INTRODUCTION: Estimating the incidence of antiretroviral discontinuations due to adverse drug reactions (ADRs) is important to inform antiretroviral treatment (ART) regimen recommendations, and to guide prescribing and monitoring policies. Routinely collected clinical data is a useful source of pharmacovigilance data. We estimated the incidences of first-line antiretroviral discontinuations due to ADRs using routine clinical data, and compared them with incidences estimated using data enhanced by folder review, in two South African cohorts. METHODS: We included patients 16 years and older on first-line ART. We selected a stratified random sample of 25% for checking of ART prescription data and reasons for antiretroviral discontinuations retrospectively, including folders reviews where required (enhanced-data sample). We estimated the incidence of antiretroviral discontinuations using Kaplan-Meier and competing risk analyses. RESULTS: In 15396 patients, 40% had a first-line antiretroviral discontinuation by three years on ART. We could determine the reason for 65% of discontinuations using routine data only, and 84% of discontinuations, in the enhanced-data sample of 3837 patients. ADR was the most common reason for discontinuations. In the enhanced-data sample, the cumulative incidence of discontinuations due to ADRs by three years was 30.4% (95% CI: 24.4-36.6) for stavudine; 2.0% (95% CI: 1.5-2.6) for tenofovir, and 1.3% (95% CI: 0.8-2.1) for efavirenz. Using routine data only, the cumulative incidences of discontinuations due to ADRs by three years for stavudine, tenofovir, and efavirenz respectively were 23.9% (95% CI: 20.3-27.7), 1.2% (95% CI: 0.9-1.4) and 0.5% (95% CI: 0.3-0.7). CONCLUSIONS: Although the relative rankings were similar using routine or enhanced data, lack of checking for missing reasons for discontinuation resulted in underestimates of the incidence of antiretroviral discontinuations due to ADRs. Systems to improve data collection of reasons for regimen changes prospectively would increase the capacity of routine data to answer pharmacovigilance questions.

OBJECTIVE: To assess changes and equity in antiretroviral therapy (ART) use in Kenya and South Africa. METHODS: We analysed national population-based household surveys conducted in Kenya and South Africa between 2007 and 2012 for factors associated with lack of ART use among people living with HIV (PLHIV) aged 15-64 years. We considered ART use to be inequitable if significant differences in use were found between groups of PLHIV (e.g. by sex). FINDINGS: ART use among PLHIV increased from 29.3% (95% confidence interval [CI]: 22.8-35.8) to 42.5% (95%CI: 37.4-47.7) from 2007 to 2012 in Kenya and 17.4% (95%CI: 14.2-20.9) to 30.3% (95%CI: 27.2-33.6) from 2008 to 2012 in South Africa. In 2012, factors independently associated with lack of ART use among adult Kenyan PLHIV were rural residency (adjusted odds ratio [aOR] 1.98, 95%CI: 1.23-3.18), younger age (15-24 years: aOR 4.25, 95%CI: 1.7-10.63, and 25-34 years: aOR 5.16, 95%CI: 2.73-9.74 versus 50-64 years), nondisclosure of HIV status to most recent sex partner (aOR 2.41, 95%CI: 1.27-4.57) and recent recreational drug use (aOR 2.50, 95%CI: 1.09-5.77). Among South African PLHIV in 2012, lack of ART use was significantly associated with younger age (15-24 years: aOR 4.23, 95%CI: 2.56-6.70, and 25-34 years: aOR 2.84, 95%CI: 1.73-4.67, versus 50-64 years), employment status (aOR 1.61, 95%CI: 1.16-2.23 in students versus unemployed), and recent recreational drug use (aOR 4.56, 95%CI: 1.79-11.57). CONCLUSION: Although we found substantial increases in ART use in both countries over time, we identified areas needing improvement including among rural Kenyans, students in South Africa, and among young people and drug users in both countries.

INTRODUCTION: Tenofovir has been associated with decline in kidney function, but in patients with low baseline kidney function, improvements over time have been reported. Additionally, the magnitude and trajectory of estimated glomerular filtration rate (eGFR) changes may differ according to how eGFR is calculated. We described changes in eGFR over time, and the incidence of, and risk factors for, kidney toxicity, in a South African cohort. METHODS: We included antiretroviral-naive patients ≥16 years old who started tenofovir-containing antiretroviral therapy (ART) between 2002 and 2013. We calculated eGFR using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft-Gault equations. We described changes in eGFR from ART initiation using linear mixed effects regression. We described the incidence of eGFR <30 mL/min on treatment, and identified associations with low eGFR using Cox regression. RESULTS: We included 15156 patients with median age of 35.4 years (IQR 29.9-42.0), median CD4 cell count of 168 cells/microL (IQR 83-243), and median eGFR (MDRD) of 98.6 mL/min (IQR 84.4-115.6). Median duration of follow up on tenofovir was 12.9 months (IQR 5.1-23.3). Amongst those with a baseline and subsequent eGFR available, mean eGFR change from baseline at 12 months was -4.4 mL/min (95% CI -4.9 to -4.0), -2.3 (-2.5 to -2.1), and 0.6 (0.04 to 1.2) in those with baseline eGFR ≥90 mL/min; and 11.9 mL/min (11.0 to 12.7), 14.6 (13.5 to 15.7), and 11.0 (10.3 to 11.7), in those with baseline eGFR <90 mL/min, according to the MDRD, CKD-EPI (n = 11 112), and Cockcroft-Gault (n = 9 283) equations, respectively. Overall, 292 (1.9%) patients developed eGFR <30 mL/min. Significant associations with low eGFR included older age, baseline eGFR <60 mL/min, CD4 count <200 cells/microL, body weight <60 kg, and concomitant protease inhibitor use. CONCLUSION: Patients on tenofovir with baseline eGFR ≥90 mL/min experienced small but significant declines in eGFR over time when eGFR was estimated using the MDRD or CKD-EPI equations. However, eGFR increased in patients with eGFR <90 mL/min, regardless of which estimating equation was used. Decreases to below 30 mL/min were uncommon. In settings with limited access to laboratory testing, monitoring guidelines should consider focusing on higher risk patients.

INTRODUCTION: There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010. METHODS: We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity. RESULTS: We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively. CONCLUSIONS: While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Limited 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 Africa's 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.

INTRODUCTION: The National HIV & Tuberculosis Health Care Worker (HCW) Hotline provides advice on the management of suspected adverse drug reactions (ADRs). We describe suspected ADRs reported to the hotline by HCWs, concordance with advice, and patient outcomes. METHODS: We reviewed suspected ADRs in HIV-infected patients, patients taking antiretrovirals and patients taking anti-tuberculosis therapy reported from May 2013 to October 2014. We performed causality assessment using the World Health Organization Uppsala Monitoring Centre (WHO-UMC) criteria. We included suspected ADRs categorized as certain, probable or possible in further analysis. RESULTS: We received 772 ADR reports, of which 87/772 (11.3 %) were classified as certain, 176/772 (22.8 %) as probable, 361/772 (46.8 %) as possible, and 148/772 (19.2 %) as unlikely or unassessable. The most frequent ADRs were rash, drug-induced liver injury (DILI) and kidney injury, comprising 110/624 (17.6 %), 87/624 (13.9 %), and 77/624 (12.3 %), respectively. The ADR was severe in 27.3 % of rashes, 36.4 % of kidney injury reports and 88.5 % of DILI reports. Most frequently implicated drugs, either alone or in combination with other potentially causative drugs, were efavirenz (rashes), efavirenz and anti-tuberculosis drugs (DILI) and tenofovir (kidney injury). In 383 cases with HCW follow-up, 254 (66.3 %) improved, 9 (2.3 %) had complete resolution, 32 (8.4 %) remained unchanged, 6 (1.6 %) deteriorated, 10 (2.6 %) died and 72 (18.8 %) had unknown outcome. Advice provided was followed in 93.2 % of these cases. Of 223 ADRs with preventability data, 40 (17.9 %) were preventable. CONCLUSION: Queries about rashes, DILIs and kidney injuries were common. Detection and management of these ADRs should be included in HCW training. In cases with follow-up, concordance with advice was high, and HCWs reported improvement in the majority.