Browsing by Author "Mirembe, Grace"

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    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 M
    Background 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.
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    Acceptability of lopinavir/r pellets (minitabs), tablets and syrups in HIV-infected children
    (Europe PMC Funders Group, 2016) Kekitiinwa, Adeodata.; Musiime, Victor.; Thomason, Margaret J.; Mirembe, Grace; Lallemant, Marc; Nakalanzi, Sarah.; Baptiste, David.; Walker, Sarah A.; Gibb, Diana M.; Judd, Ali
    Lopinavir/ritonavir ‘pellets’ were recently tentatively approved for licensing. We describe their acceptability for infants and children up to 48 weeks. Methods—CHAPAS-2 was a randomised, 2-period crossover trial comparing syrup and pellets in HIV-infected infants (n=19, group A, aged 3-<12 months) and children (n=26, group B, 1-<4yrs) and tablets and pellets in older children (n=32, group C, 4-<13yrs) from 2 clinics (“JCRC”, “PIDC”) in Uganda. At week 8, all groups chose which formulation to continue. Acceptability data were collected at weeks 0,4,8,12, and 48. Results—For groups A and B overall, the proportion preferring pellets increased between week 0 and week 12 and decreased at week 48 (group A 37%, 72%, 44%; group B 12%, 64% and 36% respectively), although there were marked differences between clinics. For group C, pellets were progressively less preferred to tablets over time: 41%,19%,13% at weeks 0,12,48 respectively. During follow-up unpleasant taste was similarly reported among young children taking pellets and syrups (37%/43% group A; 29%/26% group B), whereas among older children, pellets tasted worse than tablets (40%/2%). No participants reported problems with storage/transportation for pellets (0%/0%) unlike syrups (23%/13%). Conclusions—For children <4 years, pellets were more acceptable at week 12 but not week 48. Clinic differences could reflect bias among healthcare workers for different formulations. Pellets taste similar to syrup, are easier to store and transport than syrup, and represent an alternative formulation for young children unable to swallow tablets; improvements in taste and support for healthcare workers may help sustain acceptability
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    Coronary artery calcium, HIV and inflammation in Uganda compared with the USA
    (Open Heart, 2019) Alencherry, Ben; Erem, Geoffrey; Mirembe, Grace; Ssinabulya, Isaac; Yun, Chun-Ho; Hung, Chung-Lieh; Siedner, Mark J.; Bittencourt, Marcio; Kityo, Cissy; McComsey, Grace A.; Longenecker, Chris T.
    To compare the prevalence of detectable coronary artery calcium (CAC) among higher risk, older people living with HIV (PLWH) and uninfected persons in Uganda versus the USA, and second to explore associations of CAC with HIV-specific variables and biomarkers of inflammation. This cross-sectional study of 430 total subjects compared 100 PLWH on antiretroviral therapy and 100 age-matched and sex-matched HIV-uninfected controls in Uganda with 167 PLWH on antiretroviral therapy and 63 uninfected controls in the USA. Multivariable logistic regression was used to examine associations with detectable CAC (CAC >0). Compared with US subjects, Ugandans were older (mean age 56 vs 52 years) and were more likely to have diabetes (36% vs 3%) and hypertension (85% vs 36%), but were less likely to be male (38% vs 74%) or smokers (4% vs 56%). After adjustment for HIV serostatus, age, sex and traditional risk factors, Ugandans had substantially lower odds of CAC >0 (adjusted OR 0.07 (95% CI 0.03 to 0.17), p<0.001). HIV was not associated with CAC >0 in either country (p>0.1). Among all PLWH, nadir CD4 count was associated with the presence of CAC, and among Ugandans soluble intercellular adhesion molecule (p=0.044), soluble CD163 (p=0.004) and oxidised low-density lipoprotein (p=0.043) were all associated with the presence of CAC. Ugandans had a dramatically lower prevalence of any coronary calcification compared with US subjects. The role of HIV infection and inflammation as risk factors for subclinical coronary disease in sub-Saharan Africa merits further investigation.
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    Efficacy and Safety of Dolutegravir or Darunavir in Combination with Lamivudine plus either Zidovudine or Tenofovir for second-line Treatment of HIV Infection (NADIA): week 96 results from a Prospective, Multicentre, Open-label, Factorial, Randomised, Non-inferiority trial
    (The Lancet HIV, 2022) Paton, Nicholas I.; Musaazi, Joseph; Kityo, Cissy; Walimbwa, Stephen; Hoppe, Anne; Balyegisawa, Apolo; Mirembe, Grace; Lugemwa, Abbas; Ategeka, Gilbert; Mugerwa, Henry; Kambugu, Andrew
    WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine. In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
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    HIV and Pericardial Fat are Associated with Abnormal Cardiac Structure and Function among Ugandans
    (Heart, 2020) Buggey, Jonathan; Yun, Chun-Ho; Hung, Chung-Lieh; Kityo, Cissy; Mirembe, Grace; Erem, Geoffrey; Ssinabulya, Isaac; McComseya, Grace A.; Longenecker, Chris T.
    To examine the relationship between pericardial fat (PCF) and cardiac structure and function among HIV-infected patients in the sub-Saharan African country of Uganda. People living with HIV (PLHIV) have altered fat distribution and an elevated risk for heart failure. Whether altered quantity and radiodensity of fat surrounding the heart relates to cardiac dysfunction in this population is unknown. One hundred HIV-positive Ugandans on antiretroviral therapy were compared with 100 age and sex-matched HIV-negative Ugandans; all were >45 years old with >1 cardiovascular disease risk factor. Subjects underwent ECG-gated non-contrast cardiac CT and transthoracic echocardiography with speckle tracking strain imaging. Multivariable linear and logistic regression models were used to explore the association of PCF with echocardiographic outcomes. Median age was 55% and 62% were female. Compared with uninfected controls, PLHIV had lower body mass index (27 vs 30, p=0.02) and less diabetes (26% vs 45%, p=0.005). Median left ventricular (LV) ejection fraction was 67%. In models adjusted for traditional risk factors, HIV was associated with 10.3 g/m2 higher LV mass index (LVMI) (95% CI 3.22 to 17.4; p=0.005), 0.87% worse LV global longitudinal strain (GLS) (95% CI −1.66 to −0.07; p=0.03) and higher odds of diastolic dysfunction (OR 1.96; 95% CI 0.95 to 4.06; p=0.07). In adjusted models, PCF volume was significantly associated with increased LVMI and worse LV GLS, while PCF radiodensity was associated with worse LV GLS (all p<0.05). In Uganda, HIV infection, PCF volume and density are associated with abnormal cardiac structure and function.
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    Prevalence of latent rheumatic heart disease among HIV-infected children in Kampala, Uganda
    (Journal of acquired immune deficiency syndromes, 2016) Gleason, Brigette; Mirembe, Grace; Namuyonga, Judith; Okello, Emmy; Lwabi, Peter; Lubega, Irene; Lubega, Sulaiman; Musiime, Victor; Kityo, Cissy; Salata, Robert A.; Longenecker, Chris T.
    Rheumatic heart disease (RHD) remains highly prevalent in resource-constrained settings around the world, including countries with high rates of HIV/AIDS. Although both are immune-mediated diseases, it is unknown whether HIV modifies the risk or progression of RHD. We performed screening echocardiography to determine the prevalence of latent rheumatic heart disease in 488 HIV-infected children aged 5-18 in Kampala, Uganda. The overall prevalence of borderline/definite RHD was 0.82% (95% CI 0.26% to 2.23%) which is lower than the published prevalence rates of 1.5-4% among Ugandan children. There may be protective factors that decrease the risk of RHD in HIV-infected children.
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    Severe Neurological Sequelae and Behavior Problems after Cerebral Malaria in Ugandan Children
    (BMC research notes, 2010) Idro, Richard; Kakooza-Mwesige, Angelina; Balyejjussa, Stephen; Mirembe, Grace; Tugumisirize, Joshua; Byarugaba, Justus
    Cerebral malaria is the most severe neurological complication of falciparum malaria and a leading cause of death and neuro-disability in sub-Saharan Africa. This study aimed to describe functional deficits and behaviour problems in children who survived cerebral malaria with severe neurological sequelae and identify patterns of brain injury.Records of children attending a specialist child neurology clinic in Uganda with severe neurological sequelae following cerebral malaria between January 2007 and December 2008 were examined to describe deficits in gross motor function, speech, vision and hearing, behaviour problems or epilepsy. Deficits were classified according to the time of development and whether their distribution suggested a focal or generalized injury. Any resolution during the observation period was also documented.Thirty children with probable exposure to cerebral malaria attended the clinic. Referral information was inadequate to exclude other diagnoses in 7 children and these were excluded. In the remaining 23 patients, the commonest severe deficits were spastic motor weakness (14), loss of speech (14), hearing deficit (9), behaviour problems (11), epilepsy (12), blindness (12) and severe cognitive impairment (9). Behaviour problems included hyperactivity, impulsiveness and inattentiveness as in attention deficit hyperactivity disorder (ADHD) and conduct disorders with aggressive, self injurious or destructive behaviour. Two patterns were observed; a) immediate onset deficits present on discharge and b) late onset deficits. Some deficits e.g. blindness, resolved within 6 months while others e.g. speech, showed little improvement over the 6-months follow-up.In addition to previously described neurological and cognitive sequelae, severe behaviour problems may follow cerebral malaria in children. The observed differences in patterns of sequelae may be due to different pathogenic mechanisms, brain regions affected or extent of injury. Cerebral malaria may be used as a new model to study the pathogenesis of ADHD.