Anticoagulation control among patients on vitamin K antagonists in nine countries in Sub-Saharan Africa.

Vitamin K antagonists (VKA) is the primary anticoagulant in most settings of Sub-Saharan Africa. Understanding the quality of anticoagulation services in the continent is vital in optimising the intended benefits. This study assessed the quality of anticoagulation and associated factors among VKA-treated patients in nine SSA countries. We conducted a retrospective cohort study of randomly selected patients on anticoagulation from 20 clinics in Botswana, the Democratic Republic of Congo, Ethiopia, Gambia, Ghana, Mozambique, Nigeria, Tanzania, and South Africa. Eligible participants were those on VKAs for at least three months and with at least four international normalised ratios (INR) results in 2019-2021. We report the proportion of INR values in the therapeutic range, time-in-therapeutic range (TTR) using the Rosendaal method, and the proportion of patients with TTR ≥ 65% (optimal anticoagulation). The mean age was 51.1(16.1) years, and 64.2% were women. The most common indications for VKA included venous thromboembolism (29.6%), prosthetic valves (26.7%) and atrial fibrillation/flutter (30.1%). We analysed 6743 INR tests from 1011 participants, and of these, 48.5% were sub-therapeutic, 34.1% therapeutic, and 17.4% were supratherapeutic relative to disease-specific reference ranges. TTR was calculated for 660 patients using 4927 INR measurements. The median (interquartile range [IQR]) TTR was 35.8(15.9,57.2) %. Optimal anticoagulation control was evident in 19.2% of participants, varying from 2.7% in Tanzania to 23.1% in Ethiopia. The proportion of patients with TTR ≥ 65% was 15,4% for prosthetic heart valves, 21.1% for venous thromboembolism and 23.7% for atrial fibrillation or flutter. Countries with universal health coverage had higher odds of optimal anticoagulation control (adjusted odds ratio (aOR) 1.79, 95% confidence interval [CI], 1.15- 2.81, p = 0.01). Patients on VKAs for different therapeutic indications in SSA had suboptimal TTR. Universal health coverage increased the odds of achieving TTR by 79%. The evidence calls for more intensive warfarin management strategies in SSA, including providing VKA services without out-of-pocket payments.

Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.

AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.

Accuracy of measures for antiretroviral adherence in people living with HIV.

BACKGROUND: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings. OBJECTIVES: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment. SEARCH METHODS: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity. DATA COLLECTION AND ANALYSIS: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis. MAIN RESULTS: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results. AUTHORS' CONCLUSIONS: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

Health Technology Assessment in Support of National Health Insurance in South Africa.

South Africa has embarked on major health policy reform to deliver universal health coverage through the establishment of National Health Insurance (NHI). The aim is to improve access, remove financial barriers to care, and enhance care quality. Health technology assessment (HTA) is explicitly identified in the proposed NHI legislation and will have a prominent role in informing decisions about adoption and access to health interventions and technologies. The specific arrangements and approach to HTA in support of this legislation are yet to be determined. Although there is currently no formal national HTA institution in South Africa, there are several processes in both the public and private healthcare sectors that use elements of HTA to varying extents to inform access and resource allocation decisions. Institutions performing HTAs or related activities in South Africa include the National and Provincial Departments of Health, National Treasury, National Health Laboratory Service, Council for Medical Schemes, medical scheme administrators, managed care organizations, academic or research institutions, clinical societies and associations, pharmaceutical and devices companies, private consultancies, and private sector hospital groups. Existing fragmented HTA processes should coordinate and conform to a standardized, fit-for-purpose process and structure that can usefully inform priority setting under NHI and for other decision makers. This transformation will require comprehensive and inclusive planning with dedicated funding and regulation, and provision of strong oversight mechanisms and leadership.

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).

Improving anticoagulation in sub-Saharan Africa: What are the challenges and how can we overcome them?

Patients in sub-Saharan Africa generally have poor anticoagulation control. We review the potential reasons for this poor control, as well as the potential solutions. Challenges include the affordability and centralisation of anticoagulation care, problems with access to medicines and international normalised ratio monitoring, the lack of locally validated standardized dosing protocols, and low levels of anticoagulation knowledge among healthcare workers and patients. Increasing numbers of patients will need anticoagulation in the future because of the increasing burden of noncommunicable disease in the region. We propose that locally developed "warfarin care bundles" which address multiple anticoagulation challenges in combination may be the most appropriate solution in this setting currently.

Anticoagulation in sub-Saharan Africa: Are direct oral anticoagulants the answer? A review of lessons learnt from warfarin.

Warfarin has existed for >7 decades and has been the anticoagulant of choice for many thromboembolic disorders. The recent introduction of direct-acting oral anticoagulants (DOACs) has, however, caused a shift in preference by healthcare professionals all over the world. DOACs have been found to be at least as effective as warfarin in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism. In sub-Saharan Africa, however, the widespread use of DOACs has been hampered mainly by their higher acquisition costs. As the drugs come off patent, their use in sub-Saharan Africa is likely to increase. However, very few trials have been conducted in African settings, and safety concerns will need to be addressed with further study before widespread adoption into clinical practice.

Safety and Effectiveness of Isoniazid Preventive Therapy in Pregnant Women Living with Human Immunodeficiency Virus on Antiretroviral Therapy: An Observational Study Using Linked Population Data.

BACKGROUND: Isoniazid preventive therapy (IPT) is widely used to protect against tuberculosis (TB) in people living with human immunodeficiency virus (HIV). Data on the safety and efficacy of IPT in pregnant women living with HIV (PWLHIV) are mixed. We used an individual-level, population-wide health database to examine associations between antenatal IPT exposure and adverse pregnancy outcomes, maternal TB, all-cause mortality, and liver injury during pregnancy through 12 months postpartum. METHODS: We used linked routine electronic health data generated in the public sector of the Western Cape, South Africa, to define a cohort of PWLHIV on antiretroviral therapy. Pregnancy outcomes were assessed using logistic regression; for maternal outcomes we applied a proportional hazards model with time-updated IPT exposure. RESULTS: Of 43 971 PWLHIV, 16.6% received IPT. Women who received IPT were less likely to experience poor pregnancy outcomes (adjusted odds ratio [aOR], 0.83 [95% confidence interval {CI}, .78-.87]); this association strengthened with IPT started after the first trimester compared with none (aOR, 0.71 [95% CI, .65-.79]) or with first-trimester exposure (aOR, 0.64 [95% CI, .55-.75]). IPT reduced the risk of TB by approximately 30% (aHR, 0.71 [95% CI, .63-.81]; absolute risk difference, 1518/100 000 women). The effect was modified by CD4 cell count with protection conferred if CD4 count was ≤350 cells/µL (aHR, 0.51 [95% CI, .41-.63]) vs 0.93 [95% CI, .76-1.13] for CD4 count >350 cells/µL). CONCLUSIONS: This analysis of programmatic data is reassuring regarding the safety of antenatal IPT, with the greatest benefits against TB disease observed in women with CD4 count ≤350 cells/µL.

Detectable HIV-1 in semen in individuals with very low blood viral loads.

BACKGROUND: Several reports indicate that a portion (5-10%) of men living with HIV-1 intermittently shed HIV-1 RNA into seminal plasma while on long term effective antiretroviral therapy (ART). This is highly suggestive of an HIV-1 reservoir in the male genital tract. However, the status of this reservoir in men living with HIV-1 who are not under treatment is underexplored and has implications for understanding the origins and evolution of the reservoir. FINDING: Forty-three HIV-1 positive, antiretroviral therapy naïve study participants attending a men's health clinic were studied. Semen viral loads and blood viral loads were generally correlated, with semen viral loads generally detected in individuals with blood viral loads > 10,000 cp/ml. However, we found 1 individual with undetectable viral loads (<20cp/ml) and 2 individuals with very low blood viral load (97 and 333cp/ml), but with detectable HIV-1 in semen (485-1157 copies/semen sample). Blood viral loads in the first individual were undetectable when tested three times over the prior 5 years. CONCLUSIONS: Semen HIV-1 viral loads are usually related to blood viral loads, as we confirm. Nonetheless, this was not true in a substantial minority of individuals suggesting unexpectedly high levels of replication in the male genital tract in a few individuals, despite otherwise effective immune control. This may reflect establishment of a local reservoir of HIV-1 populations.

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.

Adverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases.

BACKGROUND: Bedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme. METHODS: We reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. "Confirmed ADRs" included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient's death as follows: major contributor, contributor or non-contributor. RESULTS: Thirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as "possible" and seven as "probable". Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths. CONCLUSIONS: Confirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity.

A comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa.

BACKGROUND: Accurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods. METHODS: Cross-sectional population-based survey in KwaZulu-Natal, South Africa. Individuals 15-59 years were eligible. Interviews included questions about ARV use. Rapid HIV testing was performed at the participants' home. Blood specimens were collected for ARV detection, LAg-Avidity HIV incidence testing and viral load quantification in HIV-positive individuals. Multivariate logistic regression models were used to identify socio-demographic covariates associated with discordance between self-reported ART and ARV detection. RESULTS: Of the 5649 individuals surveyed, 1423 were HIV-positive. Median age was 34 years and 76.3% were women. ART coverage was estimated at 51.4% (95%CI:48.5-54.3), 53.1% (95%CI:50.2-55.9) and 56.1% (95%CI:53.5-58.8) using self-reported ART, ARV detection and both methods combined (classified as ART exposed if ARV detected and/or ART reported) respectively. ART coverage estimates using the 3 methods were fairly similar within sex and age categories except in individuals aged 15-19 years: 33.3% (95%CI:23.3-45.2), 33.8% (95%CI:23.9-45.4%) and 44.3% (95%CI:39.3-46.7) using self-reported ART, ARV detection and both methods combined. Viral suppression below 1000cp/mL in individuals on ART was estimated at 89.8% (95%CI:87.3-91.9), 93.1% (95%CI:91.0-94.8) and 88.7% (95%CI:86.2-90.7) using self-reported ART, ARV detection and both methods combined respectively. HIV incidence was estimated at 1.4 (95%CI:0.8-2.0) new cases/100 person-years when employing no measure of ARV use, 1.1/100PY (95%CI:0.6-1.7) using self-reported ART, and 1.2/100PY (95%CI:0.7-1.7) using ARV detection. In multivariate analyses, individuals aged 15-19 years had a higher risk of discordance on measures of ARV exposure (aOR:9.4; 95%CI:3.9-22.8), while migrants had a lower risk (aOR:0.3; 95%CI:0.1-0.6). CONCLUSIONS: In KwaZulu-Natal, the method of identifying ARV use had little impact on estimates of ART coverage, viral suppression rate and HIV incidence. However, discordant results were more common in younger individuals. This may skew estimates of ART coverage and viral suppression, particularly in adolescent surveys.

Comparison of six methods to estimate adherence in an ART-naïve cohort in a resource-poor setting: which best predicts virological and resistance outcomes?

BACKGROUND: Incomplete adherence to antiretroviral therapy (ART) results in virologic failure and resistance. It remains unclear which adherence measure best predicts these outcomes. We compared six patient-reported and objective adherence measures in one ART-naïve cohort in South Africa. METHODS: We recruited 230 participants from a community ART clinic and prospectively collected demographic data, CD4 count and HIV-RNA at weeks 0, 16 and 48. We quantified adherence using 3-day self-report (SR), clinic-based pill count (CPC), average adherence by pharmacy refill (PR-average), calculation of medication-free days (PR-gaps), efavirenz therapeutic drug monitoring (TDM) and an electronic adherence monitoring device (EAMD). Associations between adherence measures and virologic and genotypic outcomes were modelled using logistic regression, with the area under the curve (AUC) from the receiver operator characteristic (ROC) analyses derived to assess performance of adherence measures in predicting outcomes. RESULTS: At week 48 median (IQR) adherence was: SR 100% (100-100), CPC 100% (95-107), PR-average 103% (95-105), PR-gaps 100% (95-100) and EAMD 86% (59-94), and efavirenz concentrations were therapeutic (>1 mg/L) in 92%. EAMD, PR-average, PR-gaps and CPC best predicted virological outcome at week 48 with AUC ROC of 0.73 (95% CI 0.61-0.83), 0.73 (95% CI 0.61-0.85), 0.72 (95% CI 0.59-0.84) and 0.64 (95% CI 0.52-0.76) respectively. EAMD, PR-gaps and PR-average were highly predictive of detection of resistance mutations at week 48, with AUC ROC of 0.92 (95% CI 0.87-0.97), 0.86 (0.67-1.0) and 0.83 (95% CI 0.65-1.0) respectively. SR and TDM were poorly predictive of outcomes at week 48. CONCLUSION: EAMD and both PR measures predicted resistance and virological failure similarly. Pharmacy refill data is a pragmatic adherence measure in resource-limited settings where electronic monitoring is unavailable. Trial registration The trial was retrospectively registered in the Pan African Clinical Trials Registry, number PACTR201311000641402, on the 13 Sep 2013 ( www.pactr.org ). The first participant was enrolled on the 12th July 2012. The last patient last visit (week 48) was 15 April 2014.

N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review.

AIMS: N-acetylcysteine (NAC) may be useful in the management of non-paracetamol drug-induced liver injury (DILI). Our objective was to review systematically evidence for the use of NAC as a therapeutic option for non-paracetamol DILI. METHODS: We searched for randomized controlled trials (RCTs) and prospective cohort studies. We searched several bibliographic databases, grey literature sources, conference proceedings and ongoing trials. Our pre-specified primary outcomes were all cause and DILI related mortality, time to normalization of liver biochemistry and adverse events. Secondary outcomes were proportion receiving liver transplant, time to transplantation, transplant-free survival and hospitalization duration. RESULTS: We identified one RCT of NAC vs. placebo in patients with non-paracetamol acute liver failure. There was no difference in the primary outcomes of overall survival at 3 weeks between NAC [70%, 95% confidence interval (CI) = 60%, 81%, n = 81] and placebo (66%, 95% CI = 56%, 77%, n = 92). NAC significantly improved the secondary outcomes of transplant-free survival compared with placebo: 40% NAC (95% CI = 28%, 51%) vs. 27% placebo (95% CI = 18%, 37%). A subgroup analysis according to aetiology found improved transplant-free survival in patients with non-paracetamol DILI, NAC (58%, n = 19) vs. placebo (27%, n = 26), odds ratio (OR) 0.27 (95% CI = 0.076, 0.942). Overall survival was similar, NAC (79%) vs. placebo (65%);, OR 0.50 (95% CI = 0.13, 1.98). CONCLUSION: Current available evidence is limited and does not allow for any firm conclusions to be made regarding the role of NAC in non-paracetamol DILI. We therefore highlight the need for further research in this area.

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.

Viral suppression following switch to second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch.

BACKGROUND: High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification. METHODS: Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression. RESULTS: One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77-263) and 4.3 log10 copies/mL (IQR, 3.8-4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥ 1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL. CONCLUSIONS: Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.

A review and economic analysis of the dapivirine vaginal ring as HIV pre-exposure prophylaxis for women, to inform South African public-sector guidelines.

BACKGROUND: South Africa has a high HIV incidence and oral pre-exposure prophylaxis (PrEP) is available as public-sector standard of care. Access to alternative prevention methods for women may further reduce HIV acquisition. SETTING: South African public-sector. METHODS: We performed a systematic search for high-quality up-to-date guidelines recommending dapivirine ring as PrEP using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-Adolopment process. We appraised the systematic review and randomised controlled trial (RCT) evidence underpinning the selected guideline's recommendations and conducted a cost-effectiveness analysis. The GRADE Evidence-to-Decision framework guided the adaptation of source guideline recommendations, according to our local context. RESULTS: We identified the 2021 World Health Organization PrEP Guidelines, informed by two placebo-controlled RCTs, which were included in a contemporaneous systematic review. There were 23 fewer HIV acquisitions per 1000 clients with dapivirine ring versus placebo (95% confidence interval 10-34), with no increase in adverse events (moderate certainty evidence). We found no RCTs comparing dapivirine to oral PrEP, or amongst adolescent/pregnant/breastfeeding clients. Dapivirine is less cost-effective than oral PrEP at $14.59/ring, at the current price. CONCLUSION: The source guideline recommendation was adapted for the local context. Dapivirine ring appears to be less efficacious than oral PrEP, although comparative studies are lacking. Data in adolescents and pregnancy are also lacking, currently limiting the use of dapivirine as an alternative for women unable to take oral PrEP. At the current price, dapivirine is not cost-effective and unaffordable for inclusion in the South African Essential Medicines List.