Elizabeth C George

Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial

BACKGROUND Standard first-line antiretroviral therapy for HIV-1 infection includes two nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs), but these drugs have limitations. We assessed the 96 week efficacy and safety of an NtRTI-sparing regimen. METHODS Between August, 2010, and September, 2011, we enrolled treatment-naive adults into this randomised, open-label, non-inferiority trial in treatment-naive adults in 15 European countries. The composite primary outcome was change to randomised treatment before week 32 because of insufficient virological response, no virological response by week 32, HIV-1 RNA concentration 50 copies per mL or higher at any time after week 32; death from any cause; any new or recurrent AIDS event; or any serious non-AIDS event. Patients were randomised in a 1:1 ratio to receive oral treatment with 400 mg raltegravir twice daily plus 800 mg darunavir and 100 mg ritonavir once daily (NtRTI-sparing regimen) or tenofovir-emtricitabine in a 245 mg and 200 mg fixed-dose combination once daily, plus 800 mg darunavir and 100 mg ritonavir once daily (standard regimen). This trial was registered with ClinicalTrials.gov, number NCT01066962. FINDINGS Of 805 patients enrolled, 401 received the NtRTI-sparing regimen and 404 the standard regimen, with median follow-up of 123 weeks (IQR 112-133). Treatment failure was seen in 77 (19%) in the NtRTI-sparing group and 61 (15%) in the standard group. Kaplan-Meier estimated proportions of treatment failure by week 96 were 17·8% and 13·8%, respectively (difference 4·0%, 95% CI -0·8 to 8·8). The frequency of serious or treatment-modifying adverse events were similar (10·2 vs 8·3 per 100 person-years and 3·9 vs 4·2 per 100 person-years, respectively). INTERPRETATION Our NtRTI-sparing regimen was non-inferior to standard treatment and represents a treatment option for patients with CD4 cell counts higher than 200 cells per μL. FUNDING European Union Sixth Framework Programme, Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories.

WHO guidelines on fluid resuscitation in children: missing the FEAST data

The 2013 World Health Organization guidelines continue to recommend rapid fluid resuscitation for children with shock despite evidence that this can be harmful. Sarah Kiguli and colleagues call for WHO to think again

Predicting mortality in sick African children: the FEAST Paediatric Emergency Triage (PET) Score

BackgroundMortality in paediatric emergency care units in Africa often occurs within the first 24 h of admission and remains high. Alongside effective triage systems, a practical clinical bedside risk score to identify those at greatest risk could contribute to reducing mortality.MethodsData collected during the Fluid As Expansive Supportive Therapy (FEAST) trial, a multi-centre trial involving 3,170 severely ill African children, were analysed to identify clinical and laboratory prognostic factors for mortality. Multivariable Cox regression was used to build a model in this derivation dataset based on clinical parameters that could be quickly and easily assessed at the bedside. A score developed from the model coefficients was externally validated in two admissions datasets from Kilifi District Hospital, Kenya, and compared to published risk scores using Area Under the Receiver Operating Curve (AUROC) and Hosmer-Lemeshow tests. The Net Reclassification Index (NRI) was used to identify additional laboratory prognostic factors.ResultsA risk score using 8 clinical variables (temperature, heart rate, capillary refill time, conscious level, severe pallor, respiratory distress, lung crepitations, and weak pulse volume) was developed. The score ranged from 0–10 and had an AUROC of 0.82 (95 % CI, 0.77–0.87) in the FEAST trial derivation set. In the independent validation datasets, the score had an AUROC of 0.77 (95 % CI, 0.72–0.82) amongst admissions to a paediatric high dependency ward and 0.86 (95 % CI, 0.82–0.89) amongst general paediatric admissions. This discriminative ability was similar to, or better than other risk scores in the validation datasets. NRI identified lactate, blood urea nitrogen, and pH to be important prognostic laboratory variables that could add information to the clinical score.ConclusionsEight clinical prognostic factors that could be rapidly assessed by healthcare staff for triage were combined to create the FEAST Paediatric Emergency Triage (PET) score and externally validated. The score discriminated those at highest risk of fatal outcome at the point of hospital admission and compared well to other published risk scores. Further laboratory tests were also identified as prognostic factors which could be added if resources were available or as indices of severity for comparison between centres in future research studies.

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial

BackgroundIn sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9–10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted.Methods/DesignTRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children.The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4–6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness.DiscussionIf confirmed by the trial, a cheap and widely available ‘bundle’ of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented.Trial registrationCurrent Controlled Trials ISRCTN84086586, Approved 11 February 2013

High frequency of blackwater fever among children presenting to hospital with severe febrile illnesses in Eastern Uganda

Summary We have noted a recent upsurge in blackwater fever among children presenting to hospitals in eastern Uganda and speculate that this may relate to a change in policy toward new artemisinin-based combination therapies for malaria.

Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa.

BackgroundHyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas.MethodsIn a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L).ResultsOf 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L).At 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated with death at 72 h (OR 4.62; 95% CI 2.7, 8.0; p < 0.001).ConclusionsIndependently of the underlying diagnosis, HL is a strong risk factor for death at 72 h in children admitted with severe febrile illnesses in Africa. Children able to clear lactate within 8 h had an improved chance of survival. These findings prompt the more widespread use of lactate and LC to identify children with severe disease and monitor response to treatment.Trial registrationISRCTN69856593 Registered 21 January 2009.

Authors’ reply to Southall

Southall made several points about our recent article.1 2 He suggests that “lethal hyperchloraemia” secondary to use of normal saline in FEAST (for boluses or maintenance) resulted in excess mortality. However, he did not comment on the key finding of the trial—that the increased 48 hour mortality was identical in both normal saline bolus (10.6%) and albumin bolus (10.6%) arms compared with the no bolus control group (7.3%).3 Harm was shown for every age group, in every condition, at each …

Implications for paediatric shock management in resource-limited settings: a perspective from the FEAST trial

BackgroundAlthough the African “Fluid Expansion as Supportive therapy” (FEAST) trial showed fluid resuscitation was harmful in children with severe febrile illness managed in resource-limited hospitals, the most recent evidence reviewed World Health Organization (WHO) guidelines continue to recommend fluid boluses in children with shock according to WHO criteria “WHO shock”, arguing that the numbers included in the FEAST trial were too small to provide reasonable certainty.MethodsWe re-analysed the FEAST trial results for all international definitions for paediatric shock including hypotensive (or decompensated shock) and the WHO criteria. In addition, we examined the clinical relevance of the WHO criteria to published and unpublished observational studies reporting shock in resource-limited settings.ResultsWe established that hypotension was rare in children with severe febrile illness complicating only 29/3170 trial participants (0.9%). We confirmed that fluid boluses were harmful irrespective of the definitions of shock including the very small number with WHO shock (n = 65). In this subgroup 48% of bolus recipients died at 48 h compared to 20% of the non-bolus control group, an increased absolute risk of 28%, but translating to an increased relative risk of 240% (p = 0.07 (two-sided Fisher’s exact test)). Examining studies describing the prevalence of the stringent WHO shock criteria in children presenting to hospital we found this was rare (~ 0.1%) and in these children mortality was very high (41.5–100%).ConclusionsThe updated WHO guidelines continue to recommend boluses for a very limited number of children presenting at hospital with the strict definition of WHO shock. Nevertheless, the 3% increased mortality from boluses seen across FEAST trial participants would also include this subgroup of children receiving boluses. Recommendations aiming to differentiate WHO shock from other definitions will invariably lead to “slippage” at the bedside, with the potential of exposing a wider group of children to the harm of fluid-bolus therapy.

Gastroenteritis Aggressive Versus Slow Treatment For Rehydration (GASTRO). A pilot rehydration study for severe dehydration: WHO plan C versus slower rehydration

Background: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children’s responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes. Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate (WHO plan ‘C’ – 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae. Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. Discussion: Results from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial.

Good-quality research: a vital step in improving outcomes in paediatric intensive care units in low- and middle-income countries

Child mortality in Africa is high and there are an estimated 3.5 million deaths annually in children under 5 years of age [1]. A proportion of these deaths will have occurred in hospital where inpa...