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Scholarly Works (11 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2016)

There have been remarkable achievements in the global fight against malaria over the past decade, with a growing number of countries moving towards malaria elimination. Sustaining these gains and eliminating malaria will require the right set of interventions and strategies that target the entire Plasmodium falciparum (P. falciparum) parasite reservoir, including both the mosquito vector and the human host. Primaquine is the only available drug that clears mature P. falciparum gametocytes in humans, thereby preventing transmission to the mosquito vector. However, the drug’s oxidative capacity to cause hemolytic effects in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, has limited its deployment because of safety concerns. G6PD deficiency is an X-linked enzyme defect that affects over 400 million people worldwide and is relatively common in malaria endemic areas. To reduce P. falciparum malaria transmission in eliminating settings and areas threatened by artemisinin resistance, the World Health Organization (WHO) recommends adding a 0.25 mg/kg dose of primaquine, lowered from a previously higher 0.75 mg/kg dose, to standard artemisinin-based combination therapy (ACT) without G6PD testing. This policy change, issued in 2012, was based on data gathered passively from limited pharmacovigilance systems and lacks substantive evidence to support the safety of the recommendation. The objective of this dissertation was to evaluate the safety of malaria treatment in G6PD-deficient individuals and contribute evidence to support the programmatic use of primaquine for falciparum malaria.

The study designs and populations presented in this dissertation include: 1) a secondary analysis of data from a double-blind, placebo-controlled trial of preventive antimalarial treatment in asymptomatic infants (n = 1557) in Tanzania (Chapter 1); 2) a pilot study evaluating a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine among confirmed, uncomplicated malaria cases (n = 102) in Swaziland (Chapter 2); and 3) a pooled analysis of individual-level patient data in malaria-infected patients (n = 604) from two randomized controlled trials in Senegal and Tanzania and two active pharmacovigilance programs in Bangladesh and Swaziland (Chapter 3).

In the trial of asymptomatic infants in Tanzania, findings demonstrated that treatment with an antimalarial drug known to have oxidative potential like primaquine reduced hemoglobin levels at 7 and 14 days post-treatment, relative to placebo and other antimalarial treatments. Also, at day 7, G6PD deficiency was associated with higher odds of moderate anemia (hemoglobin <8 g/dL) and greater absolute reductions in hemoglobin. However, there was no evidence that G6PD deficiency exacerbated the adverse effects of oxidative treatment. Measuring the risk of adverse effects in G6PD-deficient individuals associated with oxidative treatment is challenging due to limited data.

The pilot study of the Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT) served to facilitate the systematic collection of primaquine safety data. Results illustrated the feasibility and acceptability of implementing active safety monitoring to support surveillance of possible adverse events, including clinically important drops in hemoglobin, following primaquine treatment. Data that include sufficient G6PD-deficient individuals through the wider adoption of PROMPT can allow for pooled analyses powered to reliably detect statistically significant increased risks of hemolysis.

In the pooled analysis of data collected using PROMPT, results supported the addition of a single dose of 0.25 mg/kg primaquine to ACT in the treatment of uncomplicated P. falciparum malaria. An analysis of randomized clinical trial data among G6PD-deficient individuals found that the addition of 0.25 mg/kg primaquine to ACT did not significantly increase risk of hemolysis. An analysis using all available data showed that falls in hemoglobin following treatment appeared greater in G6PD-deficient individuals compared to G6PD-normal individuals but that doses ≤0.5 mg/kg, (double the WHO recommended 0.25 mg/kg dose) did not result in greater hemolysis in G6PD-deficient versus G6PD normal individuals.

Taken together, the studies outlined in this dissertation serve to better characterize the safety profile of primaquine to support its safe use as a gametocytocide for P. falciparum malaria elimination.

    Cover page: Evaluating the safety of malaria treatment in glucose-6-phosphate dehydrogenase-deficient individuals: evidence and tools to support malaria elimination
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2012)
    Abstract Background Policy makers have speculated that one of the economic benefits of malaria elimination includes increases in foreign direct investment, particularly tourism. Methods This study examines the empirical relationship between the demand for travel and malaria cases in two countries with large tourism industries around the time in which they carried out malaria-elimination campaigns. In Mauritius, this analysis examines historical, yearly tourist arrivals and malaria cases from 1978–1999, accounting for the background secular trend of increasing international travel. In Dominican Republic, a country embarking upon malaria elimination, it employs a time-series analysis of the monthly, international tourist arrivals from 1998–2010 to determine whether the timing of significant deviations in tourist arrivals coincides with malaria outbreaks. Results While naïve relationships exist in both cases, the results show that the relationships between tourist arrivals and malaria cases are relatively weak and statistically insignificant once secular confounders are accounted for. Conclusions This suggests that any economic benefits from tourism that may be derived from actively pursuing elimination in countries that have high tourism potential are likely to be small when measured at a national level. Rather, tourism benefits are likely to be experienced with greater impact in more concentrated tourist areas within countries, and future studies should seek to assess these relationships at a regional or local level.
      Cover page: The economic benefits of malaria elimination: do they include increases in tourism?
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2013)
      Abstract Background Swaziland has made great progress towards its goal of malaria elimination by 2015. However, malaria importation from neighbouring high-endemic Mozambique through Swaziland’s eastern border remains a major factor that could prevent elimination from being achieved. In order to reach elimination, Swaziland must rapidly identify and treat imported malaria cases before onward transmission occurs. Methods A nationwide formative assessment was conducted over eight weeks to determine if the imported cases of malaria identified by the Swaziland National Malaria Control Programme could be linked to broader social networks and to explore methods to access these networks. Results Using a structured format, interviews were carried out with malaria surveillance agents (6), health providers (10), previously identified imported malaria cases (19) and people belonging to the networks identified through these interviews (25). Most imported malaria cases were Mozambicans (63%, 12/19) making a living in Swaziland and sustaining their families in Mozambique. The majority of imported cases (73%, 14/19) were labourers and self-employed contractors who travelled frequently to Mozambique to visit their families and conduct business. Social networks of imported cases with similar travel patterns were identified through these interviews. Nearly all imported cases (89%, 17/19) were willing to share contact information to enable network members to be interviewed. Interviews of network members and key informants revealed common congregation points, such as the urban market places in Manzini and Malkerns, as well as certain bus stations, where people with similar travel patterns and malaria risk behaviours could be located and tested for malaria. Conclusion This study demonstrated that imported cases of malaria belonged to networks of people with similar travel patterns. This study may provide novel methods for screening high-risk groups of travellers using both snowball sampling and time-location sampling of networks to identify and treat additional malaria cases. Implementation of a proactive screening programme of importation networks may help Swaziland halt transmission and achieve malaria elimination by 2015.
        Cover page: Targeting imported malaria through social networks: a potential strategy for malaria elimination in Swaziland
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2016)

        Background

        A malaria eradication goal has been proposed, at the same time as a new global strategy and implementation framework. Countries are considering the strategies and tools that will enable progress towards malaria goals. The eliminating malaria case-study series reports were reviewed to identify successful programme management components using a cross-case study analytic approach.

        Methods

        Nine out of ten case-study reports were included in the analysis (Bhutan, Cape Verde, Malaysia, Mauritius, Namibia, Philippines, Sri Lanka, Turkey, Turkmenistan). A conceptual framework for malaria elimination programme management was developed and data were extracted and synthesized. Findings were reviewed at a consultative workshop, which led to a revision of the framework and further data extraction and synthesis. Success factors of implementation, programme choices and changes, and enabling factors were distilled.

        Results

        Decentralized programmes enhanced engagement in malaria elimination by sub-national units and communities. Integration of the malaria programme into other health services was also common. Decentralization and integration were often challenging due to the skill and experience levels of newly tasked staff. Accountability for programme impact was not clarified for most programmes. Motivation of work force was a key factor in maintaining programme quality but there were few clear, detailed strategies provided. Different incentive schemes targeted various stakeholders. Training and supervision, although not well described, were prioritized by most programmes. Multi-sectoral collaboration helped some programmes share information, build strategies and interventions and achieve a higher quality of implementation. In most cases programme action was spurred by malaria outbreaks or a new elimination goal with strong leadership. Some programmes showed high capacity for flexibility through introduction of new strategies and tools. Several case-studies described methods for monitoring implementation quality and coverage; however analysis and feedback to those implementing malaria elimination in the periphery was not well described. Political commitment and sustained financing contributed to malaria programme success. Consistency of malaria programmes depends on political commitment, human and financial resources, and leadership. Operational capacity of the programme and the overall health system structure and strength are also important aspects.

        Conclusions

        Malaria eradication will require adaptive, well-managed malaria programmes that are able to tailor implementation of evidence-based strategies, founded upon strong sub-national surveillance and response, with adequate funding and human resources.
          Cover page: The central role of national programme management for the achievement of malaria elimination: a cross case-study analysis of nine malaria programmes
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2016)

          Background

          There has been progress towards malaria elimination in the last decade. In response, WHO launched the Global Technical Strategy (GTS), in which vector surveillance and control play important roles. Country experiences in the Eliminating Malaria Case Study Series were reviewed to identify success factors on the road to elimination using a cross-case study analytic approach.

          Methods

          Reports were included in the analysis if final English language draft reports or publications were available at the time of analysis (Bhutan, Cape Verde, Malaysia, Mauritius, Namibia, Philippines, Sri Lanka, Turkey, Turkmenistan). A conceptual framework for vector control in malaria elimination was developed, reviewed, formatted as a matrix, and case study data was extracted and entered into the matrix. A workshop was convened during which participants conducted reviews of the case studies and matrices and arrived at a consensus on the evidence and lessons. The framework was revised and a second round of data extraction, synthesis and summary of the case study reports was conducted.

          Results

          Countries implemented a range of vector control interventions. Most countries aligned with integrated vector management, however its impact was not well articulated. All programmes conducted entomological surveillance, but the response (i.e., stratification and targeting of interventions, outbreak forecasting and strategy) was limited or not described. Indoor residual spraying (IRS) was commonly used by countries. There were several examples of severe reductions or halting of IRS coverage and subsequent resurgence of malaria. Funding and operational constraints and poor implementation had roles. Bed nets were commonly used by most programmes; coverage and effectiveness were either not measured or not articulated. Larval control was an important intervention for several countries, preventing re-introduction, however coverage and impact on incidence were not described. Across all interventions, coverage indicators were incomparable, and the rationale for which tools were used and which were not used appeared to be a function of the availability of funding, operational issues and cost instead of evidence of effectiveness to reduce incidence.

          Conclusions

          More work is required to fill gaps in programme guidance, clarify the best methods for choosing and targeting vector control interventions, and support to measure cost, cost-effectiveness and cost-benefit of vector surveillance and control interventions.
            Cover page: Strategies and approaches to vector control in nine malaria-eliminating countries: a cross-case study analysis.
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2016)

            Background

            Countries remain reluctant to adopt the 2012 World Health Organization recommendation for single low-dose (0.25 mg/kg) primaquine (SLD PQ) for Plasmodium falciparum transmission-blocking due to concerns over drug-related haemolysis risk, especially among glucose-6-phosphate dehydrogenase-deficient (G6PDd) people, without evidence demonstrating that it can be safely deployed in their settings. Pharmacovigilance methods provide a systematic way of collecting safety data and supporting the rollout of SLD PQ.

            Methods

            The Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT), comprising: (1) a standardized form to support the surveillance of possible adverse events following SLD PQ treatment; (2) a patient information card to enhance awareness of known adverse drug reactions of SLD PQ use; and (3) a database compiling recorded information, was developed and piloted. Data on patient characteristics, malaria diagnosis and treatment are collected. Blood samples are taken to measure haemoglobin (Hb) and test for G6PD deficiency. Active follow-up includes a repeat Hb measurement and adverse event monitoring on or near day 7. A 13-month prospective pilot study in two hospital facilities in Swaziland alongside the introduction of SLD PQ generated preliminary evidence on the feasibility and acceptability of PROMPT.

            Results

            PROMPT was well received by nurses as a simple, pragmatic approach to active surveillance of SLD PQ safety data. Of the 102 patients enrolled and administered SLD PQ, none were G6PDd. 93 (91.2 %) returned on or near day 7 for follow-up. Four (4.6 %) patients had falls in Hb ≥25 % from baseline, none of whom presented with signs or symptoms of anaemia. No patient's Hb fell below 7 g/dL and none required a blood transfusion. Of the 11 (11 %) patients who reported an adverse event over the study period, three were considered serious and included two deaths and one hospitalization; none were causally related to SLD PQ. Four non-serious adverse events were considered definitely, probably, or possibly related to SLD PQ.

            Conclusion

            Improved pharmacovigilance to monitor and promote the safety of the WHO recommendation is needed. The successful application of PROMPT demonstrates its potential as an important tool to rapidly generate locally acquired safety data and support pharmacovigilance in resource-limited settings.
              Cover page: Development of a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine and artemether-lumefantrine to treat Plasmodium falciparum infections in Swaziland: a pilot study
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2022)
              Leadership and management skills are critical for health programs to deliver high-quality interventions in complex systems. In malaria-eliminating countries, national and subnational health teams are reorienting strategies to address focal transmission while preventing new cases and adapting to decentralization and declines in external financing. A capacity-strengthening program in two regions in Namibia helped malaria program implementers identify and address key operational, political, and financial challenges. The program focused on developing skills and techniques in problem-solving and teamwork, engaging decision-makers, and using financial evidence to prioritize domestic resources for malaria through participatory approaches. Results of the program included an observed 40% increase in malaria case reporting, 32% increase in reporting and tracing of imported malaria cases, 10% increase in malaria case management, integration of malaria activities into local operational plans, and an increase in subnational resources for malaria teams. To promote program sustainability beyond the implementation period, key program aspects were institutionalized into existing health system structures, program staff were trained in change leadership, and participants integrated the skills and approaches into their professional roles. A capacity -strengthening program with joint focus on leadership, management, and advocacy has potential for application to other health issues and geographies.
                Cover page: Strengthening Management, Community Engagement, and Sustainability of the Subnational Response to Accelerate Malaria Elimination in Namibia
                • Article
                • Peer Reviewed
                UC Berkeley Previously Published Works (2017)
                Vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for most of the malaria burden reductions achieved recently in low and middle-income countries (LMICs). LLINs and IRS are highly effective, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, growing resistance to available insecticides and mosquitoes that behaviourally avoid contact with these interventions. However, a number of substantive opportunities now exist for rapidly developing and implementing more diverse, effective and sustainable malaria vector control strategies for LMICs. For example, mosquito control in high-income countries is predominantly achieved with a combination of mosquito-proofed housing and environmental management, supplemented with large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse, but all these interventions remain underused in LMICs. Programmatic development and evaluation of decentralised, locally managed systems for delivering these proactive mosquito population abatement practices in LMICs could therefore enable broader scale-up. Furthermore, a diverse range of emerging or repurposed technologies are becoming available for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms. Global policy must now be realigned to mobilise the political and financial support necessary to exploit these opportunities over the decade ahead, so that national malaria control and elimination programmes can access a much broader, more effective set of vector control interventions.
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2018)

                  Background

                  Subpatent malaria infections, or low-density infections below the detection threshold of microscopy or standard rapid diagnostic testing (RDT), can perpetuate persistent transmission and, therefore, may be a barrier for countries like Namibia that are pursuing malaria elimination. This potential burden in Namibia has not been well characterized.

                  Methods

                  Using a two-stage cluster sampling, cross-sectional design, subjects of all age were enrolled during the end of the 2015 malaria transmission season in Zambezi region, located in northeast Namibia. Malaria RDTs were performed with subsequent gold standard testing by loop-mediated isothermal amplification (LAMP) using dried blood spots. Infection prevalence was measured and the diagnostic accuracy of RDT calculated. Relationships between recent fever, demographics, epidemiological factors, and infection were assessed.

                  Results

                  Prevalence of Plasmodium falciparum malaria infection was low: 0.8% (16/1919) by RDT and 2.2% (43/1919) by LAMP. All but one LAMP-positive infection was RDT-negative. Using LAMP as gold standard, the sensitivity and specificity of RDT were 2.3% and 99.2%, respectively. Compared to LAMP-negative infections, a higher portion LAMP-positive infections were associated with fever (45.2% vs. 30.4%, p = 0.04), though 55% of infections were not associated with fever. Agricultural occupations and cattle herding were significantly associated with LAMP-detectable infection (Adjusted ORs 5.02, 95% CI 1.77-14.23, and 11.82, 95% CI 1.06-131.81, respectively), while gender, travel, bed net use, and indoor residual spray coverage were not.

                  Conclusions

                  This study presents results from the first large-scale malaria cross-sectional survey from Namibia using molecular testing to characterize subpatent infections. Findings suggest that fever history and standard RDTs are not useful to address this burden. Achievement of malaria elimination may require active case detection using more sensitive point-of-care diagnostics or presumptive treatment and targeted to high-risk groups.
                    Cover page: Subpatent malaria in a low transmission African setting: a cross-sectional study using rapid diagnostic testing (RDT) and loop-mediated isothermal amplification (LAMP) from Zambezi region, Namibia
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2020)

                    Background

                    Focus for improved malaria programme performance is often placed on the technical challenges, while operational issues are neglected. Many of the operational challenges that inhibit malaria programme effectiveness can be addressed by improving communication and coordination, increasing accountability, maintaining motivation, providing adequate training and supervision, and removing bureaucratic silos.

                    Methods

                    A programme of work was piloted in Zimbabwe with one malaria eliminating province, Matabeleland South in 2016-2017, and scaled up to include two other provinces, Matabeleland North and Midlands, in 2017-2018. The intervention included participatory, organization development and quality improvement methods.

                    Results

                    Workshop participants in Matabeleland South reported an improvement in data management. In Matabeleland North, motivation among nurses improved as they gained confidence in case management from training, and overall staff morale improved. There was also an improvement in data quality and data sharing. In Midlands, the poorly performing district was motivated to improve, and both participating districts became more goal-oriented. They also became more focused on monitoring their data regularly. Participants from all provinces reported having gained skills in listening, communicating, facilitating discussions, and making presentations. Participation in the intervention changed the mindset of malaria programme staff, increasing ownership and accountability, and empowering them to identify and solve problems, make decisions, and act within their sphere of influence, elevating challenges when appropriate.

                    Conclusions

                    This pilot demonstrates that a participatory, organization development and quality improvement approach has broad ranging effects, including improving local delivery of interventions, tailoring strategies to target specific populations, finding efficiencies in the system that could not be found using the traditional top-down approach, and improving motivation and communication between different cadres of health workers. Scale-up of this simple model can be achieved and benefits sustained over time if the process is imbedded into the programme with the training of health staff who can serve as management improvement coaches. Methods to improve operational performance that are scalable at the district level are urgently needed: this approach is a possible tactic that can significantly contribute to the achievement of global malaria eradication goals.
                      Cover page: Scaling up malaria elimination management and leadership: a pilot in three provinces in Zimbabwe, 2016–2018
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