Browsing by Author "Kekitiinwa, Adeodata"
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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 Antiretroviral therapy for HIV-1 infected adolescents in Uganda: Assessing the impact on growth and sexual maturation(Journal of Pediatric Infectious Diseases, 2008) Bakeera-Kitakaa, Sabrina; McKellar, Mehri; Snider, Cynthia; Kekitiinwa, Adeodata; Piloya, Theresa; Ronald, Allan; Marjan, Javanbakht; Colebunders, RobertAbstract. There is a paucity of knowledge about perinatally infected human immunodeficiency virus (HIV) positive children surviving into their adolescent years, especially from sub-Saharan Africa. Although studies have described the effects of the disease on the physical and sexual maturation of this population, their response to highly active antiretroviral therapy has not been systematically studied. At the pediatric infectious diseases clinic in Mulago hospital, Kampala, Uganda, we evaluated the effect of antiretroviral therapy (ART) on 118 treatment-naive, perinatally-infected HIV positive adolescents between the ages of 10–19 for 12 months. We monitored physical growth using The Centers for Disease Control and Prevention and recently published World Health Organization (WHO) reference growth standards for height and weight measurements as well as sexual maturation using Tanner staging. Laboratory tests including: complete blood count, absolute CD4 cell count and percentage, and HIV-1 RNA viral load, were performed at baseline and at 3-month intervals. Of 118 children, 64% were female; the median age was 13.6 years old. At baseline, 75% were classified as WHO clinical stages III and IV, with a median CD4 count of 124 cells/ul. Apart from four adolescents, all were on first-line antiretroviral therapy with 2 nucleoside reverse transcriptase inhibitors and 1 non-nucleoside reverse transcriptase inhibitors. After 6 months, the median CD4 count was 304 cells/μL, increasing to 370 cells/μL, by 12 months. Antiretroviral therapy was virologically suppressive (HIV-1 RNA viral load <400 copies/mL) in 79% of the adolescents at 6 months and in 89% at 12 months. Six (5%) patients died during the 12-month study. The median baseline height for age Z score was −2.41 which improved to a median of −1.96 by 12 months (P < 0.0001). The median baseline weight for age Z score was −2.61 and improved to −1.26 by 12 months (P < 0.0001). The median body mass index Z score increased from −1.39 to −0.47 by 12 months (P < 0.0001). At baseline, 63% of the adolescents were noted to have delayed pubertal maturation; this only reduced slightly to 60% after 12 months. Adolescents with predominantly perinatally-acquired HIV infection and significant disease burden showed appropriate virologic and immunological response to ART in addition to having clinically significant improvements in growth and some improvement in sexual maturation.Item Antiretroviral therapy initiation within seven days of enrolment: outcomes and time to undetectable viral load among children at an urban HIV clinic in Uganda(BMC Infectious Diseases, 2017) Ssebunya, Rogers; Wanyenze, Rhoda K.; Lukolyo, Heather; Mutto, Milton; Kisitu, Grace; Amuge, Pauline; Maganda, Albert; Kekitiinwa, AdeodataViral suppression is a critical indicator of HIV treatment success. In the era of test-and-start, little is known about treatment outcomes and time to undetectable viral loads. This study compares treatment outcomes, median times to achieve undetectable viral loads and its predictors under different antiretroviral (ART) treatment initiation schedules (i.e. within seven days of enrolment or later). A retrospective cohort of 367 patients <18 years who enrolled in care between January 2010 and December 2015 with a baseline viral load of >5000 copies/ml were followed up for 60 months. Undetectable viral load measurements were based on both Roche (<20copies/ml) and Abbot (<75copies/ml). Clinical treatment outcomes were compared using chi-squared test. Survival experiences between the two cohorts were assessed through incidence rates and Kaplan Meier curves. A cox model with competing risks was used to assess predictors for time to undetectable viral load. Of the 367 patients, 180 (49.1%) initiated ART within seven days from enrolment, 192 (52.3%) attained undetectable viral load of which 133 (69.3%) were children below six years and 101 (52.6%) were females. Among those who initiated ART within seven days 15 (8.3%) died and 6 (3.3%) were lost to follow-up compared to 27 (14. 4%) and 16 (8.6%) respectively in the later initiators. The median time to undetectable viral load was 24.9 months (95% CI: 19.7, 28.5) among early ART initiators and 38.5 months (95% CI: 31.1, 44.5) among those initiating beyond seven days. There was a significant difference in failure estimates between those initiating within seven and those that deferred (log rank, p = 0.001). Significant predictors for time to undetectable viral load were; starting ART within seven days (SHR = 2.02, 95% CI: 1.24, 3.28), baseline WHO stage I or II (SHR = 1.59, 95% CI: 1.06, 2.28), inconsistent adherence on three consecutive clinic visits (SHR = 0.44, 95% CI: 0.28, 0.67), and baseline weight (SRH = 1.04, 95% CI: 1.01, 1.07).Item Availability of human immunodeficiency virus prevention services in secondary schools in Kabarole District, Uganda(Journal of Public Health in Africa, 2015) Namuddu, Jane; Waiswa, Peter; Nsangi, Betty; Matovu, Joseph; Maganda, Albert; Kekitiinwa, AdeodataThe aim of this study was to assess the level of availability of HIV prevention strategies in secondary schools in Kabarole district, Uganda in order to inform the design of interventions to strengthen HIV Prevention and psychosocial support. Quantitative and qualitative research methods were used in eight secondary schools in Kabarole district to establish available HIV prevention and psychosocial support services. Questionnaires were administered to 355 students 12-24 years old. In addition, 20 Key Informant interviews were held with education service providers. Quantitative data was analyzed using Epi-data and qualitative data were analyzed by thematic content analysis. Seven of the eight schools had at least one HIV prevention strategy. Two teachers in each of the five schools had been trained in HIV prevention. No school had a nurse trained in HIV prevention, care and support. Education service providers had limited knowledge of HIV prevention support and care of students living with HIV. We found out that students had knowledge on how one can acquire HIV. HIV prevention services reported by students in schools included: talks from teachers and guests (19%), drama with HIV prevention related messages (16%), peer education clubs (15%), workshops and seminars on HIV (8%), sensitization about HIV/AIDS (7%), guidance and counseling (6%), talking compounds- (5%), abstinence talks (6%), keeping students busy in sports (4%), straight talk (4%). Sixty three percent reported receiving HIV reading materials from various sources. Preventing HIV infection among students in schools is still demanding with limited interventions for students. Efforts to support school interventions should focus on including HIV Prevention in the school curriculum, working with peer educators as well as education service providers who spend much of the time with the students while at school.Item Bacteraemia in severely malnourished children in an HIV-endemic setting(Annals of tropical paediatrics, 2006) Babirekere-Iriso, Esther; Musoke, Philippa; Kekitiinwa, AdeodataBackground: HIV infection predisposes children with malnutrition to recurrent bacterial infections and a high risk of bacteraemia. Methods: A cross-sectional descriptive study to determine the prevalence, causative organisms, antibiotic sensitivity and factors associated with bacteraemia in malnourished children was undertaken at Mulago Hospital, Kampala. The prevalence of HIV infection was also determined. A total of 134 children aged 6–59 months with severe malnutrition were recruited. Results: Sixty-one (45.5%) had oedematous malnutrition and 73 (54.5%) had severe wasting. Fifty-nine (44.0%) were HIV-infected. The prevalence of bacteraemia was 22%. The predominant organisms isolated were gramnegative enteric bacilli (77%) with Salmonella species and E. coli contributing 67% of the isolates. Hypoglycaemia was significantly associated with bacteraemia (p50.007). Most organisms were resistant to cotrimaxazole (93.3%), ampicillin (76.7%), gentamicin (66.7%) and chloramphenicol (60%). All isolates were sensitive to ceftriaxone. Sensitivity to ciprofloxacin was 97%. There was no strong association between HIV infection and bacteraemia. The relative risk of death in malnourished children with bacteraemia was ten times higher than in those without bacteraemia. Conclusions: Nearly a quarter (22%) of children admitted with severe malnutrition had bacteraemia and gram-negative organisms were the predominant cause. Forty-four per cent were HIV-infected.Most of the bacteria were sensitive to ceftriaxone and ciprofloxacin and resistant to commonly used antibiotics. In the absence of culture and sensitivity, ciprofloxacin or ceftriaxone should be considered as first-line antibiotics for severely malnourished children.Item Bacteraemia In Severely Malnourished Children In An HIV-Endemic Setting(Annals of tropical paediatrics, 2006) Iriso, Esther Babirekere; Musoke, Philippa; Kekitiinwa, AdeodataHIV infection predisposes children with malnutrition to recurrent bacterial infections and a high risk of bacteraemia.A cross-sectional descriptive study to determine the prevalence, causative organisms, antibiotic sensitivity and factors associated with bacteraemia in malnourished children was undertaken at Mulago Hospital, Kampala. The prevalence of HIV infection was also determined. A total of 134 children aged 6–59 months with severe malnutrition were recruited.Sixty-one (45.5%) had oedematous malnutrition and 73 (54.5%) had severe wasting. Fifty-nine (44.0%) were HIV-infected. The prevalence of bacteraemia was 22%. The predominant organisms isolated were gram-negative enteric bacilli (77%) with Salmonella species and E. coli contributing 67% of the isolates. Hypoglycaemia was significantly associated with bacteraemia (p=0.007). Most organisms were resistant to cotrimaxazole (93.3%), ampicillin (76.7%), gentamicin (66.7%) and chloramphenicol (60%). All isolates were sensitive to ceftriaxone. Sensitivity to ciprofloxacin was 97%. There was no strong association between HIV infection and bacteraemia. The relative risk of death in malnourished children with bacteraemia was ten times higher than in those without bacteraemia.Nearly a quarter (22%) of children admitted with severe malnutrition had bacteraemia and gram-negative organisms were the predominant cause. Forty-four per cent were HIV-infected. Most of the bacteria were sensitive to ceftriaxone and ciprofloxacin and resistant to commonly used antibiotics. In the absence of culture and sensitivity, ciprofloxacin or ceftriaxone should be considered as first-line antibiotics for severely malnourished children.Item The Collaborative African Genomics Network (CAfGEN): Applying Genomic technologies to probe host factors important to the progression of HIV and HIV-tuberculosis infection in sub-Saharan Africa [version 1; referees: awaiting peer review](AAS open research, 2018) Mboowa, Gerald; Mwesigwa, Savannah; Katagirya, Eric; Retshabile, Gaone; Mlotshwa, Busisiwe C.; Williams, Lesedi; Kekitiinwa, Adeodata; Kateete, David; Wampande, Eddie; Wayengera, Misaki; Nsangi Kintu, Betty; Kisitu, Grace P.; Kyobe, Samuel; Brown, Chester W.; Hanchard, Neil A.; Mardon, Graeme; Joloba, Moses; Anabwani, Gabriel; Pettitt, Ed; Tsimako-Johnstone, Masego; Kasvosve, Ishmael; Maplanka, Koketso; Mpoloka, Sununguko W.; Hlatshwayo, Makhosazana; Matshaba, MogomotsiThe Human Heredity and Health in Africa consortium (H3Africa) was conceived to facilitate the application of genomics technologies to improve health across Africa. Here, we describe how the Collaborative African Genomics Network (CAfGEN) of the H3Africa consortium is using genomics to probe host genetic factors important to the progression of HIV and HIV-tuberculosis (TB) coinfection in sub-Saharan Africa. Methods: CAfGEN is an H3Africa collaborative centre comprising expertise from the University of Botswana; Makerere University; Baylor College of vItem The collaborative African genomics network training program: a trainee perspective on training the next generation of African scientists(Genetics in Medicine, 2017) Mlotshwa, Busisiwe C.; Mwesigwa, Savannah; Mboowa, Gerald; Williams, Lesedi; Retshabile, Gaone; Kekitiinwa, Adeodata; Wayengera, Misaki; Kyobe, Samuel; Brown, Chester W.; Hanchard, Neil A.; Mardon, Graeme; Joloba, Moses; Anabwani, Gabriel; Mpoloka, Sununguko W.The Collaborative African Genomics Network (CAf- GEN) aims to establish sustainable genomics research programs in Botswana and Uganda through long-term training of PhD students from these countries at Baylor College of Medicine. Here, we present an overview of the CAfGEN PhD training program alongside trainees’ perspectives on their involvement. Background: Historically, collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs), or North–South collaborations, have been criticized for the lack of a mutually beneficial distribution of resources and research findings, often undermining LMICs. CAfGEN plans to address this imbalance in the genomics field through a program of technology and expertise transfer to the participating LMICs. Methods: An overview of the training program is presented. Trainees from the CAfGEN project summarized their experiences, looking specifically at the training model, benefits of the program, challenges encountered relating to the cultural transition, and program outcomes after the first 2 years. Conclusion: Collaborative training programs like CAfGEN will not only help establish sustainable long-term research initiatives in LMICs but also foster stronger North–South and South–South networks. The CAfGEN model offers a framework for the development of training programs aimed at genomics education for those for whom genomics is not their “first language.”Item Differences in body circumference, skin fold thickness and lipid profile measurements among HIV-infected children on and not on stavudine-based therapy in Uganda and Zambia in the CHAPAS-3 clinical trial(Joint Clinical Research Centre, 2013) Musiime, Victor; Cook, Adrian.; Kayiwa, Joshua; Zangata, Dorothy; Gibb, Diana M.; Kityo, Cissy; Kekitiinwa, Adeodata; Mulenga, Veronica; Nansubuga, Carol; Arach, Beatrice; Kenny, Julia; Wavamunno, Priscilla; Kabamba, Desiree; Asiimwe, Alice R.; Abongomera, GeorgeLipodystrophy is a major side effect of antiretroviral therapy (ART) especially in adults, and although there have been some reports among HIV-infected children [1,2], paediatric data are limited Stavudine (d4T) has particularly been associated with lipodystrophy among HIVinfected adults owing to intracellular accumulation of the drug and its metabolites In HIV-infected children, d4T clearance is enhanced, potentially protecting them from these effects [3]. In addition, the relative d4T dose in paediatric fixed dosecombination “baby” tablets is lower than used in adults, and is also lower compared to the 4mg/kg licensed dose for children [4] Features of lipodystrophy have been observed to reverse when children have been switched from d4T-containing regimens [5]; however, clinical lipodystrophy ismore difficult to diagnose in growing children than in adults We compared body circumferences, skin-fold thickness (SFT) and lipid levels, as objective measures of lipodystrophy, among HIV-infected ART naïve vs experienced children at enrolment into the CHAPAS-3 trial, and in HIV-uninfectedItem Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations(Frontiers in Genetics, 2021) Kyobe, Samuel; Mwesigwa, Savannah; Kisitu, Grace P.; Farirai, John; Katagirya, Eric; Mirembe, Angella N.; Ketumile, Lesego; Wayengera, Misaki; Ashaba Katabazi, Fred; Kigozi, Edgar; Wampande, Edward M.; Retshabile, Gaone; Mlotshwa, Busisiwe C.; Williams, Lesedi; Morapedi, Koketso; Kasvosve, Ishmael; Kyosiimire-Lugemwa, Jacqueline; Nsangi, Betty; Tsimako-Johnstone, Masego; Brown, Chester W.; Joloba, Moses; Anabwani, Gabriel; Bhekumusa, Lukhele; Mpoloka, Sununguko W.; Mardon, Graeme; Matshaba, Mogomotsi; Kekitiinwa, Adeodata; Hanchard, Neil A.Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV- 1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B 57:03, aOR 3.21, Pc = 0.0259; B 58:01, aOR 1.89, Pc = 0.033; C 03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B 57:03-C 07:01 (aOR 5.40, Pc = 0.025) and HLA-B 58:01- C 03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C 03:02 with B 58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.Item High Risk of Neutropenia in HIV-Infected Children following Treatment with Artesunate plus Amodiaquine for Uncomplicated Malaria in Uganda(Clinical infectious diseases, 2008) Gasasira, Anne F.; Kamya, Moses R.; Achan, Jane; Mebrahtu, Tsedal; Kalyango, Joan N.; Ruel, Theodore; Charlebois, Edwin; Staedke, Sarah G.; Kekitiinwa, Adeodata; Rosenthal, Philip J.; Havlir, Diane; Dorsey, GrantArtemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)–infected populations. Methods. We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. Results. Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; Pp.08). Importantly, the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; P ! .001). The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, !750 cells/ mm3). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; Pp.001). Conclusions. Artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals.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.Item Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy(JAIDS Journal of Acquired Immune Deficiency Syndromes, 2007) Kamya, Moses R.; Mayanja-Kizza, Harriet; Kambugu, Andrew; Bakeera-Kitaka, Sabrina; Semitala, Fred; Mwebaze-Songa, Patricia; Castelnuovo, Barbara; Gasasira, Anne F.; Katabira, Elly; Kekitiinwa, Adeodata; Thomas, David L.; the Academic Alliance for AIDS Care and Prevention in AfricaHIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART).From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months.Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations.These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.Item Prevalence and correlates of HIV testing among adolescents 10–19 years in a post-conflict pastoralist community of Karamoja region, Uganda(BMC public health, 2018) Ssebunya, Rogers N.; Wanyenze, Rhoda K.; Namale, Leticia; Lukolyo, Heather; Kisitu, Grace P.; Nahirya-Ntege, Patricia; Kekitiinwa, AdeodataAdolescents are a priority group in HIV prevention and treatment. This study sought to determine the prevalence and correlates of HIV testing services (HTS) among adolescents in the pastoralist post-conflict area of Karamoja sub region, Uganda. Methods: A cross sectional study of 1439 adolescents aged 10–19 years, attending nine public health facilities in five of the seven districts of Karamoja, was conducted between August to September 2016. Adolescents were consecutively selected and interviewed using structured interviewer administered questionnaires. All respondents who had never tested for HIV were offered HTS. The main outcome was ever tested for HIV. Correlates of ever tested were analyzed using multivariate logistic regression model. Results: Of the 1439 adolescents, 904 (62.8%) were females, 1203 (83.6%) were aged 15–19 years, 618 (43.0%) had attained primary education and 885 (61.5%) had ever had sex. Overall 1177 (81.8%) had ever tested and received HIV results. Older age (15–19 years) (adj.OR = 2.71, 95% CI: 1.85–3.96), secondary level education or higher (adj.OR = 2.33, 95% CI: 1.33–4.10), and ever had sex (adj.OR = 2.03, 95% CI: 1.42–2.90) were associated with higher odds of HIV testing. Of the 262 who had never tested, 169 (64.5%) accepted testing and 2.4% were HIV positive. Reasons for not accepting the test included fear of being tested and not ready for an HIV test because of perceived suffering HIV positive clients go through. Conclusion: Awareness of HIV status and uptake of HTS among adolescents in this hard-to-reach post-conflict region was high and close to the global UNAIDS target of 90%. However, the HIV prevalence of 2.4% among the non-testers who accepted to be tested was high and emphasises the need for targeted testing to reach the undiagnosed HIV infected adolescents in this region.Item Use Of Peers, Community Lay Persons And Village Health Team (VHT) Members Improves Six-Week Postnatal Clinic (PNC) Follow-Up And Early Infant HIV Diagnosis (EID) In Urban And Rural Health Units In Uganda: A One-Year Implementation Study(BMC Health Services Research, 2015) Namukwaya, Zikulah; Mosha, Linda Barlow; Mudiope, Peter; Kekitiinwa, Adeodata; Matovu, Joyce Namale; Musingye, Ezra; Ssebaggala, Jane Ntongo; Nakyanzi, Teopista; Abwooli, Jubilee John; Mirembe, Dorothy; Etima, Juliane; Bitarakwate, Edward; Fowler, Mary Glenn; Musoke, Philippa Martha; Peer-senga study Group at Mulago; Mengo, Rubaga and Mpigi Health UnitsEffective Prevention of Mother to child Transmission of HIV (PMTCT) relies heavily on follow-up of HIV-infected women and infants from antenatal, through postnatal, to the end of the breastfeeding period. In Uganda, postnatal (PNC) follow-up remains below 50 % creating a missed opportunity for linkage to comprehensive HIV care and early infant diagnosis (EID). We evaluated the use of HIV infected peer mothers (peers), community lay persons and Village health team (VHT) members to improve PNC follow up and EID in urban and rural health units.Study participants were HIV-infected women recruited from antenatal clinics at three urban clinics (Mulago, Rubaga and Mengo hospitals) and one rural health centre (Mpigi Health centre IV) between January and September 2010. The women were followed through delivery and the mother-infant pairs for the 6-week postnatal visit and up to 14 weeks for EID. Peers, community lay persons and VHT members were identified and trained in basic PMTCT and reproductive health (RH). They were then assigned to study clinic to support and follow study participants, their partners and infants through provision of health education, counseling, home visits, and phone call reminders. Six week PNC attendance was measured as a proportion of mother-infant pairs that returned for the 6-week postnatal follow up visit (5–8 weeks) while EID was measured as the proportion of HIV-exposed live birth that had an HIV test done by 14 weeks of age. Data at baseline (one year before the intervention) was compared with that during the one year study period among study participants and HIV infected women and their HIV-exposed infants in the whole clinic population.A total of 558 HIV-infected pregnant women were recruited for the study, 47 mother-infant pairs were censured before 6 weeks due to stillbirth (14), infant death < 6 weeks (23), death of participant (04) and loss to follow up before delivery (6). 401/511 (78.5 %) of mother-infant pairs returned to the study clinics at six-week, while 441/511 (86.3 %) infants were tested for HIV infection by 14 weeks of age. The baseline six-week PNC follow up was 37.7 % and increased during the study period to 78.5 % and 39.1 % among study participants and whole clinic population respectively, an incremental difference of 39.4 % (P < 0.001). EID increased from a baseline of 53.6 % to 86.3 % and 65.8 % among study and whole clinic population respectively during the study period, an incremental difference of 20.5 % (P < 0.001).Use of peers, community lay persons and VHT members led to a significant increase in six-week postnatal follow up of HIV infected women and EID among HIV exposed infants in the four study clinics. Our study supports the use of peers to improve early postnatal follow up and EID and should be implemented in other health units to support the PMTCT cascade.Item Virologic Response to First-Line Efavirenz- or Nevirapine-Based Anti-Retroviral Therapy in HIV-Infected African Children(The Pediatric infectious disease journal, 2017) Kekitiinwa, Adeodata; Szubert, Alexander J.; Katuramu, Richard; Musiime, Victor; Kitaka, Sabrina Bakeera; Walker, Ann Sarah; Senfuma, Oscar; Gibb, Diana M.Poorer virologic response to nevirapine vs efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies. We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ≥3 years of age initiating ART with clinician-chosen nevirapine vs efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/ml at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (p=0.1).Item Virologic, Immunologic And Clinical Response Of Infants To Antiretroviral Therapy In Kampala, Uganda(BMC pediatrics, 2013) Tukei, Vincent J.; Murungi, Miriam; Asiimwe, Alice R.; Migisha, Daniella; Maganda, Albert; Kitaka, Sabrina Bakeera; Kalyesubula, Israel; Musoke, Philippa; Kekitiinwa, AdeodataAntiretroviral therapy (ART) is known to save lives. Among HIV-infected infants living in resource constrained settings, the short and long term benefits of ART are only partially known. This study was designed to determine the virologic, immunologic and clinical outcomes of antiretroviral therapy in a cohort of HIV-infected infants receiving care from an outpatient clinic in Kampala, Uganda.A prospective cohort of HIV-infected infants receiving treatment at the Baylor-Uganda clinic was analyzed. Patients were diagnosed, enrolled and followed up at the clinic. HIV viral load, CD4 cell counts and clinical progress were assessed during follow-up. Descriptive statistical analysis and logistic regression modeling to determine predictors of treatment success were conducted.Of 91 HIV-infected infants enrolled into the cohort, 53 (58.2%) infants were female; 43 (47.3%) were 6 months of age or younger, and 50 (55.6%) had advanced HIV/AIDS disease (Clinical stage 3 or 4). Eighty four infants started ART and 78 (92.9%) completed 6 months of treatments. Fifty six (71.8%) infants attained virologic suppression by month-6 of ART, and at month-12 of ART, the cumulative probability of attaining viral suppression was 83.1%. None of the baseline infant factors (age, sex, WHO stage, CD4 cell percent, weight for age, or height for age z-score) predicted treatment success. There was an increase in CD4 cells from a baseline mean of 23% to 30% at month-6 of treatment (p<0.001) and by month-24 of ART, the mean CD4 percent was 36%. A total of 7 patients died while on ART and another 7 experienced adverse events that were related to treatment.Our results show that, even among very young patients from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe. However, baseline characteristics do not predict recovery in this age group.Item Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana(The American Journal of Human Genetics, 2018) Retshabile, Gaone; Mlotshwa, Busisiwe C.; Williams, Lesedi; Mwesigwa, Savannah; Mboowa, Gerald; Huang, Zhuoyi; Rustagi, Navin; Swaminathan, Shanker; Katagirya, Eric; Kyobe, Samuel; Wayengera, Misaki; Kisitu, Grace P.; Kateete, David P.; Wampande, Eddie M.; Maplanka, Koketso; Kasvosve, Ishmael; Pettitt, Edward D.; Matshaba, Mogomotsi; Nsangi, Betty; Marape, Marape; Tsimako-Johnstone, Masego; Brown, Chester W.; Yu, Fuli; Kekitiinwa, Adeodata; Joloba, Moses; Mpoloka, Sununguko W.; Mardon, Graeme; Anabwani, Gabriel; Hanchard, Neil A.Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa.We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana—a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%–25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p ¼ 2.2 3 10 16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists.