADR-related. Tenofovir, rifampicin and co-trimoxazole were the most commonly implicated drugs. 43% of ADRs were considered preventable. The following factors were independently associated with ADR-related death: HIV-infected patients on antiretroviral therapy (adjusted odds ratio (aOR) 4.4, 95% confidence interval (CI) 1.6, 12), exposure to more than seven drugs (aOR 2.5, 95% CI 1.3, 4.8) and increasing comorbidity score (aOR 1.3, 95% CI 1.1, 1.7). CONCLUSIONS: In our setting, where HIV and tuberculosis are highly prevalent, fatal in-hospital ADRs were more common than reported in high income settings. Most deaths were attributed to drugs used in managing HIV and tuberculosis. A large proportion of the ADRs were preventable, highlighting the need to strengthen systems for health care worker training and support.

Short term adherence tool predicts failure on second line protease inhibitor-based antiretroviral therapy: an observational cohort study.

BACKGROUND: Most patients who experience virologic failure (VF) on second line antiretroviral therapy (ART) in low-middle income countries fail due to poor adherence rather than antiretroviral resistance. A simple adherence tool designed to detect VF would conserve resources by rationally limiting need for viral load (VL) testing and, in those countries with access to third line ART, the need for resistance testing. METHODS: We conducted an observational cohort study of patients who initiated second line ART at a clinic in Kwazulu-Natal, South Africa. Using clinical and pharmacy refill data extracted from the clinic's electronic database, we determined risk factors for VF. Three different methods of calculating short term pharmacy refill adherence were evaluated and compared with long term adherence since second line initiation. We also explored the ability of differing durations of short term pharmacy refill to predict VF on second line ART. RESULTS: We included 274 patients with a median follow up of 27 months on second line ART. VF ranged between 3% and 16% within each six month interval after initiating second line ART. 243 patients with at least one VL after 4 months on second line were analysed in the statistical analysis. Pharmacy refill adherence assessed over shorter periods (4 to 6 months) predicted virologic suppression as well as pharmacy refill assessed over longer periods. The risk of VF fell 73% with each 10% increase in adherence measured from pharmacy refills over a 4 month period. Low CD4 count at second line ART initiation was a significant independent risk factor for VF. CONCLUSION: Patients identified as poorly adherent by short term pharmacy refill are at risk for VF on second line ART. This pragmatic adherence tool could assist in identifying patients who require adherence interventions, and help rationalize use of VL monitoring and resistance testing among patients on second line ART.

Establishing a database for sickle cell disease patient mapping and survival tracking: The sickle pan-african research consortium Nigeria example.

Background: The Sickle Pan-African Research Consortium (SPARCO) and Sickle Africa Data Coordinating Center (SADaCC) were set up with funding from the US National Institute of Health (NIH) for physicians, scientists, patients, support groups, and statisticians to collaborate to reduce the high disease burden and alleviate the impact of Sickle Cell Disease (SCD) in Africa. For 5 years, SPARCO and SADaCC have been collecting basic clinical and demographic data from Nigeria, Tanzania, and Ghana. The resulting database will support analyses to estimate significant clinical events and provide directions for targeting interventions and assessing their impacts. Method: The Nigerian study sited at Centre of Excellence for Sickle Cell Disease Research and Training (CESRTA), University of Abuja, adopted REDCap for online database management. The case report form (CRF) was adapted from 1,400 data elements adopted by SPARCO sites. It captures 215 data elements of interest across sub-sites, i.e., demographic, social, diagnostic, clinical, laboratory, imaging, and others. These were harmonized using the SADaCC data dictionary. REDCap was installed on University of Abuja cloud server at https://www.redcap.uniabuja.edu.ng. Data collected at the sites are sent to CESRTA for collation, cleaning and uploading to the database. Results: 7,767 people living with sickle cell disease were enrolled at 25 health institutions across the six zones in Nigeria with 5,295 having had at least one follow-up visit with their clinical data updated. They range from 44 to 1,180 from 3 centers from South East, 4 from South, 5 from South West, 8 from North Central, 4 in North West and 3 in the North East. North West has registered 1,383 patients, representing 17.8%; North East, 359 (4.6%); North Central, 2,947 (37.9%); South West, 1,609 (20.7%); South, 442 (5.7%) and South East, 1,027 patients (13.2%). Conclusion: The database is being used to support studies including analysis of clinical phenotypes of SCD in Nigeria, and evaluation of Hydroxyurea use in SCD. Reports undergoing review in journals have relied on the ease of data access in REDCap. The database is regularly updated by batch and individual record uploads while we are utilizing REDCap's in-built functions to generate simple statistic.