Jane ACHAN

Thesis summary

Background and Rationale

Malaria is a public health problem in over 100 countries worldwide that are inhabited by 40% of the world’s population. It is considered one of the world’s most important tropical parasitic infections and about 3.3 billion people are considered at risk for malaria infection worldwide. In 2010 alone, an estimated 219 million malaria cases occurred globally, and the disease killed about 660 000 people, mostly children under five years of age. Countries in sub-Saharan Africa (SSA) account for more than 90% of these cases. Uganda as a country is emblematic of the immense malaria burden in SSA as a large majority of its territory is endemic for malaria. Reports by the Ministry of Health indicate that malaria is the leading cause of morbidity and mortality, accounting for approximately 8-13 million episodes per year, 30-50% of outpatient visits at health facilities, 35% of hospital admissions, 9-14% of hospital deaths, with nearly half of these occurring in children less than 5 years of age.

SSA also bears the greatest brunt of the worldwide HIV epidemic with more than two-thirds of the worldwide HIV-infected individuals living in SSA, where 76% of all AIDS-related deaths occurred in 2007. Together, these two diseases, account for a combined 4 million deaths annually. The epidemiological and geographical overlap of HIV and malaria therefore presents a significant public health problem in terms of the management of both infections and the potential interactions between the two diseases.

Malaria is however a preventable and treatable disease and effective preventive and curative tools are available. These include (i) vector control measures, namely ITNs, IRS and, in some limited settings, larval control; (ii) chemoprevention for the most vulnerable populations, particularly pregnant women and infants; (iii) confirmed diagnosis by microscopy or rapid diagnostic tests (RDTs) for every suspected case, and (iv) timely treatment with appropriate antimalarial medicines. Of these measures, disease management stands out as a fundamental and indispensable element of malaria control. However, a number of potential challenges exist that may impact on malaria case management of including the need to review treatment options available for uncomplicated malaria management, especially in light of difficulties in the utilization of oral quinine given its complex dosing regimen, challenges in the management of severe malaria in resource limited settings that may lead to significant mismanagement and increased mortality, the need to identify alternative therapeutic agents in light of declining efficacy of previously utilized drugs and finally the challenges of management of malaria in special risk groups like HIV infected individuals where the potential for drug interactions could have an impact on of drug efficacy and occurrence of toxicity.

Objectives

In light of the current malaria control interventions, we designed a series of studies to better characterize and describe the challenges inherent to the treatment of both uncomplicated and severe malaria in Uganda, as a representative of similar settings in SSA. The specific objectives were i) to assess the effectiveness of oral quinine in the management of uncomplicated malaria, ii) to describe the current management practices for severe malaria at Ugandan health facilities iii) to critically review the historical role of quinine, document its current usage, and provide some insights into its appropriate future use in the treatment of malaria and iv) to explore the potential impact of co-treatment of HIV and malaria on malaria treatment outcomes in HIV infected populations.

Methods

Between 2009 and 2011, we conducted several studies to evaluate different aspects of malaria treatment. Sub-study 1 was an open label randomized trial evaluating the effectiveness of oral quinine and artemether-lumefantrine in the treatment of uncomplicated malaria in Ugandan children. The primary effectiveness outcomes were day-28 parasitological and clinical cure rates. Sub-study 2 was a cross sectional evaluation of severe malaria management practices in selected health facilities in Uganda using multi-stage sampling methods. The assessment employed survey instruments adapted from the World Health Organisation: Hospital assessment tool (WHO, 2002). The main outcome measure was quality of severe malaria case management. Sub-study 3 was a randomized open label trial of HIV-infected children aged 2 months to 5 years eligible for ART or currently receiving an NNRTI-based ART regimen. Participants were randomized to receive either LPV/r-based or NNRTI-based ART and followed for 2 years, and were treated with artemether-lumefantrine when they developed uncomplicated malaria. The primary endpoint was incidence of malaria. Secondary outcomes included incidence of complicated malaria, efficacy and safety of antimalarial therapy, and lumefantrine pharmacokinetics. In addition, in a review article, we detail the historical role of quinine, considered its current usage and provided some insight into its appropriate future role in the treatment of malaria.

Major Findings

Quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria

To evaluate the effectiveness of oral quinine versus artemether-lumefantrine for the treatment of uncomplicated, 175 children aged 6 to 59 months with uncomplicated malaria were randomized to receive oral quinine or artemether-lumefantrine administered by care givers at home. Day 28 cure rates unadjusted by genotyping were 96% for the artemether-lumefantrine group compared with 64% for the quinine group (hazard ratio 10.7, 95% confidence interval 3.3 to 35.5, P=0.001). In the quinine group 69% (18/26) of parasitological failures were due to recrudescence compared with none in the artemether-lumefantrine group. The mean adherence to artemether-lumefantrine was 94.5% compared with 85.4% to quinine (P=0.0008). Having adherence levels of 80% or more was associated with a decreased risk of treatment failure (0.44, 0.19 to 1.02, P=0.06). Adverse events did not differ between the two groups.

Case management of severe malaria in health facilities

To evaluate the management practices for severe malaria in Ugandan health facilities, we did a cross sectional survey of health facilities in 11 districts in the eastern and mid-western parts of Uganda. One hundred and five health facilities were surveyed and 181 health workers and 868 patients/caretakers interviewed. None of the inpatient facilities had all seven components of a basic care package for the management of severe malaria consistently available during the 3 months prior to the survey. Referral practices were appropriate for < 10% (18/196) of the patients. Prompt care at any health facility was reported by 29% (247/868) of patients. Severe malaria was correctly diagnosed in 27% of patients (233).Though the quinine dose and regimen was correct in the majority (611/868, 70.4%) of patients, it was administered in the correct volumes of 5% dextrose in only 18% (147/815). Most patients (80.1%) had several doses of quinine administered in one single 500ml bottle of 5% dextrose. Medications were purchased by 385 (44%) patients and medical supplies by 478 patients (70.6%).

Malaria treatment in HIV infected children receiving antiretroviral treatment (ART)

We enrolled 176 children HIV infected children of whom 170 received the study ART regimen: 86 received NNRTI-based ART and 84 received lopinavir-ritonavir-based ART. The incidence of malaria was lower among children receiving the lopinavir-ritonavir-based regimen than among those receiving the NNRTI-based regimen (1.32 vs. 2.25 episodes per person-year, IRR 0.59, 95% confidence interval [CI], 0.36-0.97, p=0.04), as was the risk of a recurrence of malaria after treatment with artemether-lumefantrine (28.1% vs. 54.2%, HR 0.41 95% CI 0.22-0.76, p = 0.004). The median lumefantrine level on day 7 after treatment for malaria was significantly higher in the lopinavir-ritonavir group than in the NNRTI group.  In the lopinavir-ritonavir group, lumefantrine levels exceeding 300ng per milliliter on day 7 were associated with a reduction of more than 85% in the 63-day risk of recurrent malaria. A greater number of serious adverse events occurred in lopinavir-ritonavir group than in the NNRTI group (5.6% vs. 2.3%, P = 0.16). Pruritus occurred significantly more frequently in the lopinavir-ritonavir group, and elevated alanine aminotransferase levels significantly more frequently in the NNRTI group.

Conclusions and implications for policy

These studies provide evidence that more informed treatment approaches can be designed and utilized in the management of malaria in different populations with improvement in treatment outcomes. For uncomplicated malaria this will be achieved through the consistent and timely utilization of ACTs both for first-line and second-line treatment options. For severe malaria, a package of interventions addressing health systems weaknesses, health worker skills and availability of medicines and supplies will provide the necessary positive impact. For HIV infected populations, strategic utilization of protease-inhibitor based antiretroviral regimens will contribute significantly to reduced malaria burden.