Facilitators and barriers to integrated malaria prevention in Wakiso district, Uganda: A photovoice study.

Malaria continues to cause significant morbidity and mortality globally, particularly in sub-Saharan Africa. Appropriate combinations of non-chemical and chemical methods of malaria vector control in the context of integrated vector management have been recommended by the World Health Organization. The aim of the study was to explore facilitators and barriers to using integrated malaria prevention in Wakiso district, Uganda. This qualitative study employed photovoice among 20 community members in Kasanje Town Council, Wakiso District. The photos taken by participants for 5 months using smartphones were discussed during monthly meetings with the researchers. The discussions were audio-recorded, and resulting data analysed using thematic analysis with the support of NVivo (2020) QSR International. Findings indicated that various conventional and non-conventional measures were being used for preventing malaria such as: insecticide treated nets; clearing overgrown vegetation; draining stagnant water; mosquito coils; smouldering of cow dung; spraying insecticides; plant repellents near houses; eating of prophylactic herbs; as well as closing doors and windows on houses early in the evening. Facilitators supporting the use of several malaria prevention methods holistically included: low cost and accessibility of some methods such as slashing overgrown vegetation; and support provided for certain methods such as receiving free mosquito nets from the government. Barriers to using several malaria prevention methods holistically included: inadequate knowledge of some methods such as housing improvement; allergic reactions to chemical-based methods such as insecticide treated nets; unaffordability of some methods such as insecticide sprays; and inaccessibility of certain methods such as body repellents. These barriers to integrated malaria prevention need to be addressed to achieve greater impact from the combination of methods in endemic communities.

The Effect of a Group-Based Mindfulness and Acceptance Training on Psychological Flexibility and Adherence to Antiretroviral Therapy Among Adolescents in Uganda: An Open-Label Randomized Trial.

Adherence to antiretroviral therapy (ART) is lower in adolescents with HIV (AWH) than in any other age group, partly due to self-regulatory challenges during development. Mindfulness and acceptance training have been shown to support psychological flexibility, a self-regulatory skill that potentially improves adolescent adherence to medication. We assessed the effect of weekly group-based mindfulness and acceptance training sessions on ART adherence among older adolescents (15-19 years) in Kampala, Uganda. One hundred and twenty-two AWH (median age 17, range 15-19 years, 57% female) receiving care at a public health facility in Kampala were randomized 1:1 to receive 4 weekly 90-min group sessions facilitated by experienced trainers or standard-of-care ART services. The training involved (Session 1) clarifying values, (Session 2) skillfully relating to thoughts, (Session 3) allowing and becoming aware of experiences non-judgmentally, and (Session 4) exploring life through trial and error. At baseline, postintervention, and 3-month follow-up, psychological flexibility was measured using the Avoidance and Fusion Questionnaire for Youth (AFQ-Y8), and self-reported ART adherence was assessed using the Morisky Medication Adherence Scale (MMAS-8). At baseline, the intervention and standard-of-care arms had similar psychological flexibility (AFQ-Y8 score:15.45 ± 0.82; 15.74 ± 0.84) and ART adherence (MMAS-8 score: 5.32 ± 0.24; 5.13 ± 0.23). Retention through the study was moderate (71%). Completion of mindfulness and acceptance training was associated with a significant reduction in psychological inflexibility at the 3-month follow-up (AFQ-Y8 score: 12.63 ± 1.06; 14.05 ± 1.07, P = .006). However, no significant differences were observed in self-reported adherence to ART at the 3-month follow-up (MMAS-8 score: 5.43 ± 0.23; 4.90 ± 0.33, P = .522). Group-based mindfulness and acceptance training improved psychological flexibility in this population of adolescents on ART in Uganda but did not significantly improve ART adherence. Future research should explore integrated approaches that combine behavioral management training with other empowerment aspects to improve ART adherence among AWH.

Acceptability of an adapted mindfulness and acceptance-based intervention to support adolescents with HIV: A qualitative study with Ugandan health care providers.

While the adaptation of evidence-based psychosocial support tailors the intervention components to the targeted context, minimizing the associated costs of developing new interventions for low-income contexts, the acceptability of such adapted interventions is important for augmenting successful implementation and sustainability. Given that psychosocial support to persons living with HIV is mostly rendered by healthcare providers, their acceptance of adapted interventions before implementation is crucial. This study explored healthcare providers' acceptance of an adapted mindfulness and acceptance-based intervention supporting adolescents with HIV. Ten healthcare providers at two urban clinics in Kampala, Uganda attended a three-day training on using the adapted intervention and gave feedback on its appropriateness during in-depth interviews conducted thereafter. Semi-structured interviews were based on the Theoretical Framework of Acceptability and findings were analyzed abductively within the seven components of the framework. Overall, the adapted intervention was perceived to be acceptable and appropriate for use with adolescents. Benefits included the intervention offering support beyond a focus on adherence to drugs, refocusing adolescents on aspects in their lives that matter most, and being easy to integrate into providers' work processes. Providers however expressed concern about the time the intervention requires and the possibility of increasing their workload. These findings will support further adaptation and implementation.

Culturally adapting a mindfulness and acceptance-based intervention to support the mental health of adolescents on antiretroviral therapy in Uganda.

The dual burden of living with HIV and negotiating life stage changes has been identified as a contributing factor to lapsed adherence among adolescents with HIV in sub-Saharan Africa. While psychosocial support can promote medication adherence, most interventions in use with adolescents were originally developed for the general population creating a gap in appropriate support. Life-stage-appropriate, evidence-based psychosocial support interventions have been used with young people in high-income contexts, prompting interest in their use in low-income contexts. However, many interventions are less effective when implemented outside of their original settings, hence the need for modifications before implementation. We aimed to culturally adapt an evidence-based psychosocial support intervention designed to improve the mental health of young people for use among adolescents with HIV in a sub-Saharan African context and to explore the acceptability of the adapted intervention among adolescents. We engaged thirty stakeholders (n = 30) in Kampala, Uganda including psychologists, psychiatrists, social workers, HIV counselors, religious leaders and adolescent peers from December 2021 to April 2022 to modify an evidence-based intervention for adolescents. Key adaptations included simplifying the language, adding local practices, integrating locally relevant slang and stories into therapy, introducing racially-congruent visuals and cards representing emotions, and adjusting therapy materials for use in resource-constrained settings. We then tested the acceptability of the intervention in a small sample of service users using a qualitative approach. We recruited nine adolescents with HIV from a participating clinic in Kampala, delivered six 90-minute sessions of the adapted intervention across three weeks and conducted in-depth interviews to assess the acceptability of the intervention. We used thematic analysis to analyze the qualitative data. The adapted intervention was perceived as acceptable among adolescents with HIV, with many stating that it helped them overcome fears, increased their self-acceptance, and gave them the confidence to make careful health-enhancing decisions.

Effect of a patient-centered hypertension delivery strategy on all-cause mortality: Secondary analysis of SEARCH, a community-randomized trial in rural Kenya and Uganda.

BACKGROUND: Hypertension treatment reduces morbidity and mortality yet has not been broadly implemented in many low-resource settings, including sub-Saharan Africa (SSA). We hypothesized that a patient-centered integrated chronic disease model that included hypertension treatment and leveraged the HIV care system would reduce mortality among adults with uncontrolled hypertension in rural Kenya and Uganda. METHODS AND FINDINGS: This is a secondary analysis of the SEARCH trial (NCT:01864603), in which 32 communities underwent baseline population-based multidisease testing, including hypertension screening, and were randomized to standard country-guided treatment or to a patient-centered integrated chronic care model including treatment for hypertension, diabetes, and HIV. Patient-centered care included on-site introduction to clinic staff at screening, nursing triage to expedite visits, reduced visit frequency, flexible clinic hours, and a welcoming clinic environment. The analytic population included nonpregnant adults (≥18 years) with baseline uncontrolled hypertension (blood pressure ≥140/90 mm Hg). The primary outcome was 3-year all-cause mortality with comprehensive population-level assessment. Secondary outcomes included hypertension control assessed at a population level at year 3 (defined per country guidelines as at least 1 blood pressure measure <140/90 mm Hg on 3 repeated measures). Between-arm comparisons used cluster-level targeted maximum likelihood estimation. Among 86,078 adults screened at study baseline (June 2013 to July 2014), 10,928 (13%) had uncontrolled hypertension. Median age was 53 years (25th to 75th percentile 40 to 66); 6,058 (55%) were female; 677 (6%) were HIV infected; and 477 (4%) had diabetes mellitus. Overall, 174 participants (3.2%) in the intervention group and 225 participants (4.1%) in the control group died during 3 years of follow-up (adjusted relative risk (aRR) 0.79, 95% confidence interval (CI) 0.64 to 0.97, p = 0.028). Among those with baseline grade 3 hypertension (≥180/110 mm Hg), 22 (4.9%) in the intervention group and 42 (7.9%) in the control group died during 3 years of follow-up (aRR 0.62, 95% CI 0.39 to 0.97, p = 0.038). Estimated population-level hypertension control at year 3 was 53% in intervention and 44% in control communities (aRR 1.22, 95% CI 1.12 to 1.33, p < 0.001). Study limitations include inability to identify specific causes of death and control conditions that exceeded current standard hypertension care. CONCLUSIONS: In this cluster randomized comparison where both arms received population-level hypertension screening, implementation of a patient-centered hypertension care model was associated with a 21% reduction in all-cause mortality and a 22% improvement in hypertension control compared to standard care among adults with baseline uncontrolled hypertension. Patient-centered chronic care programs for HIV can be leveraged to reduce the overall burden of cardiovascular mortality in SSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864603.

Hypertension control in integrated HIV and chronic disease clinics in Uganda in the SEARCH study.

BACKGROUND: There is an increasing burden of hypertension (HTN) across sub-Saharan Africa where HIV prevalence is the highest in the world, but current care models are inadequate to address the dual epidemics. HIV treatment infrastructure could be leveraged for the care of other chronic diseases, including HTN. However, little data exist on the effectiveness of integrated HIV and chronic disease care delivery systems on blood pressure control over time. METHODS: Population screening for HIV and HTN, among other diseases, was conducted in ten communities in rural Uganda as part of the SEARCH study (NCT01864603). Individuals with either HIV, HTN, or both were referred to an integrated chronic disease clinic. Based on Uganda treatment guidelines, follow-up visits were scheduled every 4 weeks when blood pressure was uncontrolled, and either every 3 months, or in the case of drug stock-outs more frequently, when blood pressure was controlled. We describe demographic and clinical variables among all patients and used multilevel mixed-effects logistic regression to evaluate predictors of HTN control. RESULTS: Following population screening (2013-2014) of 34,704 adults age ≥ 18 years, 4554 individuals with HTN alone or both HIV and HTN were referred to an integrated chronic disease clinic. Within 1 year 2038 participants with HTN linked to care and contributed 15,653 follow-up visits over 3 years. HTN was controlled at 15% of baseline visits and at 46% (95% CI: 44-48%) of post-baseline follow-up visits. Scheduled visit interval more frequent than clinical indication among patients with controlled HTN was associated with lower HTN control at the subsequent visit (aOR = 0.89; 95% CI 0.79-0.99). Hypertension control at follow-up visits was higher among HIV-infected patients than uninfected patients to have controlled blood pressure at follow-up visits (48% vs 46%; aOR 1.28; 95% CI 0.95-1.71). CONCLUSIONS: Improved HTN control was achieved in an integrated HIV and chronic care model. Similar to HIV care, visit frequency determined by drug supply chain rather than clinical indication is associated with worse HTN control. TRIAL REGISTRATION: The SEARCH Trial was prospectively registered with ClinicalTrials.gov : NCT01864603.

Bacteremia Among Febrile Ugandan Children Treated with Antimalarials Despite a Negative Malaria Test.

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 referral hospital in Uganda, bacteremia was a remarkably common finding in children with febrile illness who were treated for malaria despite negative malaria test results.

Missed opportunities for HIV testing and late-stage diagnosis among HIV-infected patients in Uganda.

BACKGROUND: Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis. METHODS: Patients who had never tested for HIV or tested negative over one year prior to recruitment were enrolled between May 2008 and March 2010. Participants who tested HIV positive had a blood draw for CD4. Late HIV diagnosis was defined as CD4≤250 cells/mm. Predictors of late HIV diagnosis were analyzed using multi-variable logistic regression. RESULTS: Of 1966 participants, 616 (31.3%) were HIV infected; 47.6% of these (291) had CD4 counts ≤250. Overall, 66.7% (408) of the HIV infected participants had never received care in a medical clinic. Receiving care in a non-medical setting (home, traditional healer and drug stores) had a threefold increase in the odds of late diagnosis (OR = 3.2; 95%CI: 2.1-4.9) compared to receiving no health care. CONCLUSIONS: Late HIV diagnosis remains prevalent five years after introducing provider-initiated HIV testing in Uganda. Many individuals diagnosed with advanced HIV did not have prior exposure to medical clinics and could not have benefitted from the expansion of provider initiated HIV testing within health facilities. In addition to provider-initiated testing, approaches that reach individuals using non-hospital based encounters should be expanded to ensure early HIV diagnosis.

Early virologic failure and the development of antiretroviral drug resistance mutations in HIV-infected Ugandan children.

BACKGROUND: Without virologic testing, HIV-infected African children starting antiretroviral (ARV) therapy are at risk for undetected virologic failure and the development of ARV resistance. We sought to determine the prevalence of early virologic failure (EVF), to characterize the evolution of ARV-resistance mutations and to predict the impact on second-line therapy. METHODS: The prevalence of EVF (HIV RNA >400 copies/mL on sequential visits after 6 months of therapy) was identified among 120 HIV-infected Ugandan children starting ARV therapy. ARV mutations were identified by population sequencing of HIV-1 pol in sequential archived specimens. Composite discrete genotypic susceptibility scores were determined for second-line ARV regimens. RESULTS: EVF occurred in 16 children (13%) and persisted throughout a median (interquartile ratio) 938 (760-1066) days of follow-up. M184V and nonnucleoside reverse transcriptase inhibitor-associated mutations emerged within 6 months of EVF; thymidine-analog-mutations arose after 12 months. Worse discrete genotypic susceptibility scores correlated with increasing duration of failure (Spearman R = -0.47; P = 0.001). Only 1 child met World Health Organization CD4 criteria for ARV failure at the time of EVF or during the follow-up period. CONCLUSIONS: A significant portion of HIV-infected African children experience EVF that would be undetected using CD4/clinical monitoring and resulted in the accumulation of ARV mutations that could compromise second-line therapy options.

High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda.

BACKGROUND: 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%; p = .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/mm(3)). 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%; p < .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.

Belief in divine healing can be a barrier to antiretroviral therapy adherence in Uganda.

Although recent data suggest high levels of adherence to expanding antiretroviral therapy (ART) programmes in resource-limited settings, the culture-specific barriers to adherence are poorly understood. In a prospective observational study, we found that 1.2% of patients discontinued ART because of a belief in spiritual healing. Spiritual beliefs should be an important part of ART adherence counselling in resource-limited settings, requiring close collaboration between HIV care programmes and religious leaders to identify common goals and ensure successful treatment.

Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial.

CONTEXT: Combination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas. OBJECTIVE: To compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria. DESIGN, SETTING, AND PARTICIPANTS: Single-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic. INTERVENTIONS: Study participants were randomized to receive 1 of 3 combination therapies (amodiaquine plus sulfadoxine-pyrimethamine, amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes. MAIN OUTCOME MEASURE: 28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs. RESULTS: Of enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P< or =.008 for all pairwise comparisons, except amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing. CONCLUSIONS: Artemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN37517549.

Traditional healers for HIV/AIDS prevention and family planning, Kiboga District, Uganda: evaluation of a program to improve practices.

In the face of ongoing epidemics of HIV/AIDS and STI, high demand for family planning, and limited resources, traditional healers may be under-utilized providers of reproductive health education in rural sub-Saharan Africa. We implemented a training program in HIV prevention and family planning methods for healers in the Kiboga district of Uganda and evaluated the program's impact on healers' clinical practice and the diffusion of information to their female clients. Of 46 healers recruited, 30 (65%) completed a pre- and post-training interview. Following training, traditional healers increased discussions of family planning with their clients. Of 84 female clients recruited, 44 (52%) completed the interview before and after the training for healers. Female clients corroborated that they increased discussions of family planning with their healers, as well as discussions about HIV/AIDS. Both healers and their female clients were more likely to make a connection between family planning, condom use, and HIV prevention after the training compared to before the training. Findings provide evidence that traditional healers in a rural area of Uganda can successfully adapt HIV prevention messages and family planning information into their clinical practices.

Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda.

BACKGROUND: Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. METHODS AND FINDINGS: We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%-18% and 4%-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p < 0.003). CONCLUSION: AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Prevention of increasing rates of treatment failure by combining sulfadoxine-pyrimethamine with artesunate or amodiaquine for the sequential treatment of malaria.

Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studied Ugandan children who were treated for uncomplicated malaria with sulfadoxine-pyrimethamine (SP), SP + amodiaquine (AQ), or SP + artesunate (AS). We compared treatment responses and the prevalence of resistance-conferring mutations of new infections with those of recrudescent infections due to parasites that survived prior treatment. Recrudescent infections were associated with the selection of SP resistance-conferring mutations in all treatment groups, but responses to repeat therapy differed. Compared with initial treatments, treatment of recrudescent infections was associated with a higher rate of treatment failure (hazard ratio [HR], 2.44; P=.01), for the SP group, but with a lower rate of treatment failure (HR, 0.40; P=.08), for the SP + AS group. Treatment failure in the SP + AQ group was uncommon, limiting the analysis of recrudescent parasites. Our results suggest that the use of combination antimalarial therapy in Africa may slow the spread of drug-resistant malaria and prolong the therapeutic life span of available treatment regimens.

Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial.

BACKGROUND: New antimalarial treatments are urgently needed in sub-Saharan Africa. Improved therapies should decrease failure rates in the short term, but their effect on incidence of subsequent episodes of malaria is little studied. We aimed to compare the short-term and long-term effectiveness of three antimalarial regimens in children from Kampala, Uganda. METHODS: We randomly allocated healthy children aged 6 months to 5 years to receive 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine plus either placebo, 25 mg/kg amodiaquine, or 12 mg/kg artesunate. Participants were followed up for 1 year and received the same preassigned treatment for every new episode of uncomplicated malaria diagnosed during follow-up. Recrudescent and new infections were distinguished by comparison of polymorphisms in merozoite surface protein 2 (MSP2). Our primary endpoint was the total number of treatments for malaria per time at risk. Analyses were done per protocol. FINDINGS: 183 (61%) of 316 participants were diagnosed with at least one episode of uncomplicated malaria. A total of 577 episodes of uncomplicated Plasmodium falciparum malaria were treated with study drugs; all regimens were safe and well tolerated. Clinical treatment failure after 14 days was significantly more frequent in the sulfadoxine/pyrimethamine group (38 of 215, 18%) compared with either the sulfadoxine/pyrimethamine plus amodiaquine group (two of 164, 1%; p<0.0001) or sulfadoxine/pyrimethamine plus artesunate group (one of 198, 1%; p<0.0001). After 28 and 42 days, patients in the sulfadoxine/pyrimethamine plus amodiaquine group were significantly less likely to develop malaria than were those in the other groups. Overall, sulfadoxine/pyrimethamine plus amodiaquine reduced the rate of subsequent treatments for malaria by 54% (95% CI 36-66, p<0.0001) compared with sulfadoxine/ pyrimethamine alone and by 37% (12-54, p=0.007) compared with sulfadoxine/pyrimethamine plus artesunate. INTERPRETATION: Sulfadoxine/pyrimethamine plus amodiaquine could be used as an inexpensive regimen to decrease the rate of subsequent episodes of malaria.