NRU :: Browsing by Author "Rosenthal, Philip J."

Browsing by Author "Rosenthal, Philip J."

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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.
Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treating Uncomplicated Malaria: A Randomized Trial to Guide Policy in Uganda
(PloS one, 2008) Yeka, Adoke; Dorsey, Grant; Kamya, Moses R.; Talisuna, Ambrose; Lugemwa, Myers; Rwakimari, John Bosco; Staedke, Sarah G.; Rosenthal, Philip J.; Mangen, Fred Wabwire; Bukirwa, Hasifa
Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission.Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0–28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI −0.2–7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated.DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda.
Artemisinin Combination Therapies for Treatment of Uncomplicated Malaria in Uganda
(PLoS clinical trials, 2006) Bukirwa, Hasifa; Yeka, Adoke; Kamya, Moses R.; Talisuna, Ambrose; Banek, Kristin; Bakyaita, Nathan; Rwakimari, John Bosco; Rosenthal, Philip J.; Mangen, Fred Wabwire; Dorsey, Grant; Staedke, Sarah G.
To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.Randomized single-blind controlled trial.Tororo, Uganda, an area of high-level malaria transmission.Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.Amodiaquine + artesunate or artemether–lumefantrine.Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether–lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether–lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%–24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether–lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%–25.2%). Amodiaquine + artesunate and artemether–lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.Amodiaquine + artesunate and artemether–lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether–lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.
Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda
(Antimicrobial Agents and Chemotherapy, 2020) Cuu, Gloria; Asua, Victor; Tukwasibwe, Stephen; Nsobya, Sam L.; Nanteza, Ann; Kimuda, Magambo Phillip; Mpimbaza, Arthur; Rosenthal, Philip J.
Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.
Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study
(Malaria Journal, 2020) Kakande, Elijah; Greenhouse, Bryan; Bajunirwe, Francis; Drakeley, Chris; Nankabirwa, Joaniter I.; Walakira, Andrew; Nsobya, Samuel L.; Katureebe, Agaba; Rek, John; Arinaitwe, Emmanuel; Rosenthal, Philip J.; Kamya, Moses R.; Dorsey, Grant; Rodriguez‑Barraquer, Isabel
Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A—(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes.
Bacteremia among Febrile Ugandan Children Treated with Antimalarials Despite a Negative Malaria Test
(The American journal of tropical medicine and hygiene, 2015) Kibuuka, Afizi; Byakika-Kibwika, Pauline; Achan, Jane; Yeka, Adoke; Nalyazi, Joan N.; Mpimbaza, Arthur; Rosenthal, Philip J.; Kamya, Moses R.
Bacteremia may be inappropriately treated as malaria in children admitted with a febrile illness in Africa. We determined the prevalence, clinical features, and spectrum of bacteremia among febrile children younger than 5 years of age admitted with a negative malaria test, but prescribed antimalarials at a referral hospital in Jinja, Uganda. After initial evaluation, a blood sample was drawn from 250 children for a complete blood count and bacterial culture. Of 250 samples cultured, 15 grew organisms presumed to be skin contaminants, and of the remaining 235 samples, 45 (19.1%) had bacteremia. Staphylococcus aureus (42%), non-typhoidal Salmonella (24%), Pseudomonas aeruginosa (11%), and Streptococcus pneumoniae (9%) were the most common bacterial isolates. On multivariate analysis, history of weight loss (odds ratio [OR] = 2.75; 95% confidence interval [CI] = 1.27–5.95), presence of pulmonary crackles (OR = 3.63; 95% CI = 1.40–9.45), and leukocytosis (OR = 2.21; 95% CI = 1.09–4.47) were independent predictors of bacteremia. At a hospital in Uganda, bacteremia was a remarkably common finding in children with febrile illness who were treated for malaria despite negative malaria test results.
Balanced impacts of fitness and drug pressure on the evolution of PfMDR1 polymorphisms in Plasmodium falciparum
(Malaria journal, 2021) Duvalsaint, Marvin; Conrad, Melissa D.; Tukwasibwe, Stephen; Tumwebaze, Patrick K.; Cooper, Roland A.; Rosenthal, Philip J.
Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1.Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the cultures was characterized every 4 days by pyrosequencing. The impacts of culture with anti-malarials on the growth of different haplotypes were also assessed. Lastly, the engineering of P. falciparum containing another common polymorphism, PfMDR1 D1246Y, was attempted. Co-culture results were as follows. With wild type (WT) Y184 fixed (N86/Y184 vs. 86Y/Y184), parasites WT and mutant at 86 were at equilibrium. With mutant 184 F fixed (N86/184F vs. 86Y/184F), mutants at 86 overgrew WT. With WT N86 fixed (N86/Y184 vs. N86/184F), WT at 184 overgrew mutants. With mutant 86Y fixed (86Y/Y184 vs. 86Y/184F), WT and mutant at 86 were at equilibrium. Parasites with the double WT were in equilibrium with the double mutant, but 86Y/Y184 overgrew N86/184F. Overall, WT N86/mutant 184F parasites were less fit than parasites with all other haplotypes. Parasites engineered for another mutation, PfMDR1 1246Y, were unstable in culture, with reversion to WT over time. Thus, the N86 WT is stable when accompanied by the Y184 WT, but incurs a fitness cost when accompanied by mutant 184F. Culturing in the presence of chloroquine favored 86Y mutant parasites and in the presence of lumefantrine favored N86 WT parasites; piperaquine had minimal impact.These results are consistent with those for Ugandan field isolates, suggest reasons for varied haplotypes, and highlight the interplay between drug pressure and fitness that is guiding the evolution of resistance-mediating haplotypes in P. falciparum.
The effect of HIV on malaria in the context of the current standard of care for HIV-infected populations in Africa
(Future virology, 2012) Kamya, Moses R.; Byakika-Kibwika, Pauline; Gasasira, Anne F.; Havlir, Diane; Rosenthal, Philip J.; Dorsey, Grant; Achan, Jane
HIV infection affects the clinical pattern of malaria. There is emerging evidence to suggest that previously documented interactions may be modified by recently scaled-up HIV and malaria interventions. Prophylaxis with trimethoprim– sulfamethoxazole (TS) in combination with use of insecticide-treated nets can markedly decrease the incidence of malaria in HIV-infected pregnant and nonpregnant adults and children even in the setting of antifolate resistanceconferring mutations that are currently common in Africa. Nonetheless, additional interventions are needed to protect HIV-infected people that reside in highmalaria- transmission areas. Artemether–lumefantrine and dihydroartemisinin– piperaquine are highly efficacious and safe for the treatment of uncomplicated malaria in HIV-infected persons. Coadministration of antiretroviral and antimalarial drugs creates the potential for pharmacokinetic drug interactions that may increase (causing enhancement of malaria treatment efficacy and posttreatment prophylaxis and/or unanticipated toxicity) or reduce (creating risk for treatment failure) antimalarial drug exposure. Further studies are needed to elucidate potentially important pharmacokinetic interactions between commonly used antimalarials, antiretrovirals and TS and their clinical implications. Data on the benefits of long-term TS prophylaxis among HIV patients on antiretroviral therapy who have achieved immune-reconstitution are limited. Studies to address these questions are ongoing or planned, and the results should provide the evidence base required to guide the prevention and treatment of malaria in HIV-infected patients.
Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial
(Bmj, 2009) Achan, Jane; Tibenderana, James K.; Kyabayinze, Daniel; Wabwire Mangen, Fred; Kamya, Moses R.; Dorsey, Grant; D’Alessandro, Umberto; Rosenthal, Philip J.; Talisuna, Ambrose O.
Objective To compare the effectiveness of oral quininewith that of artemether-lumefantrine in treatinguncomplicated malaria in children.Design Randomised, open label effectiveness study.Setting Outpatient clinic of Uganda’s national referral hospital in Kampala.Participants 175 children aged 6 to 59 months withuncomplicated malaria.Interventions Participants were randomised to receiveoral quinine or artemether-lumefantrine administered bycare givers at home.Main outcome measures Primary outcomes wereparasitological cure rates after 28 days of follow-upunadjusted and adjusted by genotyping to distinguishrecrudescence from new infections. Secondary outcomeswere adherence to study drug, presence of gametocytes, recovery of haemoglobin concentration from baseline at day 28, and safety profiles.Results Using survival analysis the cure rate unadjustedby genotyping was 96% for the artemether-lumefantrinegroup compared with 64% for the quinine group (hazardratio10.7, 95% confidence interval 3.3 to 35.5, P=0.001).In the quinine group 69% (18/26) of parasitologicalfailures were due to recrudescence compared with none inthe artemether-lumefantrine group. The mean adherenceto artemether-lumefantrine was 94.5% compared with85.4% to quinine (P=0.0008). Having adherence levels of80% or more was associated with a decreased risk oftreatment failure (0.44, 0.19 to 1.02, P=0.06). Adverseevents did not differ between the two groups.ConclusionsThe effectiveness of a seven day course ofquinine for the treatment of uncomplicated malariainUgandanchildren was significantly lower than that ofartemether-lumefantrine. These findings question theadvisability of the recommendation for quinine therapyfor uncomplicated malaria in Africa.Trial registration ClinicalTrials.gov NCT00540202.
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.
Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda
(Massachusetts Medical Society, 2024-08) Conrad, Melissa D.; Asua, Victor; Garg, Shreeya; Giesbrecht, David; Niaré, Karamoko; Smith, Sawyer; Namuganga, Jane F; Katairo, Thomas; Legac, Jennifer; Crudale, Rebecca M; Tumwebaze, Patrick K; Nsobya, Samuel L.; Cooper, Roland A; Kamya, Moses R; Dorsey, Grant; Bailey; Jeffrey A.; Rosenthal, Philip J.
Partial resistance of to the artemisinin component of artemisinin-based combination therapies, the most important malaria drugs, emerged in Southeast Asia and now threatens East Africa. Partial resistance, which manifests as delayed clearance after therapy, is mediated principally by mutations in the kelch protein K13 (PfK13). Limited longitudinal data are available on the emergence and spread of artemisinin resistance in Africa. We performed annual surveillance among patients who presented with uncomplicated malaria at 10 to 16 sites across Uganda from 2016 through 2022. We sequenced the gene encoding kelch 13 ( ) and analyzed relatedness using molecular methods. We assessed malaria metrics longitudinally in eight Ugandan districts from 2014 through 2021. By 2021-2022, the prevalence of parasites with validated or candidate resistance markers reached more than 20% in 11 of the 16 districts where surveillance was conducted. The PfK13 469Y and 675V mutations were seen in far northern Uganda in 2016-2017 and increased and spread thereafter, reaching a combined prevalence of 10 to 54% across much of northern Uganda, with spread to other regions. The 469F mutation reached a prevalence of 38 to 40% in one district in southwestern Uganda in 2021-2022. The 561H mutation, previously described in Rwanda, was first seen in southwestern Uganda in 2021, reaching a prevalence of 23% by 2022. The 441L mutation reached a prevalence of 12 to 23% in three districts in western Uganda in 2022. Genetic analysis indicated local emergence of mutant parasites independent of those in Southeast Asia. The emergence of resistance was observed predominantly in areas where effective malaria control had been discontinued or transmission was unstable. Data from Uganda showed the emergence of partial resistance to artemisinins in multiple geographic locations, with increasing prevalence and regional spread over time. (Funded by the National Institutes of Health.).
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, Grant
Artemisinin-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.
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.
Measures of Malaria Burden after Long- Lasting Insecticidal Net Distribution and Indoor Residual Spraying at Three Sites in Uganda: A Prospective Observational Study
(PLoS medicine, 2016) Katureebe, Agaba; Zinszer, Kate; Arinaitwe, Emmanuel; Rek, John; Kakande, Elijah; Charland, Katia; Kigozi, Ruth; Kilama, Maxwell; Nankabirwa, Joaniter; Yeka, Adoke; Mawejje, Henry; Mpimbaza, Arthur; Katamba, Henry; Donnelly, Martin J.; Rosenthal, Philip J.; Drakeley, Chris; Lindsay, Steve W.; Staedke, Sarah G.; Smith, David L.; Greenhouse, Bryan; Kamya, Moses R.; Dorsey, Grant
Long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are the primary vector control interventions used to prevent malaria in Africa. Although both interventions are effective in some settings, high-quality evidence is rarely available to evaluate their effectiveness following deployment by a national malaria control program. In Uganda, we measured changes in key malaria indicators following universal LLIN distribution in three sites, with the addition of IRS at one of these sites. Methods and Findings Comprehensive malaria surveillance was conducted from October 1, 2011, to March 31, 2016, in three sub-counties with relatively low (Walukuba), moderate (Kihihi), and high transmission (Nagongera). Between 2013 and 2014, universal LLIN distribution campaigns were conducted in all sites, and in December 2014, IRS with the carbamate bendiocarb was initiated in Nagongera. High-quality surveillance evaluated malaria metrics and mosquito exposure before and after interventions through (a) enhanced health-facility-based surveillance to estimate malaria test positivity rate (TPR), expressed as the number testing positive for malaria/number tested for malaria (number of children tested for malaria: Walukuba = 42,833, Kihihi = 28,790, and Nagongera = 38,690); (b) cohort studies to estimate the incidence of malaria, expressed as the number of episodes per person-year [PPY] at risk (number of children observed: Walukuba = 340, Kihihi = 380, and Nagongera = 361); and (c) entomology surveys to estimate household-level human biting rate (HBR), expressed as the number of female Anopheles mosquitoes collected per house-night of collection (number of households observed: Walukuba = 117, Kihihi = 107, and Nagongera = 107). The LLIN distribution campaign substantially increased LLIN coverage levels at the three sites to between 65.0% and 95.5% of households with at least one LLIN. In Walukuba, over the 28-mo post-intervention period, universal LLIN distribution was associated with no change in the incidence of malaria (0.39 episodes PPY pre-intervention versus 0.20 post-intervention; adjusted rate ratio [aRR] = 1.02, 95% CI 0.36±2.91, p = 0.97) and nonsignificant reductions in the TPR (26.5% pre-intervention versus 26.2% post-intervention; aRR = 0.70, 95% CI 0.46±1.06, p = 0.09) and HBR (1.07 mosquitoes per house-night preintervention versus 0.71 post-intervention; aRR = 0.41, 95% CI 0.14±1.18, p = 0.10). In Kihihi, over the 21-mo post-intervention period, universal LLIN distribution was associated with a reduction in the incidence of malaria (1.77 pre-intervention versus 1.89 post-intervention; aRR = 0.65, 95% CI 0.43±0.98, p = 0.04) but no significant change in the TPR (49.3% pre-intervention versus 45.9% post-intervention; aRR = 0.83, 95% 0.58±1.18, p = 0.30) or HBR (4.06 pre-intervention versus 2.44 post-intervention; aRR = 0.71, 95% CI 0.30±1.64, p = 0.40). In Nagongera, over the 12-mo post-intervention period, universal LLIN distribution was associated with a reduction in the TPR (45.3% pre-intervention versus 36.5% post-intervention; aRR = 0.82, 95% CI 0.76±0.88, p < 0.001) but no significant change in the incidence of malaria (2.82 pre-intervention versus 3.28 post-intervention; aRR = 1.10, 95% 0.76±1.59, p = 0.60) or HBR (41.04 pre-intervention versus 20.15 postintervention; aRR = 0.87, 95% CI 0.31±2.47, p = 0.80). The addition of three rounds of IRS at ~6-mo intervals in Nagongera was followed by clear decreases in all outcomes: incidence of malaria (3.25 pre-intervention versus 0.63 post-intervention; aRR = 0.13, 95% CI 0.07±0.27, p < 0.001), TPR (37.8% pre-intervention versus 15.0% post-intervention; aRR = 0.54, 95% CI 0.49±0.60, p < 0.001), and HBR (18.71 pre-intervention versus 3.23 postintervention; aRR = 0.29, 95% CI 0.17±0.50, p < 0.001). High levels of pyrethroid resistance were documented at all three study sites. Limitations of the study included the observational study design, the lack of contemporaneous control groups, and that the interventions were implemented under programmatic conditions. Conclusions Universal distribution of LLINs at three sites with varying transmission intensity was associated with modest declines in the burden of malaria for some indicators, but the addition of IRS at the highest transmission site was associated with a marked decline in the burden of malaria for all indicators. In highly endemic areas of Africa with widespread pyrethroid resistance, IRS using alternative insecticide formulations may be needed to achieve substantial gains in malaria control.
Neurocognitive and Motor Deficits in HIV-Infected Ugandan Children With High CD4 Cell Counts
(Clinical Infectious Diseases, 2012) Ruel,Theodore D.; Boivin, Michael J.; Boal, Hannah E.; Bangirana, Paul; Charlebois,Edwin; Havlir, Diane V.; Rosenthal, Philip J.; Dorsey,Grant; Achan, Jane; Akello, Carolyne; Kamya, Moses R.; Wong, Joseph K.
Background. Human immunodeficiency virus (HIV) infection causes neurocognitive or motor function deficits in children with advanced disease, but it is unclear whether children with CD4 cell measures above the World health Organization (WHO) thresholds for antiretroviral therapy (ART) initiation suffer significant impairment
Pharmacokinetics of Artemether-Lumefantrine and Artesunate-Amodiaquine in Children in Kampala, Uganda
(Antimicrobial agents and chemotherapy, 2010) Mwesigwa, Julia; Parikh, Sunil; McGee, Bryan; German, Polina; Drysdale, Troy; Kalyango, Joan N.; Clark, Tamara D.; Dorsey, Grant; Lindegardh, Niklas; Annerberg, Anna; Rosenthal, Philip J.; Kamya, Moses R.; Aweeka, Francesca
The World Health Organization recommends the use of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria. The two most widely adopted ACT regimens are artemether (AR)- lumefantrine (LR) (the combination is abbreviated AL) and amodiaquine (AQ)-artesunate (AS). Pharmacokinetic (PK) data informing the optimum dosing of these drug regimens is limited, especially in children. We evaluated PK parameters in Ugandan children aged 5 to 13 years with uncomplicated malaria treated with AL (n 20) or AQ-AS (n 21), with intensive venous sampling occurring at 0, 2, 4, 8, 24, and 120 h following administration of the last dose of 3-day regimens of AL (twice daily) or AQ-AS (once daily). AS achieved an estimated maximum concentration in plasma (Cmax) of 51 ng/ml and an area under the concentration-time curve from time zero to infinity (AUC0– ) of 113 ng h/ml; and its active metabolite, dihydroartemisinin (DHA), achieved a geometric mean Cmax of 473 ng/ml and an AUC0– of 1,404 ng h/ml. AR-DHA exhibited a Cmax of 34/119 ng/ml and an AUC0– of 168/382 ng h/ml, respectively. For LR, Cmax and AUC0– were 6,757 ng/ml and 210 g h/ml, respectively. For AQ and its active metabolite, desethylamodiaquine (DEAQ), the Cmaxs were 5.2 ng/ml and 235 ng/ml, respectively, and the AUC0– s were 39.3 ng h/ml and 148 g h/ml, respectively. Comparison of the findings of the present study to previously published data for adults suggests that the level of exposure to LR is lower in children than in adults and that the level of AQ-DEAQ exposure is similar in children and adults. For the artemisinin derivatives, differences between children and adults were variable and drug specific. The PK results generated for children must be considered to optimize the dosing strategies for these widely utilized ACT regimens.
Prolonged Selection of pfmdr1 Polymorphisms After Treatment of Falciparum Malaria With Artemether-Lumefantrine in Uganda
(iseases, 2011) Baliraine, Frederick N.; Rosenthal, Philip J.
We compared the prevalence of key pfmdr1 alleles between pretreatment Plasmodium falciparum parasite isolates and parasites that emerged after treatment of uncomplicated malaria in a longitudinal cohort of Ugandan children. The pfmdr1 86N, 184F, and 1246D alleles were selected after treatment with artemether-lumefantrine, but not after artesunate-amodiaquine or amodiaquine-sulfadoxine-pyrimethamine. Remarkably, selection persisted in infections presenting up to about 60 days after treatment with artemether-lumefantrine. Thus, parasites selected for decreased drug sensitivity can appear long after predicted exposure to antimalarial drugs. Continued surveillance of the clinical efficacy and in vitro activity of new combination therapies is warranted.
Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial doi:10.1371/journal.pmed.1001689
(PLoS medicine, 2014) Bigira, Victor; Kapisi, James; Clark, Tamara D.; Kinara, Stephen; Mwangwa, Stephen; Muhindo, Mary K.; Osterbauer, Beth; Aweeka, Francesca T.; Huang, Liusheng; Achan, Jane; Havlir, Diane V.; Rosenthal, Philip J.; Kamya, Moses R.; Dorsey, Grant
Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children. Methods and Findings: This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%–67%, p,0.001) for DP, 28% (95% CI, 7%–44%, p = 0.01) for TS, and 7% for SP (95% CI, 219% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.Conclusions: For preventing malaria in children living in an area of high transmission intensity, monthly DP was the mostefficacious and safe, although adherence may pose a problem.Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.
Quinine, an old anti-malarial drug in a Modern world: role in the treatment of Malaria
(Malaria journal, 2011) Achan, Jane; Talisuna, Ambrose O.; Erhart, Annette; Yeka, Adoke; Tibenderana, James K.; Baliraine, Frederick N.; Rosenthal, Philip J.; D’Alessandro, Umberto;
Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented.However, itscontinued use is challenged by its poor tolerability, poor compliance with complex dosing regimens,and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine,considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In lightof recent research findings intravenous artesunate should be thefirst-line drug for severe malaria, with quinine asan alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored,but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the managementof malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives becomeavailable. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option thanquinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapidwithdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions toACT stock-outs, maintain quinine in case ofACT stock-outs, and evaluate strategies for improving quininetreatment outcomes by combining it with antibiotics. In HIV andTB infected populations, concerns about potentialinteractions between quinine and antiretroviral and antituberculosis drugs exist, andthese will need furtherresearch and pharmacovigilance.

Browsing by Author "Rosenthal, Philip J."

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