Browsing by Author "Kakuru, Abel"

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    Antiretroviral Agents and Prevention of Malaria in HIV-Infected Ugandan Children
    (The New England Journal of Medicine, 2012) Achan, Jane; Kakuru, Abel; Ikilezi, Gloria; Ruel, Theodore; Clark, Tamara D.; Nsanzabana, Christian; Charlebois, Edwin; Aweeka, Francesca; Dorsey, Grant; Rosenthal, Philip J.; Havlir, Diane; Kamya, Moses R
    Human immunodeficiency virus (HIV) protease inhibitors show activity against Plasmodium falciparum in vitro. We hypothesized that the incidence of malaria in HIV infected children would be lower among children receiving lopinavir–ritonavir– based antiretroviral therapy (ART) than among those receiving nonnucleosidereverse transcriptase inhibitor (NNRTI)–based ART.
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    Artemisinin-Based Combination Therapies Are Efficacious and Safe for Treatment of Uncomplicated Malaria in HIV-Infected Ugandan Children
    (Clinical infectious diseases, 2014) Kakuru, Abel; Achan, Jane; Muhindo, Mary K.; Ikilezi, Gloria; Arinaitwe, Emmanuel; Mwangwa, Florence; Ruel, Theodore; Clark, Tamara D.; Charlebois, Edwin; Kamya, Moses R.; Tappero, Jordan W.; Dorsey, Grant
    Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)–infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited. We evaluated 28-day outcomes following malaria treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV-infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor–based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine-based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes. There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine-based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated. Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine-based ART.
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    Clinical Presentation and Outcome of Epidemic Kaposi Sarcoma in Ugandan Children
    (Pediatric blood & cancer, 2010) Gantt, Soren; Kakuru, Abel; Wald, Anna; Walusansa, Victoria; Corey, Lawrence; Casper, Corey; Orem, Jackson
    Kaposi sarcoma (KS) is one of the most common pediatric cancers in sub-Saharan Africa. Few data are available about the clinical presentation or response to treatment of children with epidemic (HIV-associated) KS. Methods. Medical records of all children with KS and HIV infection referred to the Uganda Cancer Institute in Kampala, Uganda from October 2004 to June 2007 were reviewed. Charts were abstracted for age, sex, location of KS lesions at presentation, biopsy results, CD4 T-cell count and percentage, and KS treatment and outcome. Results. Seventy-three children with epidemic KS were identified, 37 males and 36 females. The median age was 10.1 years (range 2–18). KS presented with lymph node (LN) involvement in 60% of cases. The median absolute and percentage CD4 T-cells at presentation were 210 cells/ml and 7.4%, respectively. Those children with lymphadenopathic KS were younger (mean difference 3.7 years; P¼0.01) and had higher CD4 T-cell counts (mean difference 242 cells/ml; P¼0.03) than those without LN involvement. Of 32 patients for whom outcome data were available, a complete response to chemotherapy and/or antiretroviral therapy was documented in 20 (62.5%) patients. Conclusions. In comparison to cutaneous involvement, LN involvement of epidemic KS occurs at younger ages and at higher CD4 levels. This clinical presentation may reflect recent infection with human herpesvirus 8 followed by a rapid progression to malignancy. Favorable response to treatment was observed in the majority of cases, but prospective studies are needed to determine optimal management. Pediatr Blood Cancer
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    Efficacy and Safety of Three Regimens for the Prevention of Malaria in Young HIV-Exposed Ugandan Children: A Randomized Controlled Trial
    (AIDS, 2014) Kamya, Moses R.; Kapisi, James; Bigira, Victor; Tamara, D. Clark; Kinara, Stephen; Mwangwa, Florence; Muhindo, Mary K.; Kakuru, Abel; Aweeka, Francesca T.; Achan, Jane; Havlir, Diane V.; Rosenthal, Philip J.; Dorsey, Grant
    Trimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children. Tororo, Uganda, a rural area with intense, year-round, malaria transmission. 200 infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age). No chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily TS, or monthly dihydroartemisinin-piperaquine (DP) given from randomization to 24 months of age. The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrheal illness, or respiratory tract infection; prevalence of anemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped. During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% (95% CI, 53-80%, p<0.001) for DP, 49% (95% CI, 23-66%, p=0.001) for TS, and 9% for SP (95% CI, −35 to 38%, p=0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the DP arm. Monthly chemoprevention with DP was safe and associated with a significant reduction in malaria in young HIV-exposed children.
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    Growth Recovery Among HIV-Infected Children Randomized to Lopinavir/Ritonavir or NNRTI-Based Antiretroviral Therapy
    (The Pediatric infectious disease journal, 2016) Achan, Jane; Kakuru, Abel; Ikilezi, Gloria; Mwangwa, Florence; Charlebois, Edwin; Young, Sera; Havlir, Diane; Kamya, Moses; Ruel, Theodore
    Diminished growth is highly prevalent among HIV-infected children and might be improved by antiretroviral therapy (ART). We examined growth recovery in a rural Ugandan cohort of HIV-infected children randomized to lopinavir/ritonavir or non-nucleoside-reverse-transcription-inhibitor-based ART. HIV-infected children 2 months to 6 years of age were randomized to Lopinavir/ritonavir- or non-nucleoside-reverse-transcription-inhibitor-based ART. Changes in weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) Z-scores for 24 months were evaluated using generalized linear repeated-measures models. Recovery from being underweight (WAZ<−2), stunted (HAZ<−2) and wasted (WHZ<−2) to Z-scores > −2 was also compared by arm using Kaplan-Meier survival and Cox proportional hazard modeling. A total of 129 children with median age of 3 years initiated therapy; 64 received Lopinavir/ritonavir-based and 65 non-nucleoside-reverse-transcription-inhibitor-based ART (nevirapine: 36 and efavirenz: 29). The median (IQR) difference in growth measures between baseline and 24 months for Lopinavir/ritonavir (n= 45) vs. non-nucleoside-reverse-transcription-inhibitor-based therapy (n=40) were as follows, WAZ: 0.47 (0.10, 1.62) vs. 0.53 (0.03, 1.14) (p=0.59) and HAZ: median 1.55 (0.78, 1.86) vs. 1.19 (0.62, 1.65) (p=0.23), respectively. ART regimen was not predictive of change in WAZ (beta: −0.02, 95%CI: −0.25, 0.20) or HAZ (beta: 0.05, 95%CI: −0.10, 0.19). Presence of confirmed virologic failure was not associated with growth. Most ART-naive children experienced recovery of both WAZ and HAZ over the 24 months following ART-initiation, with no significant difference between those receiving Lopinavir/ritonavir vs. non-nucleoside-reverse-transcriptase-inhibitor-based ART. However, the persistence of median Z-scores below zero underscores the need for additional strategies to improve growth outcomes in HIV+ African children.
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    Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children
    (Antimicrobial agents and chemotherapy, 2015) Tumwebaze, Patrick; Conrad, Melissa D.; Walakira, Andrew; LeClair, Norbert; Byaruhanga, Oswald; Nakazibwe, Christine; Okiring, Jaffer; Kakuru, Abel; Bigira, Victor; Kapisi, James; Kamya, Moses R.; Greenhouse, Bryan; Nsobya, Samuel L.; Rosenthal, Philip J.
    Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.