Browsing by Author "Gibb, Diana M"
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Item Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial(The Lancet Infectious Diseases, 2016) Mulenga, Veronica; Musiime, Victor.; Kekitiinwa, Adeodata; Cook, Adrian D; Abongomera, George; Kenny, Julia; Chabala, Chisala; Mirembe, Grace; Asiimwe, Alice; Owen-Powell, Ellen; Burger, David; McIlleron, Helen; Klein, Nigel.; Chintu, Chifumbe; Thomason, Margaret J.; Kityo, Cissy.; Walker, Sarah A.; Gibb, Diana MBackground WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fi xed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. Methods In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2–4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. Findings Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2–4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75–1·29]; abacavir vs stavudine: HR 0·88 [0·67–1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). Interpretation All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profi le and oncedaily dosing favours abacavir for African children, supporting WHO 2013 guidelines.Item The cost-effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa(John Wiley & Sons Ltd, 2020) Walker, Simon M.; Cox, Edward; Revill, Paul; Musiime, Victor; Bwakura-Dangarembizi, Mutsa; Mallewa, Jane; Cheruiyot, Priscilla; Maitland, Kathryn; Ford, Nathan; Gibb, Diana M; Walker, Sarah A.; Soares, MartaMany HIV-positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced-prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4 <100 cells/mm3. We investigated the cost-effectiveness of this enhanced-prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4 <200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision-analytic model was developed to estimate the cost-effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard-prophylaxis, enhanced-prophylaxis, standard-prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced-prophylaxis (CrAg-positive) or standard-prophylaxis (CrAg-negative), the second to enhanced-prophylaxis (CrAg-positive) or enhanced-prophylaxis without fluconazole (CrAg-negative) and the third to standardprophylaxis with fluconazole (CrAg-positive) or without fluconazole (CrAg-negative). The model estimated costs, life-years and quality-adjusted life-years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced-prophylaxis was cost-effective at cost-effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost-effectiveness ratio (ICER) of US$157 per QALY in the CD4 <200 cells/mm3 population providing enhancedprophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4 <100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US $722 per QALY). Results were sensitive to prices of the enhanced-prophylaxis components. Enhanced-prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced-prophylaxis still conveyed health gains in CrAg-negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost-effective unless the price of CrAg testing fell below US$2.30. Conclusions: The REALITY enhanced-prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost-effective. Efforts should continue to ensure that components are accessed at lowest available prices.Item Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial(Elsevier Ltd., 2018) Mallewa, Jane.; Berkley, James A; Szubert, Alexander J.; Mugyenyi, Peter; Chidziva, Ennie; Thomason, Margaret J; Walker, Sarah A.; Chepkorir, Priscilla; Abongomera, George; Baleeta, Keith; Etyang, Anthony; Warambwa, Colin; Melly, Betty; Gibb, Diana M; Prendergast, Andrew J; Mudzingwa, Shepherd; Kelly, Christine; Agutu, Clara; Wilkes, Helen; Nkomani, Sanele; Musiime, Victor; Lugemwa, Abbas; Pett, Sarah L; Bwakura-Dangarembizi, MutsaIn sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing readyto- use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only. Methods We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks’ of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5–12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16–18 kg/m² or BMI-for-age Z scores <–3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374). Findings Between June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0–13·1) participants allocated to RUSF and 92 (10·3%, 8·5–12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79–1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45). Interpretation In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present. Funding Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).Item Hospitalization for severe malnutrition among HIV-infected children starting antiretroviral therapy(Wolters Kluwer Health, 2011) Prendergast, Andrew; Mutsa, F; Bwakura-Dangarembizi; Cook, Adrian D; Bakeera-Kitaka, Sabrina; Natukunda, Eva; Ntege, Patricia Nahirya; Nathoo, Kusum J; Karungi, Christine; Lutaakome, Joseph; Kekitiinwa, Adeodata; Gibb, Diana MHIV and malnutrition overlap and interact in resourcelimited settings [1]. There is high HIV prevalence among children with severe malnutrition, and mortality in these children is approximately three-fold higher than in HIV-uninfected children with severe malnutrition [2]. Similarly, malnutrition is a major risk factor for mortality in HIV-infected children. Studies from resource-limited settings, in which the majority of HIV-infected children have severe immunosuppression and poor nutritional status at presentation, consistently report 5–10% early mortality among HIV-infected children starting antiretroviral therapy (ART) [3,4]. Severe malnutrition presents as two main clinical syndromes: nonoedematous malnutrition (marasmus) and oedematous malnutrition (kwashiorkor and marasmic kwashiorkor) [5]. Although several studies report that HIV-infected children are more likely to present with nonoedematous malnutrition [6,7], there are anecdotal reports of oedematous malnutrition occurring soon after ART initiation in sub-Saharan Africa (J. Bunn, B. Amadi, personal communication); however, no study has described the frequency of this clinical observation. To better understand the interaction between malnutrition and HIV in children starting ART, we describe the frequency of hospital admissions for severe malnutrition and assess the impact of severe malnutrition on early mortality in a cohort of ART-treated children in Uganda and Zimbabwe.